Polyaryl derivative and use thereof

Abstract

Provided are a polyaryl HPK1 degrader and a preparation method therefor, a pharmaceutical composition containing the degrader, and a use thereof as an HPK1 degrader in medicine. The polyaryl HPK1 degrader comprises a polyaryl derivative represented by general formula (I), or a stereoisomer, a tautomer and a pharmaceutically acceptable salt thereof. The polyaryl HPK1 degrader possesses the ability to strongly inhibit the activity of HPK1 kinase and the ability to effectively degrade HPK1 proteins, has excellent degradation selectivity, and achieves favorable exposure levels when administered orally.

Description

A polyaryl derivative and its use Technical Field

[0001] The present invention belongs to the technical field of drug synthesis and design, and in particular relates to a polyaryl HPK1 degrader, a composition containing the derivative, and the preparation and use of the composition as an HPK1 degrader. Background Art

[0002] In recent years, harnessing the patient's own immune system to overcome the immune evasion strategies employed by tumor cells and enhance anti-tumor immunity has become a novel cancer treatment strategy. One such strategy involves inhibiting negative regulators of the immune response that typically maintain peripheral tolerance, thereby enabling tumor antigens to be recognized as non-self antigens and thereby overcoming tumor cell immune evasion. Hematopoietic progenitor cell kinase 1 (HPK1), also known as MAP4K1 (a member of the MAP4K family), is a negative regulator of activation responses in dendritic cells (DCs), T cells, and B cells. Inhibiting its activity can specifically enhance anti-tumor immunity. HPK1 is primarily expressed by hematopoietic cells, including early hematopoietic progenitor cells. In T cells, HPK1 is believed to negatively regulate T cell activation by phosphorylating downstream proteins SLP76 at Ser376 and Gads at Thr254 and recruiting 14-3-3 proteins for degradation, thereby reducing the persistence of signaling microclusters. HPK1 can also be activated in response to prostaglandins (PGE2), which are commonly secreted by tumors, thereby helping tumor cells evade the immune system. Targeted disruption of HPK1 kinase alleles can enhance T cell production of Th1 cytokines (such as IL-2 and IFNγ) in TCR responses. HPK1 plays multiple roles in immunity and has been implicated in the pathogenesis of autoimmune diseases, cancer, and inflammatory responses. HPK1 kinase-deficient T cells proliferate significantly faster than their wild-type counterparts, and mice transfected with HPK1 kinase-deficient T cells resist tumor growth. Furthermore, dendritic cells (DCs) lacking HPK1 kinase have enhanced antigen presentation capacity compared to wild-type cells, leading to enhanced anti-tumor immune responses. Furthermore, animal studies have demonstrated that HPK1 inhibition and PD-1 / PD-L1 antibody drugs have significant synergistic anti-tumor activity. Therefore, HPK1 kinase plays a key role in disease treatment, particularly cancer therapy.

[0003] In recent years, significant progress has been made in the field of PROTACs, a targeted protein degradation technology that degrades target proteins by inducing ubiquitination. Drugs using this technology do not require a continuous occupancy of the target protein; instead, they can achieve target degradation at a catalytic concentration, demonstrating high selectivity, high activity, and low toxicity.

[0004] Currently, no HPK1 inhibitors are marketed. Furthermore, HPK1 inhibitors suffer from weak immune activation, a narrow window of efficacy, and cytotoxicity at high concentrations. Therefore, further modification and optimization are necessary. To meet the enormous clinical needs of the future, we are designing and developing selective and highly active HPK1 degraders to provide novel therapeutics for immune-related diseases, particularly tumors. These agents can be used alone or in combination with chemotherapy, radiotherapy, tumor-targeted drugs, other tumor immunotherapies (small molecule compounds and antibodies), tumor vaccines, and CAR-T immunotherapy. Summary of the Invention

[0005] The purpose of the present invention is to provide a novel, selective and highly active HPK1 degrader or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof that has not been reported in the literature.

[0006] The present invention relates to a class of HPK1 protein degrading agents or their stereoisomers, tautomers or pharmaceutically acceptable salts, as well as their use in the preparation of a method for preventing and / or treating diseases related to the activity or expression of HPK1 protein, wherein the diseases include solid tumors, blood system diseases or autoimmune system diseases.

[0007] The present invention provides a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0008] in:

[0009] Cy1 is selected from: 5-12 membered heteroaryl or 8-10 membered fused bicyclic group;

[0010] Cy2 is selected from: C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl or 8-10 membered fused bicyclic group;

[0011] X8 and X9 are each independently selected from: CR a or N;

[0012] L1 and L2 are each independently selected from: a chemical bond, a C1-C8 alkylene group, a C3-C 12 Cycloalkylene, 3-12 membered heterocyclylene, -O-C1-C8 alkylene, -C1-C8 alkylene-O-, -NR b -C1-C8 alkylene-, -C1-C8 alkylene-NR b -、-O-、-NR b C(O)-、-C(O)-NR b -, -CO-, -SO-, -SO2-, C2-C8 alkenylene or C2-C8 alkynylene;

[0013] R1 is selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c 、-POR b R c or -Linker-E3, the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, halogenated C1-C8 alkyl, -C1-C8 alkyl-CONR b R c 、-C1-C8 alkyl-NR b COR c 、-C1-C8 alkyl-OR b , oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b Rc 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c 、-POR b R c ;

[0014] Or two R1 together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 substituted by a cycloalkyl group, a 3-12 membered heterocyclic group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group;

[0015] R2 is selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c Rd 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c or-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )Rc or-POR b R c ;

[0016] Or two R2 together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 substituted by a cycloalkyl group, a 3-12 membered heterocyclic group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group;

[0017] R3 is selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c or-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c or-POR b R c ;

[0018] Linker selected from: -(CH2) r -, the above one or more CH2 are optionally replaced by one or more selected from -COO-, -CONR b -、-OCONR b -、-NR b CONR b -、-O-、-NR b -、-S-、-CO-、-CR b =CR b -、-C≡C-、-CR b CR c -、-CR b =N-, -SO-, -SO2-, -POR b -、C3-C 10 Cycloalkylene, 3-10 membered heterocyclylene, phenylene, 5-6 membered heteroarylene or -CR bR c - group replacement; the heterocyclylene group may be further substituted by halogen, C1-C3 alkyl;

[0019] E3 is selected from: E3 ubiquitin ligase ligand;

[0020] R a Selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c or-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c or-POR b R c ;

[0021] R b 、R c 、R d Each is independently selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, halogenated C1-C4 alkyl, -C1-C4 alkyl-CONR e R f 、-C1-C3 alkyl-OR e 、-OR e or -NR e R f The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, halogenated C1-C8 alkyl, -C1-C8 alkyl-CONR e R f 、-C1-C8 alkyl-OR e , oxo, -CN, -NO2, -OR e 、-SO2R e、-SO2NR e R f 、-COR e 、-COOR e 、-CONR e R f 、-C(=NR e )NR f R g 、-NR e R f 、-NR e COR f 、-NR e CONR f R g 、-NR e CO2R f 、-NR e SONR f R g 、-NR e SO2NR f R g 、-NR e SO2R f ,-SO(=NR e )R f or-POR e R f ;

[0022] Where R is substituted on the same atom c and R b or R d and R c The ring may be connected to form a ring, which may be further substituted by one or more substituents selected from: halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR e 、-SO2R e 、-SO2NR e R f 、-COR e 、-COOR e 、-CONR e R f 、-C(=NR e )NR f R g 、-NR e R f 、-NR e COR f 、-NR e CONRf R g 、-NR e CO2R f 、-NR e SONR f R g 、-NR e SO2NR f R g 、-NR e SO2R f ,-SO(=NR e )R f or-POR e R f ;

[0023] R e 、R f 、R g Each is independently selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl; the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl may be further substituted by one or more substituents selected from: halogen, C1-C8 alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 aryl, 5-12 membered heteroaryl, cyano, hydroxy, amino or nitro;

[0024] m, n, o, and p are each independently selected from the group consisting of: 0, 1, 2, 3, 4, 5, and 6;

[0025] r is selected from an integer of 0-20.

[0026] r is preferably: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

[0027] A preferred embodiment of the present invention is a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0028] Wherein Cy1 is selected from;

[0029] in:

[0030] is a single bond or a double bond;

[0031] X1, X2, X3, X4, X5, X6, X 10Independently selected from O, S, C, CH, CH2, N, NH or CO; provided that the compound valence theory is satisfied;

[0032] X7 is selected from: CR a 'or N;

[0033] R a 'Selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OH, -NH2, -O-C1-C8 alkyl.

[0034] A preferred embodiment of the present invention is a compound represented by general formula (IIa) or (IIb) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0035] A preferred embodiment of the present invention is a compound represented by general formula (IIIa) or (IIIb) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0036] in:

[0037] X1 is selected from: CH or N;

[0038] X4 is selected from: NH or S;

[0039] X8, X9 are independently selected from: CH, N or C-Me;

[0040] when When selected from double bonds, X6 is C, X5 can be CH, N; when When selected from single bonds, X6 is N, CH, and X5 is CO, CH2;

[0041] L1 and L2 are each independently selected from: a chemical bond, -O-, -O-C1-C3 alkylene or -C1-C3 alkylene-O-;

[0042] Cy2 is selected from:

[0043] R2 is selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COORb 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c 、-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups may be further substituted by one or more substituents selected from the group consisting of: halogen, oxo, -CN, -OR b 、-NR b R c ;

[0044] m is selected from: 0, 1, 2, 3, 4, 5;

[0045] n is selected from: 0, 1, 2, 3.

[0046] A preferred embodiment of the present invention is a compound represented by general formula (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0047] in:

[0048] X1 is selected from: N or CH;

[0049] X 11 Selected from: N or CH;

[0050] R1 is selected from the group consisting of: H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR b 、-COR b 、-CONR b R c 、-NR b R c 、-NR b COR c or SO(=NRb )R c 、SO2NR b R c , cyano, oxo; the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl may be further substituted by halogen, C1-C3 alkyl, C3-C5 cycloalkyl, halogenated C1-C3 alkyl, -C1-C3 alkyl-NR b COR c 、-C1-C3 alkyl-CONR b R c 、-C1-C3 alkyl-OR b , hydroxy, cyano, amino or nitro substitution;

[0051] R1' is selected from: H, halogen, C1-C4 alkyl, hydroxy, cyano, amino, nitro;

[0052] Or R1 and R1' together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 substituted by a cycloalkyl group, a 3-12 membered heterocyclic group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group;

[0053] Or R1' and R1' together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 substituted by a cycloalkyl group, a 3-12 membered heterocyclic group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group;

[0054] R b Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by C1-C3 alkyl, C1-C3 alkoxy, hydroxy, cyano, amino or nitro;

[0055] R c Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by C1-C3 alkyl, C1-C3 alkoxy, hydroxy, cyano, amino or nitro;

[0056] R2 is selected from: H or

[0057] n or m' is selected from: 0, 1, 2 or 3.

[0058] A preferred embodiment of the present invention is a compound represented by general formula (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0059] in:

[0060] R1 is selected from: H, C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, cyano, oxo, hydroxymethyl, hydroxyethyl, Cyclopropyl, cyclobutyl, cyclopentyl,

[0061] R1' is selected from: H, Cl, F, methyl, ethyl or cyano;

[0062] X8 and X9 are independently selected from CR a or N;

[0063] R a Selected from: H, methyl, ethyl, isopropyl, F, methylamino, ethylamino, methoxy, ethoxy,

[0064] n or m' is selected from: 0, 1, 2 or 3.

[0065] A preferred embodiment of the present invention is a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0066] in:

[0067] Selected from:

[0068] R1 is selected from the group consisting of: H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 Aryl, 5-6 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b Rc 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c 、-POR b R c or -Linker-E3, the above alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl may be further substituted by one or more substituents, the substituents are selected from: halogen, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocyclic, C6-C 10 Aryl, 5-7 membered heteroaryl, halogenated C1-C3 alkyl, -C1-C3 alkyl-CONR b R c 、-C1-C3 alkyl-NR b COR c 、-C1-C3 alkyl-OR b , oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR bSONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c 、-POR b R c ;

[0069] Or two R1 together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 substituted by a cycloalkyl group, a 3-12 membered heterocyclic group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group;

[0070] m is selected from: 0, 1, 2, 3, 4, 5;

[0071] R b 、R c 、R d Each is independently selected from: H, halogen, methyl, ethyl, propyl, isopropyl, C3-C6 cycloalkyl, 5-7 membered heterocyclyl, C6-C 10 Aryl, 5-6 membered heteroaryl, halogenated C1-C4 alkyl, -C1-C4 alkyl-CON(CH3)2, -C1-C3 alkyl-OCH3, -OR e or -NR e R f The above methyl, ethyl, propyl, isopropyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclic, C6-C 10 Aryl, 5-6 membered heteroaryl, halogenated C1-C4 alkyl, -C1-C4 alkyl-CON(CH3)2, -C1-C3 alkyl-OCH3, oxo, -CN, -NO2, -OH, -NH2.

[0072] A preferred embodiment of the present invention is a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0073] in:

[0074] Selected from:

[0075] R1 is selected from: H, C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, cyano, oxo, hydroxymethyl, hydroxyethyl, Cyclopropyl, cyclobutyl, cyclopentyl,

[0076] A preferred embodiment of the present invention is a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0077] in:

[0078] Selected from:

[0079] A preferred embodiment of the present invention is a compound represented by general formula VI or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0080] X 13 Selected from: NH or O;

[0081] X1 is selected from: CH or N;

[0082] R 10 is selected from: H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, hydroxy, cyano, amino or nitro;

[0083] R 10’ Selected from: H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 3-8 membered heterocyclic group, halogenated C1-C4 alkyl, -C1-C4 alkyl-CONR b R c 、-C1-C8 alkyl-OR b , oxo or -CN, the alkyl, cycloalkyl or heterocyclic group is optionally further substituted by one or more selected from halogen, C1-C8 alkyl, -CN, -CONR b R c 、-NR b COR c 、-OR b substituted by a substituent.

[0084] Preferably, R 10’ Selected from: H, halogen, cyano, oxo, methyl, ethyl, propyl, isopropyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl,

[0085] R2 is selected from: H, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -CN, -NO2, -OR b 、-NR b R c The above alkyl, cycloalkyl and heterocyclic groups may be further substituted by one or more selected from halogen, oxo, -CN, -OR b 、-NR b R c Substituent substitution;

[0086] R b Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted with halogen, C1-C3 alkyl, hydroxyl, cyano, amino or nitro;

[0087] R c Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted with halogen, C1-C3 alkyl, hydroxyl, cyano, amino or nitro;

[0088] q or q' is selected from: 0, 1, 2 or 3;

[0089] Cy2 is selected from a 5-membered heteroaromatic ring containing 1-3 heteroatoms.

[0090] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein the 5-membered heteroaromatic ring of Cy2 is preferably selected from:

[0091] Preferably, Cy2 is selected from

[0092] A preferred embodiment of the present invention is a compound represented by general formula VII or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0093] CyA is selected from: phenyl, 5-10 membered heteroaryl or 8-10 membered fused bicyclic group;

[0094] The heteroaryl group selected from the group consisting of CyA is preferably selected from: The fused bicyclic group is preferably selected from:

[0095] R A1Selected from H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, oxo, -CN, -OR b 、-COR B 、-CONR B R C 、-NR B R C 、-NR B COR C or SO(=NR B )R C The alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups may be further substituted by halogen, C1-C3 alkyl, hydroxy, cyano, amino, or nitro groups;

[0096] R B Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by C1-C3 alkyl, hydroxyl, cyano, amino or nitro;

[0097] R C Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by C1-C3 alkyl, hydroxyl, cyano, amino or nitro;

[0098] q is selected from: 0, 1, 2 or 3.

[0099] X1, X8, X9, R2, n, Linker, and E3 are as defined in formula (I).

[0100] In a preferred embodiment of the present invention, X8 and X9 are selected from CRa and N;

[0101] Ra is selected from the group consisting of: H, halogen, methyl, ethyl, isopropyl, Methoxy, ethoxy.

[0102] L1 is selected from the group consisting of: a chemical bond, -O-, and -CH2-O-.

[0103] In a preferred embodiment of the present invention, the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein the linker is selected from:

[0104] In the preferred embodiment of the present invention, Linker is preferably selected from:

[0105] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein E3 is selected from:

[0106] in,

[0107] q, u or s are each independently selected from: 0, 1 or 2;

[0108] Y1 is independently selected from: CO, methylene, vinylene or ethyl;

[0109] Y2 is independently selected from: CH or N;

[0110] Y3 is independently selected from: absent, CH2, NH, NMe or O;

[0111] Y4 is independently selected from: CH or N;

[0112] Y5 is independently selected from: CH or N;

[0113] R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2Rc ,-SO(=NR b )R c 、-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 6-10 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c or-POR b R c ;

[0114] Rd' is selected from: H, -R f OCOR g 、-R f OCOOR g 、-R f OCONR g R h 、-COOR f 、-CONR f R g ;

[0115] R f 、R g 、Rh Each is independently selected from: H, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, C1-C6 alkyl 3-8 membered cycloalkyl, C1-C6 alkyl 3-8 membered heterocyclic group;

[0116] Cy3 is selected from:

[0117] Cy4 is selected from:

[0118] Cy5 is selected from:

[0119] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein E3 is selected from:

[0120] In a preferred embodiment of the present invention, E3 is preferably selected from:

[0121] As a more specific choice, X8 and X9 are each independently selected from: CR a Or N; wherein Ra is selected from H, C1-C3 alkyl, -CH2N(CH3)2, halogen, -NHCH3, -OC1-C3 alkyl.

[0122] Selected from

[0123] L1 and L2 are each independently selected from a chemical bond, O, and -OCH2-.

[0124] In a preferred embodiment of the present invention, the compound described by general formula (I) is selected from: Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0125] It should be noted that when a specific compound is involved in the present invention, the corresponding number below the compound (such as 115 in the above table) corresponds to the corresponding compound; when the compound number is mentioned in the rest of this article, it refers to the compound, for example, "Compound 115" refers to the compound structure corresponding to the number 115.

[0126] In addition, in the same group, when substituents expressed by the same letters appear at different positions, the substituents corresponding to the different positions are independent of each other and can be the same or different. For example, "-NR b CONR b -" R on the two N atoms before and after b They can be the same or different, and the above explanation also applies to other identical situations.

[0127] When substituents expressed by the same letters appear in different groups, the same letters in different substituents are independent of each other and have no restriction on each other. They can be the same or different. For example, R1, L1, L2, R2, Linker, R3, etc. all have R b The R in R1, L1, L2, R2, Linker, and R3 b Independent of each other, they can be the same or different.

[0128] The present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound according to any one of the general formulas (I), (VI), (IIa), (IIb), (IIIa), (IIIb), (IV), (V) or (VII), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0129] The pharmaceutical carriers provided herein can be one or more solid or liquid fillers or gel substances suitable for human use. The pharmaceutical carriers can be any conventional carrier and / or diluent in the field of pharmaceutical formulations, preferably having sufficient purity and sufficiently low toxicity, and being compatible with the active ingredient of the present invention and not significantly reducing the efficacy of the active ingredient. For example, the pharmaceutical carrier can be a filler, a binder, a disintegrant, a lubricant, an aqueous solvent, or a non-aqueous solvent.

[0130] The pharmaceutical preparations provided herein can be prepared into any pharmaceutically acceptable dosage form and administered to patients or subjects in need of such treatment by any suitable route of administration, such as oral, parenteral, rectal, or transpulmonary administration. For oral administration, the pharmaceutical preparations can be prepared into solid dosage forms such as capsules, tablets, pills, lozenges, dragees, granules, powders, ointments, creams, and drops; and can also be prepared into liquid dosage forms such as elixirs, syrups, emulsions, dispersions, suspensions, solutions, and sprays. For parenteral administration, the pharmaceutical preparations can be prepared into injections or sterile powders for injection.

[0131] The present invention provides a compound of general formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V) or (VII) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a drug for degrading HPK1 protein.

[0132] The present invention provides a compound of formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V) or (VII) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the preparation of a method for preventing and / or treating diseases associated with the activity or expression of HPK1 protein, wherein the diseases include solid tumors, hematological diseases or autoimmune system diseases.

[0133] The present invention provides a use of a compound of formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V) or (VII) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing and / or treating a disease associated with the activity or expression of an HPK1 protein, wherein the solid tumor disease includes, but is not limited to, one or more of lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary duct cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, in situ pain, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testis, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, colorectal villous adenoma, melanoma, cell tumor and sarcoma; the autoimmune disease includes inflammatory bowel disease, ... Enteropathy, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Odd's thyroiditis, Graves' disease, rheumatoid arthritis syndrome, multiple sclerosis, infectious neuronitis, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis , celiac disease, Goodpasture's syndrome, immune thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia and chronic graft-versus-host disease. The hematological diseases include but are not limited to one or more of acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, myelofibrosis, myelodysproliferative syndrome, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, and T-cell lymphoma;

[0134] Terminology

[0135] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0136] "Bond" means that the indicated substituent does not exist and the two end portions of the substituent are directly linked to form a bond.

[0137] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C8 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted.

[0138] "Alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, and the alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene containing 1 to 6 carbon atoms (i.e., C 1-6 Alkylene), further preferably an alkylene containing 1 to 4 carbon atoms (i.e., C 1-4 Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (—CH—), 1,1-ethylene (—CH(CH)—), 1,2-ethylene (—CHCH)—, 1,1-propylene (—CH(CHCH)—), 1,2-propylene (—CHCH(CH)—), 1,3-propylene (—CHCHCHCH—), and 1,4-butylene (—CHCHCHCHCH—). Alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0139] "Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which can be straight chain or branched. 10 Representative examples include, but are not limited to, vinyl, etc. The alkenyl group may be substituted or unsubstituted.

[0140] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight chain or branched. 10 The alkynyl group is more preferably a C2-C8 alkynyl group, and most preferably a C2-C4 alkynyl group. Examples of alkynyl groups include, but are not limited to, ethynyl, etc. The alkynyl group may be substituted or unsubstituted.

[0141] "Alkenylene" refers to a divalent straight or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, which contains a specified number of carbon atoms, for example, 2 to 8 carbon atoms, such as -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, etc., and the alkenylene group can be optionally substituted with one or more (such as 1 to 3) the same or different substituents.

[0142] "Alkyne" refers to a divalent straight or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds, containing a specified number of carbon atoms, e.g., 2 to 8 carbon atoms, including but not limited to, etc., which may be optionally substituted with one or more (e.g., 1 to 3) substituents that are the same or different.

[0143] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. 12 Cycloalkyl, more preferably C3-C8 cycloalkyl, most preferably C3-C6 cycloalkyl. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl may be substituted or unsubstituted.

[0144] "Cycloalkylene" refers to a divalent saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring that is connected to one group through a single bond and to another group through another single bond, such as C 3-10 Cycloalkylene contains 3-10 carbon atoms, C 3-6 Cycloalkylene is a cycloalkylene group containing 3-6 carbon atoms; common cycloalkylene groups include (but are not limited to) cyclopropane-1,1-ylidene, cyclopropane-1,2-ylidene, cyclobutane-1,1-ylidene, cyclobutane-1,2-ylidene, cyclobutane-1,3-ylidene, etc.

[0145] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called spiro atom) shared between the monocyclic rings. The ring may contain one or more double bonds, but no ring has aromaticity. It is preferably 6 to 14 members, and more preferably 7 to 10 members. Spiroalkyl is divided into single spiro, double spiro or multiple spiroalkyl according to the number of shared spiro atoms between the rings, preferably single spiro and double spiroalkyl, preferably 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0146] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but none of the rings are aromatic. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. Examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthrenyl.

[0147] "Bridged cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected. One or more rings may contain one or more double bonds, but none of the rings are aromatic. It is preferably 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, and more preferably a bicyclic or tricyclic group. Examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl, and bicyclo[1.1.1]pentyl.

[0148] "Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and refer to non-aromatic heterocyclic groups in which one or more atoms forming the ring are heteroatoms, such as N, O, S, P, Se, including monocyclic, fused, bridged and spirocyclic rings, and may contain one or more double bonds within the ring. Preferably, it has 3 to 12 ring atoms, more preferably a 4 to 7 membered monocyclic ring or a 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m (wherein m is selected from 0 or 1), an atom of Se. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, or 3,6-dihydro-2H-pyranyl. A heterocyclyl group may be substituted or unsubstituted.

[0149] "Heterocyclylene" refers to a divalent non-aromatic heterocyclic group in which one or more of the atoms forming the ring is a heteroatom, such as N, O, S, P, Se, including monocyclic, fused, bridged and spirocyclic rings, which may contain one or more double bonds in the ring, connected to one group through a single bond and connected to other groups (or ring systems) through another single bond, such as a 3-10 membered heterocyclylene, a 3-7 membered heterocyclylene or a 4-10 membered heterocyclylene; common heterocyclylene groups include (but are not limited to) oxirane-2,2-ylidene, oxirane-2,3-ylidene, azetidine-2,2-ylidene, azetidine-2,3-ylidene, azetidine alkane-2,4-ylidene, tetrahydrofuran-2,5-ylidene, tetrahydro-2H-pyran-2,3-ylidene, tetrahydro-2H-pyran-2,4-ylidene, tetrahydro-2H-pyran-2,5-ylidene, tetrahydro-2H-pyran-2,6-ylidene, pyrrolidine-1,2-ylidene, pyrrolidine-1,3-ylidene, pyrrolidine-2,3-ylidene, pyrrolidine-2,4-ylidene, pyrrolidine-2,5-ylidene, piperidine-1,2-ylidene, piperidine-1,3-ylidene, piperidine-1,4-ylidene, piperidine-2,3-ylidene, piperidine-2,4-ylidene, piperidine-2,5-ylidene, piperidine-2,6-ylidene and the like.

[0150] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, which may contain one or more double bonds, but none of the rings are aromatic, wherein one or more ring atoms are selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m (wherein m is selected from 0 or 1), Se heteroatom, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Spiro heterocyclyls are divided into monospiro heterocyclyls, bispiro heterocyclyls or polyspiro heterocyclyls according to the number of spiro atoms shared between rings, preferably monospiro heterocyclyls and bispiro heterocyclyls. More preferably, it is a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclyl. Examples of "spiro heterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0151] "Fused heterocyclic group" refers to a carbon-containing polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but none of the rings are aromatic, wherein one or more ring atoms are selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m(wherein m is selected from 0 or 1), Se heteroatom, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin.

[0152] "Bridged heterocyclic group" refers to a polycyclic group of 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but none of the rings is aromatic, wherein one or more ring atoms are selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m (wherein m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0153] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. "Aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably phenyl. The aryl group may be substituted or unsubstituted.

[0154] "Arylene" refers to an aryl group as defined herein having two monovalent radical centers derived from the same carbon atom or two different carbon atoms of a parent aryl group by removing two hydrogen atoms. Typical arylene groups include, but are not limited to, phenylene and naphthylene.

[0155] "Heteroaryl" and "heteroaromatic ring" are used interchangeably in this application and refer to a monocyclic or polycyclic aromatic ring group containing 5 to 14 ring atoms, which may contain 1 to 4 atoms selected from N, O, S, and Se. Preferably, it contains 5 to 12 ring atoms, more preferably a 5- to 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl. The heteroaryl group may be substituted or unsubstituted.

[0156] "Heteroarylene" refers to a heteroaryl group as defined above having two monovalent radical centers derived by the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, or by the removal of one hydrogen atom from a carbon atom and one hydrogen atom from a nitrogen atom, of a parent heteroaryl group.

[0157] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, one or more of which may contain one or more double bonds, but at least one ring is not aromatic and at least one ring is aromatic, wherein zero, one or more of the ring atoms are selected from N, O, S(O) n (wherein n is selected from 0, 1 or 2), P(O) m (wherein m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl or monocyclic cycloalkyl group. Preferably, it includes 7 to 14 members, more preferably 9 to 10 members. Examples of "fused rings" include but are not limited to:

[0158] The fused rings may be substituted or unsubstituted.

[0159] "Alkoxy" refers to a group (alkyl-O-). Alkoxy is defined herein. C1-C8 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Alkoxy groups may be substituted or unsubstituted.

[0160] "Alkenyloxy" refers to a group of (alkenyl-O-). Alkenyl is as defined herein. C2-C8 alkenyloxy is preferred. Alkenyloxy may be substituted or unsubstituted.

[0161] "Hydroxyalkyl" is a radical of (-alkyl-OH). Alkyl is as defined herein. Hydroxyalkyl groups of C1-C8 are preferred. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and hydroxybutyl. Hydroxyalkyl groups may be substituted or unsubstituted.

[0162] "Alkylamino" refers to a group (alkyl-NH-). Alkyl is defined herein. C1-C8 alkylamino groups are preferred. Examples include, but are not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutoxy, and tert-butoxy. Alkylamino groups may be substituted or unsubstituted, and the substituents may be on the alkyl group or on the nitrogen, such as dimethylamino and diethylamino.

[0163] "Aminoalkyl" refers to a group (-alkyl-NH2). Alkyl is as defined herein. Examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, and aminopentyl. Aminoalkyl groups may be substituted or unsubstituted, and the substituents may be on the alkyl group or on the nitrogen, as exemplified by dimethylaminoalkyl.

[0164] "Alkylcarbonyl" refers to a group (alkyl-C(O)-). "Alkyl" is as defined herein. Examples include, but are not limited to, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, and isobutylcarbonyl. Alkylcarbonyl groups may be substituted or unsubstituted.

[0165] "Alkoxycarbonyl" refers to a group of (alkyl-OC(O)-). Alkyl is as defined herein. Examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and isopropoxycarbonyl. Alkoxycarbonyl groups may be substituted or unsubstituted.

[0166] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein halogen and alkyl are as defined herein.

[0167] "Haloalkoxy" refers to an alkoxy group substituted by a halogen, wherein halogen and alkoxy are as defined herein.

[0168] "Halohydroxyalkyl" refers to a hydroxyalkyl group substituted by a halogen, wherein halogen and hydroxyalkyl are as defined herein.

[0169] "Haloalkylamino" refers to an alkylamino group substituted by a halogen, wherein halogen and alkylamino are as defined herein.

[0170] "Cycloalkoxy" refers to a group of (cycloalkyl-O-) wherein cycloalkyl is as defined herein.

[0171] "Heterocyclyloxy" refers to a group of (heterocyclyl-O-), wherein heterocyclyl is as defined herein.

[0172] "Hydroxy" refers to an -OH group.

[0173] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0174] "Amino" refers to -NH2.

[0175] "Cyano" refers to -CN.

[0176] "Nitro" refers to -NO2.

[0177] "Carboxyl" refers to -C(O)OH.

[0178] "Amide" refers to -C(O)NH2.

[0179] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0180] The term "substituted" or "substituted" as used herein, unless otherwise specified, means that the group may be substituted by one or more groups selected from the following groups: H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C8 alkyl, C3-C8 alkynyl, C3-C8 alkoxy, C3-C8 alkyl, C3-C8 alkoxy ... 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, aminosulfonyl, C6-C 10 Aryl, 5-12 membered heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR g 、-SR g 、-C1-C8 alkylene-R g 、-OC(O)R g 、-C(O)R g 、-C(O)OR g 、-C(O)N(R x )R y 、-NR x R y 、-N(CH3)R g 、-N(R x )C(O)R y 、-N(Rx )C(O)NR x R y 、-N(R x )C(O)OR g 、-N(R x )S(O)NR x R y 、-N(R x )S(O)2NR x R y 、-N(R x )S(O)2R g 、-S(O)R g 、-S(O)2R g 、-S(O)2NR x R y 、-P(O)R x R y The alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenyloxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, aryl, heteroaryl, 3-12 membered ring, amino, hydroxyl or amide may be further substituted by one or more R o replace;

[0181] When 2 R o When substituted on the same atom, two R o Together with the atoms to which they are attached, they form a 3-6 membered ring, or when two R o When substituted on adjacent atoms, the two R o Together with the atoms to which they are attached, they form a 3-12 membered ring;

[0182] R g 、R x 、R y 、R o Each is independently selected from H, deuterium, halogen, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyloxy, C3-C 12 Cycloalkyl, C3-C8 cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group, aminosulfonyl, C6-C 10 Aryl, 5-12 membered heteroaryl, cyano, amino, nitro, hydroxy, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, C1-C8 alkylamino, C1-C8 haloalkylamino, -OR s 、-SR s 、-C1-C8 alkylene-R s 、-OC(O)R s 、-C(O)R s 、-C(O)OR s 、-C(O)N(Rs )R t 、-NR s R t 、-N(CH3)R s 、-N(R s )C(O)R t 、-N(R s )C(O)NR s R t 、-N(R s )C(O)OR t 、-N(R s )S(O)NR s R t 、-N(R s )S(O)2NR s R t 、-N(R s )S(O)2R t 、-S(O)R s 、-S(O)2R s 、-S(O)2NR s R t or-P(O)R s R t The alkyl, alkylene, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further replaced by one or more R r replace;

[0183] When 2 R r When substituted on the same atom, two R r Together with the atoms to which they are attached, they form a 3-6 membered ring, or when two R r When substituted on adjacent atoms, the two R r Together with the atoms to which they are attached, they form a 3-12 membered ring;

[0184] R r 、R s 、R t Each is independently selected from H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxyalkyl, aminoalkyl, C1-C8 alkylamino, alkylcarbonyl, alkoxycarbonyl, halohydroxyalkyl, C1-C8 haloalkylamino, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, carboxyl, amide, C6-C 10 aryl or 5-12 membered heteroaryl.

[0185] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0186] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0187] The C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes. At the same time, the C, H, O, S, N, F, Cl, Br, I involved in the groups and compounds of the present invention may be optionally replaced by one or more of their corresponding isotopes, including but not limited to carbon isotopes. 12 C. 13 C. 14 C, hydrogen isotopes protium (H), deuterium (D), tritium (T), oxygen isotopes 16 O. 17 O. 18 O, isotope of sulfur 32 S. 33 S. 34 S. 36 S, isotope of nitrogen 14 N. 15 N, an isotope of fluorine 17 F. 19 F, an isotope of chlorine 35 Cl, 37 Cl, an isotope of bromine 79 Br, 81 Br et al.

[0188] It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of any claims. It should be noted that, throughout the specification and the appended claims, unless otherwise indicated, singular references such as "a," "an," and "the" include plural references. It should also be noted that "or" stands for "and / or" unless otherwise indicated. Furthermore, terms such as "include," "comprising," and similar terms are not limiting.

[0189] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by formula (I) may be metal salts, salts formed with suitable acids, or salts formed with suitable bases. A preferred salt type is a salt formed by a compound of the present invention with an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzenesulfonic acid, isethionic acid, pamoic acid, and tannic acid; and acidic amino acids such as aspartic acid and glutamic acid. A preferred salt is a salt formed by the compound of the present invention and a base. Suitable bases for forming salts include, but are not limited to, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, and organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, and diethanolamine.

[0190] As used herein, "administration," "administering," "leating," and "treatment" refer to the contact of an exogenous agent, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treatment" also refer to in vitro and ex vivo treatment of, for example, a cell, by an agent, diagnostic agent, binding compound, or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0191] "Effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (such as a compound) that is sufficient to affect such treatment of a disease, disorder, or symptom when the compound is administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder. The "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. In any given example, the appropriate amount will be clear to one skilled in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof that is effective to "treat" (as defined above) a disease or disorder in a subject. In the context of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination of subjects used to effectively treat the disease, disorder, or condition.

[0192] "Pharmaceutically acceptable carrier" refers to one or more solid or liquid fillers or gel substances suitable for human use. The pharmaceutical carrier can be any conventional carrier and / or diluent in the field of pharmaceutical formulations, preferably having sufficient purity and sufficiently low toxicity, and being compatible with the active ingredient of the present invention and not significantly reducing the efficacy of the active ingredient. For example, a pharmaceutical carrier can be a filler, binder, disintegrant, lubricant, aqueous solvent or non-aqueous solvent, etc. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form generally refers to the amount of compound that can produce a therapeutic effect.

[0193] "Pharmaceutical formulation" refers to any pharmaceutically acceptable dosage form for administration to a patient or subject in need of such treatment by any suitable route of administration, such as topical, oral, transdermal, rectal, vaginal, parenteral, intranasal, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneous, subcutaneous, or by inhalation. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, liquid formulations such as aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs or solutions or suspensions. Tablets contain the active ingredient in admixture with a nontoxic, pharmaceutically acceptable carrier suitable for tablet preparation. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oily suspension concentrate, lyophilized powder, or the like. Preferably, the pharmaceutical composition is formulated from tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably tablets or capsules. The pharmaceutical composition may be administered as a single unit with a precise dosage. In addition, the pharmaceutical composition may also include other active ingredients. Topical or transdermal dosage forms may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed with a pharmaceutically acceptable carrier under aseptic conditions, and it may be mixed with any preservatives, buffers, or propellants that may be needed.

[0194] The term "disease" refers to any illness, ailment, disease, symptom, or indication and is interchangeable with the terms "condition" or "disorder."

[0195] The experimental verification results show that the compound of the present invention has good inhibitory activity on HPK1 kinase.

[0196] The experimental verification results show that the compound of the present invention has a strong ability to degrade HPK1 protein.

[0197] The experimental verification results show that the compound of the present invention has high selectivity for HPK1 protein degradation.

[0198] The experimental verification results show that the compound of the present invention has a good exposure amount after oral administration. DETAILED DESCRIPTION

[0199] Chemical substances represented by some abbreviations in the present invention: DCM: dichloromethane; DMF: N,N-dimethylformamide; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; H2SO4: sulfuric acid; STAB: sodium triacetylborohydride; Dioxane: dioxane; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd / C: palladium on carbon.

[0200] Example 1 Synthesis of Intermediate A1

[0201] Synthesis step 1: Synthesis of A1-1

[0202] 4-Bromobenzoic acid (3 g, 15.00 mmol) was dissolved in DCM (30 mL). Dimethylamine (810 mg, 18.00 mmol), HATU (8.55 g, 22.50 mmol), and triethylamine (3.04 g, 30 mmol) were added sequentially to the system and reacted at room temperature for 5 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 2.2 g of A1-1 with a yield of 65%. ESI-MS (M+H) + =228.0.

[0203] Synthesis step 2: Synthesis of A1

[0204] A1-1 (2.00 g, 8.81 mmol) was dissolved in dioxane (20 mL). Diboronic acid pinacol ester (3.34 g, 13.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (644 mg, 0.88 mmol), and potassium acetate (2.60 g, 26.43 mmol) were added sequentially to the system. The mixture was reacted at 80°C under nitrogen for 4 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 1.5 g of A1 with a yield of 67%. ESI-MS (M+H) + =276.2.

[0205] Referring to the synthetic route and method of intermediate A1, the following intermediate compounds were synthesized:

[0206] Referring to the synthesis method of step 2 of the synthesis of intermediate A1, the following intermediate compound was synthesized:

[0207] Example 2 Synthesis of Intermediate A10

[0208] Synthesis step 1: Synthesis of A10-1

[0209] Dissolve tert-butyl 4-(4-bromopyrazol-1-yl)piperidine-1-carboxylate (3 g, 9.09 mmol) in dioxane (30 mL). Add HCl in 1,4-dioxane (30 mL, 4 mol / L) and allow to react at room temperature for 5 h. After completion of the reaction, concentrate under reduced pressure to obtain 2.3 g of crude product A10-1, with a yield of 95%. ESI-MS (M+H) + =230.0.

[0210] Synthesis step 2: Synthesis of A10-2

[0211] A10-1 (2 g, 8.70 mmol) was dissolved in DCM (20 mL), and cyclobutanone (1 ml, 13.05 mmol) was added to the system. The mixture was stirred at room temperature for 0.5 h. STAB (5.5 g, 26.10 mmol) was then added and allowed to react at room temperature for 3 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 1.8 g of A10-2 with a yield of 82%. ESI-MS (M+H) + =284.1.

[0212] Synthesis step 3: Synthesis of A10

[0213] The synthesis of A10 refers to the synthesis method of step 2 of the synthesis of intermediate A1.

[0214] Referring to the synthesis method of step 2 of the synthesis of intermediate A10, the following intermediate compound was synthesized:

[0215] Example 3 Synthesis of Intermediate A15

[0216] Synthesis step 1: Synthesis of A15-1

[0217] The synthesis of A15-1 was carried out according to the synthesis method of intermediate A10, step 1.

[0218] Synthesis step 2: Synthesis of A15-2

[0219] A15-1 (2 g, 8.70 mmol) was dissolved in DMF (20 mL). Cesium carbonate (5.7 g, 17.4 mmol) and iodoethane (1 ml, 13.05 mmol) were added sequentially to the system, and the reaction was stirred at room temperature for 2 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 1.6 g of A15-2, with a yield of 71%. ESI-MS (M+H) + =258.1.

[0220] Synthesis step 3: Synthesis of A15

[0221] The synthesis of A15 refers to the synthesis method of step 2 of intermediate A1.

[0222] Referring to the synthesis method of intermediate A15, the following intermediate compounds were synthesized:

[0223] Example 4 Synthesis of Intermediate B1

[0224] Synthesis step 1: Synthesis of B1-1

[0225] 5-Bromo-2-iodo-1,3-dimethylbenzene (3 g, 9.71 mmol) was dissolved in dioxane (30 mL) and water (6 mL). N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.6 g, 11.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (710 mg, 0.97 mmol), and sodium carbonate (3.1 g, 29.13 mmol) were added sequentially to the system. The mixture was allowed to react at room temperature for 5 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 2.1 g of B1-1 with a yield of 59%. ESI-MS (M+H) + =366.1.

[0226] Synthesis step 2: Synthesis of B1

[0227] B1-1 (2.00 g, 5.48 mmol) was dissolved in dioxane (20 mL). Bis(pyrazol)diboron (2.1 g, 8.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (401 mg, 0.55 mmol), and potassium acetate (1.6 g, 16.44 mmol) were added sequentially to the system. The mixture was reacted at 80°C under nitrogen for 4 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 1.5 g of B1 with a yield of 66%. ESI-MS (M+H) + =414.3.

[0228] Referring to the synthetic route and method of intermediate B1, the following intermediate compounds were synthesized:

[0229] Example 5 Synthesis of Intermediate B6

[0230] Synthesis step 1: Synthesis of B6-1

[0231] The synthesis of B6-1 refers to the synthesis method of intermediate B1, step 1.

[0232] Synthesis step 2: Synthesis of B6-2

[0233] B6-1 (2.00 g, 5.48 mmol) was dissolved in dichloromethane (20 mL). Dimethylamine (370 mg, 8.22 mmol) and STAB (3.5 g, 16.44 mmol) were added sequentially to the system and reacted at room temperature for 5 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 1.5 g of B6-2 with a yield of 70%. ESI-MS (M+H) + =395.1.

[0234] Synthesis step 3: Synthesis of B6

[0235] The synthesis of B6 refers to the synthesis method of step 2 of the synthesis of intermediate B1.

[0236] Example 6 Synthesis of Intermediate B7

[0237] Synthesis step 1: Synthesis of B7-1

[0238] The synthesis of B7-1 refers to the synthesis method of intermediate B1, step 1.

[0239] Synthesis step 2: Synthesis of B7-2

[0240] B7-1 (5.00 g, 14.15 mmol) was dissolved in DMF (20 mL). Sodium hydride (407 mg, 16.98 mmol) was slowly added to the system at 0°C. After stirring at 0°C for 10 min, borane trimethylamine complex (1.5 ml, 16.98 mmol) was added to the system at 0°C and reacted at 80°C for 2 h. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 3.1 g of B7-2 with a yield of 81%. ESI-MS (M+H) + =267.0.

[0241] Synthesis step 3: Synthesis of B7-3

[0242] B7-2 (3.00 g, 11.23 mmol) was dissolved in dichloromethane (30 mL). Triethylamine (4.7 ml, 33.68 mmol) and di-tert-butyl dicarbonate (3.8 ml, 16.84 mmol) were added sequentially at 0°C. The mixture was stirred at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography yielded 3.3 g of B7-3 with a yield of 80%. ESI-MS (M+H) + =367.1.

[0243] Synthesis step 3: Synthesis of B7

[0244] The synthesis of B7 refers to the synthesis method of step 2 of the synthesis of intermediate B1.

[0245] Example 7 Synthesis of Intermediate M1

[0246] Synthesis step 1: Synthesis of M1-1

[0247] 2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (3.20 g, 9.93 mmol) was dissolved in DMF (20 mL). p-Toluenesulfonyl chloride (2.40 g, 12.90 mmol) and sodium hydride (500 mg, 12.90 mmol) were added to the system in sequence. The mixture was reacted at room temperature for 3 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M1-1 was obtained by column chromatography. ESI-MS (M+H) + =477.9.

[0248] Synthesis step 2: Synthesis of M1-2

[0249] M1-1 (3.00 g, 6.29 mmol) was dissolved in 30 mL of dioxane, and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (2.0 g, 7.54 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (460 mg, 0.63 mmol), potassium carbonate (1.7 g, 12.58 mmol), and water (10 mL) were added to the system in sequence. The mixture was reacted at 50°C under nitrogen protection for 4 h. After the reaction was completed, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M1-2 was obtained by column chromatography. ESI-MS (M+H) + =499.0.

[0250] Synthesis step 3: Synthesis of M1-3

[0251] M1-2 (2.0 g, 4.01 mmol) was dissolved in 15 mL of dioxane, and 4-[2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylic acid-2-methylpropane-2-yl ester (1.9 g, 4.81 mmol), Pd(dppf)Cl2 (290 mg, 0.40 mmol), potassium carbonate (1.6 g, 12.03 mmol), and water (5 mL) were added to the system in sequence. The mixture was reacted at 100°C under nitrogen for 4 h. After the reaction was completed, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M1-3 was obtained by column chromatography. ESI-MS (M+H) +=706.3.

[0252] Synthesis step 4: Synthesis of M1-4

[0253] M1-3 (2.3 g, 3.26 mmol) was dissolved in tetrahydrofuran (15 mL), and a saturated aqueous solution of sodium hydroxide (15 mL) was added to the system. The reaction was allowed to proceed at 70°C for 4 h. After the reaction was completed, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M1-4 was obtained by column chromatography (eluted with dichloromethane / methanol). ESI-MS (M+H) + =552.3.

[0254] Synthesis step 5: Synthesis of intermediate M1

[0255] M1-4 (1.4 g, 2.53 mmol) was dissolved in dichloromethane (10 mL), and a solution of hydrogen chloride in 1,4-dioxane (14 mL, 6 N) was added to the system. The mixture was allowed to react at room temperature for 4 h. After the reaction was complete, the mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate. The organic phases were combined, dried, and concentrated under reduced pressure to obtain intermediate M1. ESI-MS (M+H) + =452.2.

[0256] Referring to the synthetic route and method of intermediate M1, the following intermediate compounds were synthesized:

[0257] Example 8: Synthesis of intermediate M27

[0258] Synthesis step 1: Synthesis of M27-1

[0259] 3,5-Dibromopyrazin-2-amine (2.0 g, 7.91 mmol) was dissolved in N,N-dimethylformamide (40 mL). 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ol (1.4 g, 7.91 mmol) and cesium carbonate (5.2 g, 15.82 mmol) were added to the system in sequence. The mixture was reacted at 90°C for 2 h. After the reaction was completed, the mixture was cooled and quenched with water. The mixture was extracted with ethyl acetate, and the organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain M27-1. ESI-MS (M+H) + =353.1.

[0260] Step 2: Synthesis of intermediate M27

[0261] Refer to the synthesis steps 3 and 5 of intermediate M1 to obtain intermediate M27, ESI-MS (M+H) +=460.2.

[0262] Referring to the synthetic route and method of intermediate M27, the following intermediate compounds were synthesized:

[0263] Example 9 Synthesis of Intermediate M31

[0264] Synthesis step 1: Synthesis of M31-1

[0265] M1-1 (5.0 g, 10.49 mmol) was dissolved in DMSO (50 mL), and cesium carbonate (10.2 g, 31.47 mmol), cuprous iodide (200 mg, 1.05 mmol), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (768 mg, 1.05 mmol) were added to the system in sequence. The system was evacuated under nitrogen protection, and the temperature was raised to 80°C. A DMSO solution of trimethylsilyl acetylene (3.7 g, 52.45 mmol) was added dropwise. The reaction was stirred at 80°C for 2 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M31-1 was obtained by column chromatography. ESI-MS (M+H) + =448.0.

[0266] Step 2: Synthesis of M31-2

[0267] M31-1 (3.9 g, 8.72 mmol) was dissolved in MeOH (40 mL), potassium carbonate (414 mg, 26.16 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was quenched with water and concentrated under reduced pressure to a fixed volume. EA was added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M31-2 was obtained by column chromatography. ESI-MS (M+H) + =376.0.

[0268] Step 3: Synthesis of M31-3

[0269] M31-2 (3.0 g, 7.92 mmol) was dissolved in DMF (30 mL), and methanol (3 mL), trimethylsilylazide (1.4 g, 11.88 mmol), and cuprous iodide (75 mg, 0.40 mmol) were added to the system in sequence. The system was replaced with nitrogen protection and heated to 100°C for 2 h. After the reaction was completed, the reaction was quenched with water, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M31-3 was obtained by column chromatography. ESI-MS (M+H) + =419.0.

[0270] Step 4: Synthesis of M31-4

[0271] M31-3 (2.7 g, 6.53 mmol) was dissolved in DCM (30 mL), and 2,2,2-trifluoroacetaldehyde (961 mg, 9.80 mmol) and STAB (4.2 g, 19.59 mmol) were added sequentially to the system. The mixture was reacted at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water, extracted with EA, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M31-4 was obtained by column chromatography. ESI-MS (M+H) + = 501.0. The structure of the product was confirmed by HH COSY.

[0272] Step 5: Synthesis of M31

[0273] The synthesis method of M31-5, M31-6 and M31 refers to the synthesis steps 3, 4 and 5 of intermediate M1 to obtain intermediate M31, ESI-MS (M+H) + =454.2.

[0274] Example 10 Synthesis of Intermediate M32

[0275] Synthesis step 1: Synthesis of M32-1

[0276] M1-1 (5.0 g, 10.49 mmol) was dissolved in dioxane (50 mL), and 2-(2,5-dichlorothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.51 g, 12.59 mmol), potassium carbonate (4.2 g, 31.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (768 mg, 1.05 mmol), and water (16 mL) were added to the system in sequence. The mixture was reacted at 100°C under nitrogen for 4 h. After the reaction was completed, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M32-1 was obtained by column chromatography. ESI-MS (M+H) + =501.9.

[0277] Step 2: Synthesis of M32

[0278] The synthesis method of M32-2, M32-3 and M32 refers to the synthesis steps 3, 4 and 5 of intermediate M1 to obtain intermediate M32, ESI-MS (M+H) + =455.1.

[0279] Referring to the synthetic route and method of intermediate M32, the following intermediate compounds were synthesized:

[0280] Example 11 Synthesis of Intermediate M33

[0281] Synthesis step 1: Synthesis of M33-1

[0282] Dissolve 3-bromo-6-cyanoimidazolo[1,2-A]pyridine (5.0 g, 22.52 mmol) in tetrahydrofuran (50 mL). Add n-butyllithium in n-hexane (11.7 mL, 29.28 mmol) dropwise at -70°C and stir for 1 h. Add zinc chloride in tetrahydrofuran (29 mL, 29.28 mmol) at -50°C and react at 0°C for 1 h. Use directly in the next step.

[0283] Step 2: Synthesis of M33-2

[0284] M1-1 (5.0 g, 10.49 mmol) was dissolved in tetrahydrofuran (50 mL), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium (412 mg, 0.52 mmol) and M33-1 (11.54 mmol) were added to the system and reacted at 40°C for 1 hour. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M33-2 was obtained by column chromatography. ESI-MS (M+H) + =493.0.

[0285] Step 3: Synthesis of M33

[0286] The synthesis method of M33-3, M33-4 and M33 refers to the synthesis steps 3, 4 and 5 of intermediate M1 to obtain intermediate M33, ESI-MS (M+H) + =446.2.

[0287] Referring to the synthetic route and method of intermediate M33, the following intermediate compounds were synthesized:

[0288] Example 12 Synthesis of Intermediate M34

[0289] Synthesis step 1: Synthesis of M34-1

[0290] M1-1 (5.0 g, 10.49 mmol) was dissolved in DMSO (50 mL), and cesium carbonate (6.8 g, 20.98 mmol), 4-(1H-pyrazol-4-yl)morpholine (2.4 g, 15.74 mmol), and cuprous oxide (150 mg, 1.05 mmol) were added sequentially to the system. The mixture was reacted at 100°C under nitrogen for 4 h. After completion of the reaction, the mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. M34-1 was obtained by column chromatography. ESI-MS (M+H)+ =503.0.

[0291] Step 2: Synthesis of M34

[0292] The synthesis method of M34-2, M34-3 and M34 refers to the synthesis steps 3, 4 and 5 of intermediate M1 to obtain intermediate M34, ESI-MS (M+H) + =456.2.

[0293] Referring to the synthetic route and method of intermediate M34, the following intermediate compounds were synthesized:

[0294] Example 13: Synthesis of Intermediate E71

[0295] Synthesis step 1: Synthesis of E71-1

[0296] Methyl 6-fluorobenzoate (5.0 g, 32.22 mmol) was dissolved in 30 mL of N,N-dimethylformamide. 3-Hydroxymethylazetidine hydrochloride (4.8 g, 38.67 mmol) and potassium carbonate (13.3 g, 96.66 mmol) were added sequentially to the system and reacted at 90°C for 16 h. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to afford E71-1 in a 98% yield. ESI-MS (M+H) + =222.1.

[0297] Synthesis step 2: Synthesis of E71-2

[0298] E71-1 (3 g, 13.5 mmol) was dissolved in dichloromethane (50 mL) and stirred at room temperature until clear. Dess-Martin reagent (8.6 g, 20.25 mmol) was added in 10 batches and allowed to react at room temperature for 1 h. After the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain E71-2 in a 67% yield. ESI-MS (M+H) + =220.1.

[0299] Synthesis step 3: Synthesis of E71-3

[0300] E71-2 (1.9 g, 8.63 mol) was dissolved in methanol (20 mL), and trimethoxymethane (1.3 g, 12.94 mmol) was added sequentially. After stirring at room temperature for 15 minutes, p-toluenesulfonic acid (150 mg, 0.86 mmol) was added and the mixture was allowed to react at 60°C for 4 hours. After completion of the reaction, the pH was adjusted to 8 with aqueous sodium bicarbonate solution, and the methanol was removed by concentration. The organic phases were extracted with dichloromethane, and the combined organic phases were dried, concentrated under reduced pressure, and subjected to column chromatography to afford 1.5 g of E71-3 in a 65% yield. ESI-MS (M+H) + =266.1.

[0301] Synthesis step 4: Synthesis of intermediate E71

[0302] E71-3 (800 mg, 3.17 mmol) was dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature until dissolved. 3-Aminopiperidine-2,6-dione (800 mg, 6.34 mmol), 1-hydroxybenzotriazole (510 mg, 3.80 mmol), and triethylamine (1.6 mL, 12.68 mmol) were added and stirred at room temperature for 30 min. Carbodiimide hydrochloride (1.8 g, 9.51 mmol) was added and reacted at room temperature for 3 h. After completion of the reaction, aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by column chromatography to obtain intermediate E71 in a yield of 49%. ESI-MS (MH) - =316.1.

[0303] Referring to the synthetic route and method of intermediate E71, the following intermediate compounds were synthesized:

[0304] Example 14: Synthesis of Intermediate E11

[0305] Synthesis step 1: Synthesis of E11-1

[0306] 1-Fluoro-4-nitrobenzene (2.2 g, 15.60 mmol) was dissolved in N,N-dimethylformamide (10 mL). 3-Hydroxymethylazetidine hydrochloride (1.7 g, 15.60 mmol) and potassium carbonate (6.5 g, 46.8 mmol) were added to the system in sequence and reacted at room temperature for 16 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and column chromatography was performed to obtain 3.1 g of E11-1. ESI-MS (M+H) + =209.1.

[0307] Synthesis step 2: Synthesis of E11-2

[0308] E11-1 (2.5 g, 12.01 mmol) was dissolved in dichloromethane (50 mL). Dess-Martin reagent (7.2 g, 16.93 mmol) was added to the system in 10 batches and allowed to react at room temperature for 1 h. After completion of the reaction, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phases were combined, dried, concentrated under reduced pressure, and column chromatography was performed to obtain E11-2 in an 81% yield. ESI-MS (M+H) + =207.1.

[0309] Synthesis step 3: Synthesis of E11-3

[0310] E11-2 (1.8 g, 8.73 mmol) was dissolved in methanol (20 mL). Trimethyl orthoformate (1.4 g, 13.09 mmol) and p-toluenesulfonic acid (150 mg, 0.87 mmol) were added sequentially to the system. The mixture was reacted at 50°C for 16 h. After completion of the reaction, water was added to quench the reaction. The organic solvent was concentrated, and the mixture was extracted with dichloromethane. The combined organic phases were dried, concentrated under reduced pressure, and then column chromatography was performed to obtain E11-3 in a yield of 78%. ESI-MS (M+H) + =253.1.

[0311] Synthesis step 4: Synthesis of E11-4

[0312] E11-3 (1.6 g, 6.35 mmol) was dissolved in tetrahydrofuran (20 mL), and palladium on carbon (160 mg, 10% wt) was added. The mixture was reacted at 50°C under a hydrogen atmosphere for 16 h. After completion of the reaction, the mixture was rapidly filtered, and the mother liquor was concentrated and purified by column chromatography to afford E11-4 in an 85% yield. ESI-MS (M+H) + =223.1.

[0313] Synthesis Step 5: Synthesis of E11-5

[0314] E11-4 (1 g, 4.50 mmol) was dissolved in N,N-dimethylformamide (10 mL). 3-Bromopiperidine-2,6-dione (1.3 g, 6.75 mmol) and sodium bicarbonate (1.1 g, 13.50 mmol) were added sequentially to the system and allowed to react at room temperature for 16 h. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain E11-5 in an 87% yield. ESI-MS (M+H) + =334.2.

[0315] Synthesis step 6: Synthesis of intermediate E11

[0316] E11-5 (1 g, 3.00 mmol) was dissolved in tetrahydrofuran (10 mL). Aqueous sulfuric acid (10 mL, 1 mol / L) was added to the mixture and allowed to react at 50°C for 16 h. After completion of the reaction, the pH was adjusted to 7 with aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the combined organic phases were dried, concentrated under reduced pressure, and then column chromatography was performed to obtain intermediate E11 in a 32% yield. ESI-MS (M+H) + =288.1.

[0317] The following intermediate compounds were synthesized using the synthetic route and method of reference intermediate E11:

[0318] Example 15: Synthesis of Intermediate E23

[0319] Synthesis step 1: Synthesis of E23-1

[0320] 4-Bromo-2-methylaniline (5.0 g, 27.03 mmol) was dissolved in toluene (50 mL), and acrylic acid (3.9 g, 54.06 mmol) was added to the system. The reaction was allowed to react at 100°C for 16 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and column chromatography was performed to obtain 5.6 g of E23-1. ESI-MS (M+H) + =258.0.

[0321] Synthesis step 2: Synthesis of E23-2

[0322] E23-1 (5.6 g, 21.78 mmol) was dissolved in acetic acid (50 mL), and urea (2.6 g, 43.56 mmol) was added to the system. The reaction was allowed to react at 110°C for 16 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and column chromatography was performed to obtain E23-2. ESI-MS (M+H) + =283.0.

[0323] Synthesis step 3: Synthesis of E23-3

[0324] E23-2 (3.5 g, 12.41 mmol) was dissolved in dichloromethane (30 mL), and 3-(1,3-dioxolan-2-yl)azetidine (1.9 g, 14.89 mmol) and sodium triacetyl borohydride (7.9 g, 37.23 mmol) were added to the system in sequence. The mixture was reacted at room temperature for 16 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and column chromatography was performed to obtain E23-3. ESI-MS (M+H) + =332.2.

[0325] Synthesis step 4: Synthesis of intermediate E23

[0326] E23-3 (2.8 g, 8.45 mmol) was dissolved in tetrahydrofuran (20 mL). Aqueous sulfuric acid (10 mL, 1 mol / L) was added to the system and reacted at 50°C for 16 h. After the reaction, the pH was adjusted to 7 with sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and then column chromatography was performed to obtain E23. ESI-MS (M+H) + =288.1.

[0327] The following intermediate compounds were synthesized using the synthetic route and method of reference intermediate E23:

[0328] Example 16: Synthesis of Intermediate E36

[0329] Synthesis step 1: Synthesis of E36-1

[0330] 3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (1.5 g, 5.68 mmol) was dissolved in 15 mL of N,N-dimethylformamide. 3-(1,3-dioxolan-2-yl)azetidine (879 mg, 6.81 mmol), 1-hydroxybenzotriazole (996 mg, 7.38 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.2 g, 17.04 mmol), and triethylamine (1.8 g, 17.04 mmol) were added sequentially to the mixture. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The combined organic phases were dried, concentrated under reduced pressure, and purified by column chromatography to afford 1.6 g of E36-1, a yield of 75%. ESI-MS (M+H) revealed that the reaction was complete. + =376.1.

[0331] Synthesis step 2: Synthesis of intermediate E36

[0332] E36-1 (1.5 g, 4.00 mmol) was dissolved in trifluoroacetic acid (15 mL) and reacted at 70°C for 1 h. 1N sulfuric acid was added to the system and the reaction was continued at 70°C for 1 h. After the reaction, saturated sodium carbonate was added to adjust the pH to neutral to alkaline. The mixture was extracted with dichloromethane. The organic phases were combined, dried, concentrated under reduced pressure, and column chromatography was performed to obtain 1.3 g of intermediate E36 in a 98% yield. ESI-MS (M+H) + =332.1.

[0333] The following intermediate compounds were synthesized using the synthetic route and method of reference intermediate E36:

[0334] Example 17 Synthesis of Intermediate D21

[0335] Synthesis step 1: Synthesis of D21-1

[0336] Dissolve 3-amino-4-chlorobenzoic acid (5.0 g, 29.24 mmol) in toluene (50 ml), add acrylic acid (4.2 g, 58.48 mmol) to the system, and react at 100°C for 16 h. After the reaction is completed, concentrate under reduced pressure and use it directly in the next step. ESI-MS (M+H) + =244.0.

[0337] Synthesis step 2: Synthesis of D21-2

[0338] The above residue was dissolved in acetic acid (50 ml), and urea (2.6 g, 43.56 mmol) was added to the system. The reaction was allowed to react at 110°C for 16 h. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and column chromatography was performed to obtain 2.1 g of D21-2. ESI-MS (M+H) + =269.0.

[0339] Synthesis steps 3-4: Synthesis of D21

[0340] The synthesis of D21 refers to the synthetic route and method of steps 1-2 of the synthesis of intermediate E36.

[0341] Referring to the synthetic route and method of intermediate D21, the following intermediate compounds were synthesized:

[0342] Example 18: Synthesis of Intermediate E45

[0343] Synthesis step 1: Synthesis of E45-1

[0344] 2-Bromooxazole-5-carboxylic acid (1.5 g, 7.85 mmol) was dissolved in tetrahydrofuran (15 mL). 3-(1,3-dioxolan-2-yl)azetidine (1.3 g, 10.20 mmol) and cesium carbonate (7.6 g, 23.55 mmol) were added sequentially to the system. The mixture was reacted at 50°C for 5 h. After the reaction was completed, the mixture was extracted with dichloromethane. The organic phases were combined, dried, concentrated under reduced pressure, and subjected to column chromatography to obtain E45-1 in a yield of 69%. ESI-MS (M+H) + =241.1.

[0345] Synthesis step 2: Synthesis of E45-2

[0346] E45-1 (1.2 g, 5.00 mmol) was dissolved in N,N-dimethylformamide (15 mL). 3-Aminopiperidine-2,6-dione hydrochloride (1.0 g, 6.50 mmol), 1-hydroxybenzotriazole (877 mg, 6.50 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.8 g, 15.00 mmol), and triethylamine (1.6 g, 15.00 mmol) were added to the system in sequence. The mixture was reacted at room temperature for 1 h. After the reaction was completed, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain E45-2. ESI-MS (M+H) + =351.1.

[0347] Synthesis step 3: Synthesis of intermediate E45

[0348] E45-2 (1.2 g, 3.42 mmol) was dissolved in trifluoroacetic acid (15 mL) and reacted at 70°C for 1 h. 1N sulfuric acid was added to the system and the reaction was continued at 70°C for 1 h. After the reaction, saturated sodium carbonate was added to adjust the pH to neutral to alkaline. The mixture was extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain E45. ESI-MS (M+H) + =307.1.

[0349] The following intermediate compounds were synthesized using the synthetic route and method of reference intermediate E45:

[0350] Example 19: Synthesis of Intermediate E48

[0351] Synthesis step 1: Synthesis of E48-1

[0352] 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (3 g, 8.90 mmol) was dissolved in toluene (30 mL). 3-(1,3-dioxolan-2-yl)azetidine (1.7 g, 13.35 mmol), lithium bistrimethylsilylamide (22 mL, 22.25 mmol), and chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (689 mg, 0.89 mmol) were added to the system in sequence. The mixture was reacted at 100°C for 4 h. After the reaction was completed, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried, concentrated under reduced pressure, and column chromatography was performed to obtain E48-1. ESI-MS (M+H) + =387.2.

[0353] Synthesis step 2: Synthesis of intermediate E48

[0354] E48-1 (900 mg, 2.33 mmol) was dissolved in trifluoroacetic acid (10 mL) and reacted at 70°C for 1 h. 1N sulfuric acid was added to the system and the reaction was continued at 70°C for 1 h. After the reaction, saturated sodium carbonate was added to adjust the pH to neutral to alkaline. The mixture was extracted with dichloromethane. The organic phases were combined, dried, concentrated under reduced pressure, and then column chromatography was performed to obtain E48. ESI-MS (M+H) + =343.1. Using the synthetic route and method of reference intermediate E48, the following intermediate compounds were synthesized:

[0355] Example 20: Synthesis of Intermediate E55

[0356] Synthesis step 1: Synthesis of E55-1

[0357] Dissolve 1,4-diiodobenzene (5.0 g, 15.16 mmol) in dimethyl sulfoxide, and add 3-hydroxymethylazetidine hydrochloride (5.6 g, 45.48 mmol), L-proline (349 mg, 3.03 mmol), potassium carbonate (10.5 g, 75.80 mmol), and cuprous iodide (289 mg, 1.52 mmol) sequentially to the system. React at 90°C for 12 h. After the reaction, adjust the system with aqueous hydrochloric acid (2 mol / L) until clear, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and column chromatography to obtain E55-1. ESI-MS (M+H) + =290.0.

[0358] Synthesis step 2: Synthesis of E55-2

[0359] E55-1 (2.9 g, 10.12 mmol) was dissolved in dichloromethane (50 mL), and Dess-Martin reagent (6.5 g, 15.18 mmol) was added to the system in 10 batches. The reaction was allowed to react at room temperature for 1 h. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to obtain E55-2. ESI-MS (M+H) + =288.0.

[0360] Synthesis step 3: Synthesis of E55-3

[0361] E55-2 (2.7 g, 9.46 mmol) was dissolved in methanol (30 mL). Trimethyl orthoformate (1.5 g, 14.19 mmol) and p-toluenesulfonic acid (164 mg, 0.95 mmol) were added sequentially to the system and reacted at 50°C for 16 h. After completion of the reaction, the mixture was quenched with water and concentrated to remove the methanol. The mixture was extracted with dichloromethane, and the organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to obtain E55-3. ESI-MS (M+H) + =334.0.

[0362] Synthesis step 4: Synthesis of E55-4

[0363] E55-3 (1.9 g, 7.57 mmol) was dissolved in dimethyl sulfoxide (20 mL). 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.2 g, 7.57 mmol), sodium tert-butoxide (1.5 g, 15.14 mmol), trisdibenzylideneacetone dipalladium (695 mg, 0.76 mmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, (±)-BINAP, [1,1′-binaphthyl]-2,2′-bisdiphenylphosphine (473 mg, 0.76 mmol) were added sequentially to the system. The mixture was reacted at 95°C for 12 h. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography. E55-4. ESI-MS (M+H) + =497.2.

[0364] Synthesis Step 5: Synthesis of E55-5

[0365] E55-4 (1.5 g, 3.06 mmol) was dissolved in tetrahydrofuran (15 mL), and Pd / C (150 mg, 10% Wt) was added to the system. The reaction was allowed to proceed at 50°C under a H2 atmosphere for 16 h. After the reaction was complete, the mixture was rapidly filtered, and the mother liquor was concentrated and purified by column chromatography to obtain E55-5. ESI-MS (M+H) + =319.2.

[0366] Synthesis Step 6: Synthesis of E55

[0367] E55-5 (1 g, 3.12 mmol) was dissolved in tetrahydrofuran (10 mL). Aqueous H2SO4 (10 mL, 1 mol / L) was added to the system and reacted at 50°C for 16 h. After the reaction, the pH was adjusted to 7 with aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography. ESI-MS (M+H) + =273.1.

[0368] The following intermediate compounds were synthesized using the synthetic route and method of reference intermediate E55:

[0369] Example 21 Synthesis of Intermediate D16

[0370] Synthesis step 1: Synthesis of D16-1

[0371] Methyl 2,4-difluorobenzoate (5.0 g, 32.22 mmol) was dissolved in N,N-dimethylformamide (50 ml). 3-Hydroxymethylazetidine hydrochloride (4.8 g, 38.67 mmol) and potassium carbonate (13.3 g, 96.66 mmol) were added sequentially to the system. The mixture was reacted at 90°C for 16 h. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to afford D16-1 in a 98% yield. ESI-MS (M+H) + =240.1.

[0372] Synthesis step 2: Synthesis of D16-2

[0373] D16-1 (3 g, 13.5 mmol) was dissolved in dichloromethane (50 ml) and stirred at room temperature until clear. Dess-Martin reagent (8.6 g, 20.25 mmol) was added in 10 batches and allowed to react at room temperature for 1 h. After the reaction, an appropriate amount of saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain D16-2 in a 67% yield. ESI-MS (M+H) + =238.1.

[0374] Synthesis step 3: Synthesis of D16-3

[0375] D16-2 (1.9 g, 8.63 mol) was dissolved in methanol (20 ml), and trimethoxymethane (1.3 g, 12.94 mmol) was added sequentially. After stirring at room temperature for 15 minutes, p-toluenesulfonic acid (150 mg, 0.86 mmol) was added and the mixture was allowed to react at 60°C for 4 hours. After completion of the reaction, the pH was adjusted to 8 with aqueous sodium bicarbonate solution, and the methanol was removed by concentration. The organic phases were extracted with dichloromethane, and the combined organic phases were dried, concentrated under reduced pressure, and subjected to column chromatography to afford 1.5 g of D16-3 in a 65% yield. ESI-MS (M+H) + =284.1.

[0376] Synthesis step 4: Synthesis of D16-4

[0377] D16-3 (1.4 g, 5.26 mmol) was dissolved in a mixed solvent (15 mL) of methanol / tetrahydrofuran / water (1:1:1). Lithium hydroxide (1.2 g, 52.60 mmol) was added and the mixture was allowed to react at room temperature for 4 h. After completion of the reaction, the pH was adjusted to 6 with 2N hydrochloric acid. The organic solvent was concentrated and extracted with dichloromethane (containing 10% methanol). The combined organic phases were dried, concentrated under reduced pressure, and column chromatography was performed to obtain D16-4 in a yield of 68%. ESI-MS (MH) + =270.1.

[0378] Synthesis Step 5: Synthesis of Intermediate D16-5

[0379] D16-4 (800 mg, 3.17 mmol) was dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature until dissolved. 3-Aminopiperidine-2,6-dione (800 mg, 6.34 mmol), 1-hydroxybenzotriazole (510 mg, 3.80 mmol), and triethylamine (1.6 mL, 12.68 mmol) were added and stirred at room temperature for 30 min. Carbodiimide hydrochloride (1.8 g, 9.51 mmol) was added and allowed to react at room temperature for 3 h. After completion of the reaction, aqueous ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by column chromatography to obtain intermediate D16-5 in a yield of 49%. ESI-MS (MH) + =380.2.

[0380] Synthesis step 6: Synthesis of intermediate D16

[0381] The synthesis of D16 was carried out according to the synthesis procedure of step 6 of intermediate E55.

[0382] Example 22 Synthesis of Intermediate D17

[0383] Synthesis step 1-2: Synthesis of intermediate D17-2

[0384] The synthesis of D17-2 was carried out by referring to the synthetic procedures of steps 1 and 4 of the synthesis of intermediate E55.

[0385] Synthesis step 3: Synthesis of intermediate D17-3

[0386] D17-2 (2 g, 4.17 mmol) was dissolved in a mixed solvent (20 mL, methanol / tetrahydrofuran / water = 1:1:1). Lithium hydroxide (500 mg, 20.83 mmol) was added and the mixture was allowed to react at room temperature for 4 h. After completion of the reaction, the pH was adjusted to 6 with 2N hydrochloric acid. The organic solvent was concentrated, and the mixture was extracted with dichloromethane. The combined organic phases were dried, concentrated under reduced pressure, and then column chromatography was performed to obtain D17-3 in a 61% yield. ESI-MS (MH) +=467.2.

[0387] Synthesis step 4: Synthesis of intermediate D17

[0388] The synthesis of D17 was carried out by referring to the synthetic procedure of step 5 of the synthesis of intermediate E55.

[0389] Example 23 Synthesis of Intermediate D19

[0390] Synthesis step 1: Synthesis of D19-1

[0391] The synthesis of D19-1 was carried out by referring to the synthesis procedure of step 4 of the intermediate E55.

[0392] Synthesis step 2-3: Synthesis of D19-3

[0393] The synthesis of D19-3 was carried out by referring to the synthetic procedures of steps 1 and 5 of the synthesis of intermediate E55.

[0394] Synthesis step 4: Synthesis of D19

[0395] The synthesis of D19 was carried out according to the synthetic procedure of step 2 of the synthesis of intermediate E55.

[0396] Example 24 Synthesis of Intermediate D20

[0397] Synthesis step 1: Synthesis of D20-1

[0398] Under nitrogen, 3-bromo-2-hydroxyacetophenone (20 g, 93.04 mmol) was dissolved in chloroform (100 ml) and ethyl acetate (100 ml). Copper bromide (41.54 g, 186 mmol) was then added. The reaction mixture was heated to 90°C and stirred for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was rinsed with dichloromethane (1.5 L) to obtain a solution of D20-1, which was used directly in the next step. ESI-MS (M+H) + =292.9.

[0399] Synthesis step 2: Synthesis of D20-2

[0400] The solution of D20-1 obtained above (350 ml) was cooled to 0°C, and triethylamine (14.11 g, 140 mmol) was then slowly added dropwise. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was complete, water (200 mL) was added to separate the liquids, and the aqueous phase was extracted with dichloromethane (500 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain D20-2. ESI-MS (M+H) + =212.9.

[0401] Synthesis step 3: Synthesis of D20-3

[0402] Under nitrogen protection, D20-2 (19.8 g, 93.00 mmol) was dissolved in toluene (150 ml), followed by the addition of ethoxycarbonylmethylenetriphenylphosphine (38.88 g, 112 mmol). The reaction mixture was heated to 130°C and stirred for 36 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Methyl tert-butyl ether (700 mL x 3) was added to the resulting residue, stirred at room temperature for 20 minutes, filtered, and the filter cake was rinsed with methyl tert-butyl ether (100 mL). The filtrate was collected. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by column chromatography to obtain D20-3 in a yield of 32%. ESI-MS (M+H) + =283.0.

[0403] Synthesis step 4: Synthesis of D20-4

[0404] D20-3 (3 g, 10.60 mmol) was added to N, N-dimethylformamide (20 mL), followed by the addition of acrylamide (903.79 mg, 12.72 mmol) and potassium tert-butoxide (1.78 g, 15.89 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 1N hydrochloric acid (15 mL), water (25 mL) was added, and the mixture was extracted with ethyl acetate (35 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography to obtain D20-4. The yield was 69%. ESI-MS (M+H) + =308.0.

[0405] Synthesis steps 5-6: Synthesis of D20

[0406] The synthesis of D20 refers to the synthetic route and operation of steps 1-2 of the synthesis of intermediate E55.

[0407] Example 25: Synthesis of Intermediate E68

[0408] Synthesis step 1: Synthesis of E68-1

[0409] 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (3.0 g, 10.86 mmol) was dissolved in N,N-dimethylformamide (30 mL). 3-(1,3-dioxolan-2-yl)azetidine (1.4 g, 10.86 mmol) and N,N-diisopropylethylamine (2.8 g, 21.72 mmol) were added to the system in sequence. The mixture was reacted at 90°C for 6 h. After the reaction was completed, water was added to quench the mixture, and the mixture was extracted with dichloromethane. The organic phases were combined, dried, concentrated under reduced pressure, and then column chromatography was performed to obtain E68-1. ESI-MS (M+H) + =386.1.

[0410] Synthesis step 2: Synthesis of intermediate E68

[0411] Dissolve E68-1 (4.2 g, 8.76 mmol) in aqueous hydrochloric acid (200 mL, 3 mol / L) and react at 50°C for 2 h. After the reaction, adjust the pH to 7 with sodium bicarbonate, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and column chromatography to obtain intermediate E68. ESI-MS (M+H) + =342.1.

[0412] The following intermediate compounds were synthesized using the synthetic route and method of reference intermediate E68:

[0413] Example 26: Synthesis of Compound 014

[0414] M1 (102 mg, 0.22 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature until clear. E23 (65 mg, 0.222 mmol) was added to the system and the reaction was allowed to proceed at room temperature for 1 hour. Sodium cyanoborohydride (44 mg, 0.66 mmol) was then added to the system and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction. The ethanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by column chromatography to afford 80 mg of 0014 in a 48% yield. ESI-MS (M+H) +=723.2.1H NMR (400MHz, DMSO-d) δ10.54(s,1H),9.11–8.83(m,1H),8.75(s,1H),8.25(d,J=8.0Hz,2H),7.78(d,J=1 1.9Hz,3H),7.52(d,J=7.9Hz,2H),7.02(d,J=8.8Hz,1H),6.27(d,J=5.5Hz,2H),5.44(s,1H),3.98(d,J= 7.5Hz,2H),3.77(dt,J=13.8,7.1Hz,1H),3.63(dt,J=12.7,6.2Hz,1H),3.53(d,J=6.6Hz,2H),3.21–3.1 0(m,6H),3.07(s,2H),2.84(d,J=6.4Hz,2H),2.80–2.71(m,4H),2.35(m,6H),2.27(m,3H),2.23(m,3H).

[0415] The following compounds were synthesized using the synthetic route and method of reference 014 (the compound numbers in the table follow the compound numbers in the claims and description):

[0416] Example 27: Synthesis of Compound 006

[0417] M1 (102 mg, 0.22 mmol) was dissolved in acetonitrile (5 mL) and stirred at room temperature until dissolved. E65 (66 mg, 0.19 mmol) and cesium carbonate (110 mg, 0.34 mmol) were added sequentially to the system and reacted at 70°C for 1 h. After the reaction, the mixture was extracted with dichloromethane, and the organic phases were combined, washed with saturated ammonium chloride solution, dried, concentrated under reduced pressure, and subjected to column chromatography to obtain 006. ESI-MS (M+H) + =713.2.

[0418] Example 28: Synthesis of Compound 009

[0419] M1 (102 mg, 0.22 mmol) was dissolved in ethanol (5 mL) and stirred at room temperature until clear. E66 (58 mg, 0.21 mmol) was added to the system and reacted at 70°C for 1 h. After the reaction, the mixture was extracted with dichloromethane, and the organic phases were combined, washed with saturated ammonium chloride solution, dried, concentrated under reduced pressure, and subjected to column chromatography to obtain 009. ESI-MS (M+H) + =725.3.

[0420] Example 29: Synthesis of Compound 047

[0421] E35 (75 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (5 mL), and M1 (102 mg, 0.22 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (105 mg, 0.27 mmol), and diisopropylethylamine (81 mg, 0.63 mmol) were added sequentially to the system and reacted at room temperature for 1 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated ammonium chloride aqueous solution, dried, concentrated under reduced pressure, and then column chromatography was performed to obtain 047. ESI-MS (M+H) + =732.3.

[0422] Compound 104 was synthesized using the synthetic route and method of reference 047. ESI-MS (M+H) + =722.3

[0423] Biological evaluation

[0424] Test Example 1. HPK1 kinase activity

[0425] Lantha screen Assay was used to evaluate the inhibitory effect of compounds on HPK1 kinase.

[0426] a) Kinase buffer: 50 mM HEPES (pH 7.5), 10 mM MgCl2, 4 mM DTT, 0.01% Tween-20, 0.01% BSA.

[0427] b) Compound preparation: The compound was diluted with DMSO. The initial detection concentration of the compound was 1 μM and diluted to the corresponding concentration.

[0428] c) Kinase reaction and termination: Prepare kinase solution by adding kinase buffer. Add kinase solution and compound to the assay plate and incubate at room temperature for 10 minutes. Add kinase buffer to Fluorescein-PKC and ATP to form substrate solution. Add 5 μl of substrate solution to the assay plate to initiate the reaction and incubate at room temperature for 90 minutes. Terminate the reaction by adding 10 μl of antibody and EDTA mixture and incubate at room temperature for 60 minutes.

[0429] d) The Envision instrument reads the data and plots a curve with the Log concentration of the inhibitor as the X-axis and the inhibition rate as the Y-axis. According to the formula Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)^HillSlope) to get IC 50 .

[0430] Table 1 HPK1 kinase inhibitory activity of the compounds of the present invention

[0431] +:IC 50 <10nM;++:10nM≤IC 50 <50nM;+++:50nM≤IC 50 <100nM.

[0432] As shown in Table 1, the compounds of the present invention have good inhibitory activity against HPK1 kinase.

[0433] Test Example 2. HPK1 degradation activity

[0434] Experimental steps:

[0435] 1) Cell plating: Thaw cells, select Jurkat cell lines in good growth condition, collect and count cells in logarithmic growth phase, inoculate the cell suspension into 12- or 24-well plates, and incubate in a 37°C, 5% CO2 incubator overnight.

[0436] 2) Preparation of test compounds: The test compounds were diluted with DMSO in a concentration gradient according to experimental requirements, added to the corresponding cell wells, and incubated in a 37° C., 5% CO 2 incubator for 24 h.

[0437] 3) Sample Preparation: After the test compound is exposed, cells are collected into a 1.5 mL EP tube and centrifuged at 1500 rpm for 5 minutes. The supernatant is discarded and the cells are washed once with PBS. Protein is quantified by BCA assay and the concentration is adjusted. The adjusted sample is added to 5× loading buffer and boiled at 100°C for 10 minutes. After returning to room temperature, the sample is loaded.

[0438] 4) Sample Detection: Perform electrophoresis using 10% SDS-PAGE, loading 8 μL / well. After transfer, block with 5% BSA at room temperature for 1 hour. Wash away any remaining blocking buffer with TBST, then incubate with HPK1 and GAPDH antibodies at 4°C overnight. Wash three times with TBST on a shaker for 10 minutes each. After washing, add secondary antibody and incubate at room temperature for 1 hour. Wash three times with TBST on a shaker for 10 minutes each. Finally, develop the bands using ECL imaging solution to detect changes in HPK1 protein.

[0439] Table 2 The degradation ability of the compounds of the present invention on HPK1 protein

[0440] +:DC 50 <10nM;++:10nM≤DC 50 <50nM;+++:50nM≤DC 50 <100nM.

[0441] Compound a is C196 of WO2024 / 125631A1.

[0442] As shown in Table 2, the compounds of the present invention have a strong ability to degrade HPK1 protein.

[0443] Test Example 3. HPK1 / GLK Degradation Selectivity

[0444] Experimental steps:

[0445] 1) Cell plating: Thaw cells, select Jurkat cell lines with good growth status, collect and count cells in logarithmic growth phase, inoculate the cell suspension into 12- or 24-well plates (20W / well), and incubate in a 37°C, 5% CO2 incubator overnight.

[0446] 2) Preparation of test compounds: The test compounds were diluted with DMSO in a concentration gradient according to experimental requirements, added to the corresponding cell wells, and incubated in a 37° C., 5% CO 2 incubator for 24 h.

[0447] 3) Sample Preparation: After the test compound is exposed, cells are collected into a 1.5 mL EP tube and centrifuged at 1500 rpm for 5 minutes. The supernatant is discarded and the cells are washed once with PBS. Protein is quantified by BCA assay and the concentration is adjusted. The adjusted sample is added to 5× loading buffer and boiled at 100°C for 10 minutes. After returning to room temperature, the sample is loaded.

[0448] 4) Sample Detection: Perform electrophoresis using 10% SDS-PAGE, loading 10 μL / well. After transfer, block the membrane with 5% skim milk for 1 hour at room temperature. Wash away any remaining blocking buffer with TBST, then incubate with HPK1 and GLK antibodies at 4°C overnight. Wash three times with TBST on a shaker for 5 minutes each. After washing, add secondary antibody and incubate on a shaker for 1 hour at room temperature. Wash three times with TBST on a shaker for 5 minutes each. Finally, soak the membrane in TBST and perform chemiluminescence imaging.

[0449] 5) Data processing: After developing the PVDF membrane, the data were exported and plotted using Image J. The grayscale values ​​of protein bands were analyzed using Image J software. DC was fitted using Graphpad Prism 9. 50 Curve to obtain the results of the compound's selectivity for HPK1 / GLK degradation: HPK1 / GLK Fold = DC 50 (HPK1) / DC 50 (GLK).

[0450] Table 3 Selectivity of the compounds of the present invention for HPK1 / GLK degradation

[0451] +: Fold<10; ++: 10≤Fold<100; +++: 100≤Fold<1000; ++++: 1000≤Fold

[0452] As shown in Table 3, the compounds of the present invention showed high selectivity for degradation of HPK1 in the degradation selectivity test of HPK1 and GLK proteins.

[0453] Test Example 4. Pharmacokinetic Properties

[0454] The test compound was administered orally to SD rats at 10 mg / kg. Blood was collected at 0 h (pre-dose) and 0.083, 0.25, 1, 2, 4, 6, 8, and 24 h after oral administration. The blood was placed in a sodium heparinized anticoagulant tube, thoroughly vortexed, and centrifuged at 6000 rpm for 3 minutes. Plasma concentrations were determined by LC-MS / MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 pharmacokinetic software.

[0455] Table 4 Pharmacokinetic properties of the compounds of the present invention

[0456] As shown in Table 4, the compound of the present invention has a good exposure after oral administration.

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof: in: Cy1 is selected from: 5-12 membered heteroaryl or 8-10 membered fused bicyclic group; Cy2 is selected from: C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl or 8-10 membered fused bicyclic group; X8 and X9 are each independently selected from: CR a or N; L1 and L2 are each independently selected from: a chemical bond, a C1-C8 alkylene group, a C3-C 12 Cycloalkylene, 3-12 membered heterocyclylene, -O-C1-C8 alkylene, -C1-C8 alkylene-O-, -NR b -C1-C8 alkylene-, -C1-C8 alkylene-NR b -、-O-、-NR b C(O)-、-C(O)-NR b -, -CO-, -SO-, -SO2-, C2-C8 alkenylene or C2-C8 alkynylene; R1 is selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c ,-SO(=NR b )R c 、-POR b R c or -Linker-E3, the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, halogenated C1-C8 alkyl, -C1-C8 alkyl-CONR b R c 、-C1-C8 alkyl-NR b COR c 、-C1-C8 alkyl-OR b 、Oxo、-CN、-NO2、-OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c 、-SO(=NR b )R c ,-PORE b R c ; Or two R1 together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 Substituted by a cycloalkyl group, a 3-12 membered heterocyclyl group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group; R2 is selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c ,-SO(=NR b )R c Or-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、 -NR b COR c 、 -NR b CONR c R d 、 -NR b CO2R c 、 -NR b SONR c R d 、 -NR b SO2NR c R d 、 -NR b SO2R c 、 -SO(=NR b )R c or -POR b R c ; Or two R2 together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 Substituted by a cycloalkyl group, a 3-12 membered heterocyclyl group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group; R3 is selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c ,-SO(=NR b )R c Or-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、 -NR b COR c 、 -NR b CONR c R d 、 -NR b CO2R c 、 -NR b SONR c R d 、 -NR b SO2NR c R d 、 -NR b SO2R c 、 -SO(=NR b )R c or -POR b R c ; Linker selected from: -(CH2) r -, the above one or more CH2 are optionally replaced by one or more selected from -COO-, -CONR b -、-OCONR b -、-NR b CONR b -、-O-、-NR b -、-S-、-CO-、-CR b =CR b -、-C≡C-、-CR b CR c -、-CR b =N-, -SO-, -SO2-, -POR b -、C3-C 10 Cycloalkylene, 3-10 membered heterocyclylene, phenylene, 5-6 membered heteroarylene or -CR b R c - is replaced by a group; the heterocyclylene group may be further substituted by halogen, C1-C3 alkyl; E3 is selected from: E3 ubiquitin ligase ligand; R a Selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c 、-SO(=NR b )R c Or-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、 -NR b COR c 、 -NR b CONR c R d 、 -NR b CO2R c 、 -NR b SONR c R d 、 -NR b SO2NR c R d 、 -NR b SO2R c 、 -SO(=NR b )R c or -POR b R c ; R b , R c , R d Each is independently selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, halogenated C1-C4 alkyl, -C1-C4 alkyl-CONR e R f 、-C1-C3 alkyl-OR e 、-OR e or -NR e R f The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl groups are optionally further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, halogenated C1-C8 alkyl, -C1-C8 alkyl-CONR e R f 、-C1-C8 alkyl-OR e 、Oxo、-CN、-NO2、-OR e 、-SO2R e 、-SO2NR e R f 、-COR e 、-COOR e 、-CONR e R f 、-C(=NR e )NR f R g 、-NR e R f 、-NR e COR f 、-NR e CONR f R g 、-NR e CO2R f 、-NR e SONR f R g 、-NR e SO2NR f R g 、-NR e S02R f ,-SO(=NR e )R f Or-POR e R f ； or replace R on the same atom c and R b or R d and R c The ring may be connected to form a ring, which may be further substituted by one or more substituents, the substituents being selected from: halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OR e 、-SO2R e 、-SO2NR e R f 、-COR e 、-COOR e 、-CONR e R f 、-C(=NR e )NR f R g 、-NR e R f 、-NR e COR f 、-NR e CONR f R g 、-NR e CO2R f 、-NR e SONR f R g 、-NR e SO2NR f R g 、-NR e S02R f ,-SO(=NR e )R f Or-POR e R f ; R e , R f , R g Each is independently selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl; the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl may be further substituted by one or more substituents selected from: halogen, C1-C8 alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, cyano, hydroxy, amino or nitro; m, n, and p are each independently selected from: 0, 1, 2, 3, 4, 5, and 6; r is selected from: an integer from 0 to 20.

2. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy1 is selected from: in: is a single bond or a double bond; X1, X2, X3, X4, X5, X6, X 10 Independently selected from O, S, C, CH, CH2, N, NH or CO; provided that the compound valence theory is satisfied; X7 selected from: CR a ’ or N; R a ’ Selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, C6-C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO2, -OH, -NH2, -O-C1-C8 alkyl.

3. The compound according to claim 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIa) or (IIb), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

4. The compound according to claim 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIIa) or (IIIb), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: X1 is selected from: CH or N; X4 is selected from: NH or S; X8, X9 are independently selected from: CH, N or C-Me; when When selected from double bonds, X6 is C, X5 can be CH, N; when When selected from single bonds, X6 is N, CH, and X5 is CO, CH2; L1 and L2 are each independently selected from: a chemical bond, -O-, -O-C1-C3 alkylene or -C1-C3 alkylene-O-; Cy2 is selected from: R2 is selected from: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic group, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c 、-SO(=NR b )R c 、-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups may be further substituted by one or more substituents selected from the group consisting of halogen, oxo, -CN, -OR b 、-NR b R c ; m is selected from: 0, 1, 2, 3, 4, 5; n is selected from: 0, 1, 2, 3.

5. The compound according to claim 4, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof represented by general formula IV: in: X1 is selected from: N or CH; X 11 Selected from: N or CH; R1 is selected from: H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, -OR b 、-COR b 、-CONR b R c 、-NR b R c 、-NR b COR c or SO(=NR b )R c 、SO2NR b R c , cyano, oxo; the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl may be further substituted with halogen, C1-C3 alkyl, C3-C5 cycloalkyl, halogenated C1-C3 alkyl, -C1-C3 alkyl-NR b COR c 、-C1-C3 alkyl-CONR b R c 、-C1-C3 alkyl-OR b , hydroxy, cyano, amino or nitro substitution; R1' is selected from: H, halogen, C1-C4 alkyl, hydroxyl, cyano, amino, nitro; Or R1 and R1' together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 Substituted by a cycloalkyl group, a 3-12 membered heterocyclyl group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group; Or R1' and R1' together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 Substituted by a cycloalkyl group, a 3-12 membered heterocyclyl group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group; R b Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, cyano, amino or nitro; R c Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, cyano, amino or nitro; R2 is selected from: H or n or m' is selected from: 0, 1, 2 or 3.

6. The compound according to claim 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof represented by general formula IV: R1 is selected from: H, C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, cyano, oxo, hydroxymethyl, hydroxyethyl, Cyclopropyl, cyclobutyl, cyclopentyl, R1' is selected from: H, Cl, F, methyl, ethyl or cyano; X8 and X9 are independently selected from CR a or N; R a Selected from: H, methyl, ethyl, isopropyl, halogen, methylamino, ethylamino, methoxy, ethoxy, n or m' is selected from: 0, 1, 2 or 3.

7. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof: in: Selected from: R1 is selected from: H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, C6-C 10 Aryl, 5-6 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c ,-SO(=NR b )R c 、-POR b R c or -Linker-E3, the above alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further substituted by one or more substituents, the substituents are selected from: halogen, C1-C3 alkyl, C3-C5 cycloalkyl, 3-6 membered heterocyclic, C6-C 10 Aryl, 5-7 membered heteroaryl, halogenated C1-C3 alkyl, -C1-C3 alkyl-CONR b R c 、-C1-C3 alkyl-NR b COR c 、-C1-C3 alkyl-OR b 、Oxo、-CN、-NO2、-OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b SO2R c ,-SO(=NR b )R c ,-PORE b R c ; Or two R1 together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, C3-C 12 Substituted by a cycloalkyl group, a 3-12 membered heterocyclyl group, a C1-C8 alkoxy group, a C1-C8 alkylamino group, an amino group, a hydroxyl group, an oxo group, a nitro group, a carboxyl group or a cyano group; m is selected from: 0, 1, 2, 3, 4, 5; R b , R c , R d Each is independently selected from: H, halogen, methyl, ethyl, propyl, isopropyl, C3-C6 cycloalkyl, 5-7 membered heterocyclyl, C6-C 10 Aryl, 5-6 membered heteroaryl, halogenated C1-C4 alkyl, -C1-C4 alkyl-CON(CH3)2, -C1-C3 alkyl-OCH3, -OR e or -NR e R f The above methyl, ethyl, propyl, isopropyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C1-C3 alkyl, C3-C6 cycloalkyl, 3-8 membered heterocyclyl, C6-C 10 Aryl, 5-6 membered heteroaryl, halogenated C1-C4 alkyl, -C1-C4 alkyl-CON(CH3)2, -C1-C3 alkyl-OCH3, oxo, -CN, -NO2, -OH, -NH2.

8. The compound according to claim 7 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof: in: Selected from: R1 is selected from: H, C1-C3 alkyl, halogen, halogenated C1-C3 alkyl, cyano, oxo, hydroxymethyl, hydroxyethyl, Cyclopropyl, cyclobutyl, cyclopentyl, 9. The compound according to claim 8 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof: Selected from:

10. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof represented by general formula VI: X 13 Selected from: NH or O; X1 is selected from: CH or N; R 10 is selected from: H, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, hydroxy, cyano, amino or nitro; R 10’ Selected from: H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, 3-8 membered heterocyclic group, halogenated C1-C4 alkyl, -C1-C4 alkyl-CONR b R c 、-C1-C8 alkyl-OR b , oxo or -CN, the alkyl, cycloalkyl or heterocyclic group is optionally further substituted by one or more selected from halogen, C1-C8 alkyl, -CN, -CONR b R c 、-NR b COR c 、-OR b Preferably, R 10’ Selected from: H, halogen, cyano, oxo, methyl, ethyl, propyl, isopropyl, isobutyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, R2 is selected from: H, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, -CN, -NO2, -OR b 、-NR b R c The above alkyl, cycloalkyl and heterocyclic groups may be further substituted by one or more selected from halogen, oxo, -CN, -OR b 、-NR b R c Substituent substitution; R b Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by halogen, C1-C3 alkyl, hydroxyl, cyano, amino or nitro; R c Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by halogen, C1-C3 alkyl, hydroxyl, cyano, amino or nitro; q or q' is selected from: 0, 1, 2 or 3; Cy2 is selected from: a 5-membered heteroaromatic ring containing 1-3 heteroatoms; preferably, Cy2 is selected from 11. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof represented by general formula VII: CyA is selected from: phenyl, 5-10 membered heteroaryl or 8-10 membered fused bicyclic group; The heteroaryl group selected from the group consisting of CyA is preferably selected from: The fused bicyclic group is preferably selected from: R A1 is selected from H, halogen, C1-C4 alkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl, oxo, -CN, -OR b 、-COR B 、-CONR B R C 、-NR B R C 、-NR B COR C or SO(=NR B )R C ; The alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl may be further substituted by halogen, C1-C3 alkyl, hydroxyl, cyano, amino or nitro; R B Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by C1-C3 alkyl, hydroxyl, cyano, amino or nitro; R C Selected from: H, C1-C3 alkyl, C3-C6 cycloalkyl, 5-7 membered heterocyclic group, C6-C 10 Aryl or 5-10 membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may be further substituted by C1-C3 alkyl, hydroxyl, cyano, amino or nitro; q is selected from: 0, 1, 2 or 3. The definitions of X1, X8, X9, R2, n, Linker, and E3 are as described in claim 1.

12. The compound according to any one of claims 1 to 11, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, E3 is selected from: in, q, u or s are each independently selected from: 0, 1 or 2; Y1 is independently selected from: CO, methylene, vinylene or ethyl; Y2 is independently selected from: CH or N; Y3 is independently selected from: absent, CH2, NH, NMe or O; Y4 is independently selected from: CH or N; Y5 is independently selected from: CH or N; R4, R5, R6, R7, R8, and R9 are each independently selected from the group consisting of: H, halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R a 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c 、-NR b CONR c R d 、-NR b CO2R c 、-NR b SONR c R d 、-NR b SO2NR c R d 、-NR b S02R c ,-SO(=NR b )R c 、-POR b R c The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups may be further substituted by one or more substituents selected from the group consisting of halogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 6-10 membered heteroaryl, oxo, -CN, -NO2, -OR b 、-SO2R b 、-SO2NR b R c 、-COR b 、-COOR b 、-CONR b R c 、-C(=NR b )NR c R d 、-NR b R c 、-NR b COR c ,-NR b CONR c R d ,-NR b CO2R c ,-NR b SONR c R d ,-NR b SO2NR c R d ,-NR b SO2R c ,-SO(=NR b )R c or -POR b R c ; Rd' is selected from: H, -R f OCOR g , -R f OCOOR g , -R f OCONR g R h 、-COOR f 、-CONR f R g ; R f , R g , R h Each is independently selected from: H, C1-C8 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, C1-C6 alkyl 3-8 membered cycloalkyl, C1-C6 alkyl 3-8 membered heterocyclic group; Cy3 is selected from: Cy4 is selected from: Cy5 is selected from:

13. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, The Linker is selected from: E3 is selected from:

14. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: X8 and X9 are each independently selected from: CR a or N; wherein Ra is selected from H, C1-C3 alkyl, -CH2N(CH3)2, halogen, -NHCH3, -O C1-C3 alkyl; Selected from L1 and L2 are each independently selected from a chemical bond, O, and -OCH2-.

15. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein the compound is selected from:

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 15 or its stereoisomer, tautomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or a combination thereof.

17. Use of the compound according to any one of claims 1 to 15 or its stereoisomer, tautomer or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 16 in the preparation of a drug for degrading HPK1 protein.

18. The use according to claim 17, wherein the drug is a drug for preventing and / or treating diseases related to the activity or expression of HPK1 protein, wherein the diseases include solid tumors, blood system diseases or autoimmune system diseases; preferably, the solid tumor is selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast duct cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, Preferably, the blood system diseases include one or more of acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, myelofibrosis, myelodysplastic syndrome, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, and T-cell lymphoma; the autoimmune diseases are selected from one or more of systemic lupus erythematosus, rheumatoid arthritis, psoriasis, Graves' disease, Sjögren's syndrome, multiple sclerosis, and multiple sclerosis.

Images