Polyaryl derivative and application thereof

Abstract

The invention discloses a polyaryl HPK1 degradation agent, a preparation method of the polyaryl HPK1 degradation agent, a pharmaceutical composition containing the polyaryl HPK1 degradation agent and application of the polyaryl HPK1 degradation agent in medicine. The polyaryl HPK1 degradation agent has a polyaryl derivative as shown in a general formula (I), or a stereoisomer, a tautomer and a pharmaceutically acceptable salt thereof, and an application of the polyaryl HPK1 degradation agent as the HPK1 degradation agent. The compound disclosed by the invention has the capability of strongly inhibiting the activity of HPK1 kinase. The compound disclosed by the invention has the capability of strongly degrading the HPK1 protein. The compound provided by the invention has excellent degradation selectivity. Oral administration of the compound provided by the invention has good exposure. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis and design, and particularly relates to a multi-aryl HPK1 degrader, a composition containing the derivative, and the preparation and use thereof as an HPK1 degrader. Background Art

[0002] In recent years, using the patient's own immune system to overcome the immune escape strategy adopted by tumor cells and enhancing the body's anti-tumor immunity is a new type of cancer treatment strategy. One of the strategies is to overcome tumor cell immune escape by inhibiting the negative regulators of the immune response that usually play a role in maintaining peripheral tolerance, so that tumor antigens are recognized as non-self antigens. Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1 (a member of the MAP4K family), is a negative regulator of the activation responses of dendritic cells (DCs), T cells, and B cells. Inhibiting its activity can specifically enhance the body's anti-tumor immunity. HPK1 is mainly expressed by hematopoietic cells, including early hematopoietic progenitors. In T cells, HPK1 is considered to be able to phosphorylate the Ser376 site of the downstream SLP76 protein and the Thr254 site of the Gads protein and recruit 14-3-3 proteins to degrade these proteins, thereby reducing the persistence of signal microclusters and playing a negative regulatory role in T cell activation. HPK1 can also be activated by responding to prostaglandin (PGE2) usually secreted by tumors, thus contributing to the escape of tumor cells from the immune system. Targeted disruption of the alleles of the HPK1 kinase can increase the production of Th1 cytokines (IL-2, IFNγ, etc.) in T cell TCR responses. HPK1 has multiple roles in immunity and is related to the pathogenesis of autoimmune diseases, cancer, and inflammatory responses. The proliferation of HPK1 kinase - / - T cells is much faster than that of the monomer wild type, and mice transfected with HPK1 kinase - / - T cells can resist the growth of cancer tumors. Moreover, dendritic cells (DCs) lacking the HPK1 kinase have better antigen presentation ability than wild type and can better exhibit anti-tumor immune responses. In addition, animal experimental studies have shown that the inhibition of HPK1 and PD-1 / PD-L1 antibody drugs have obvious synergistic anti-tumor activities. Therefore, the HPK1 kinase plays a key role in disease treatment, especially cancer treatment.

[0003] In recent years, significant progress has been made in the targeted protein degradation technology (PROTAC). This technology realizes the degradation of target proteins by inducing the ubiquitination of target proteins. Drugs using this technology can achieve target degradation at catalytic concentrations without continuously occupying the target protein, and have high selectivity, high activity, and low toxicity.

[0004] Currently, there are no drugs on the market for HPK1 target inhibitors. At the same time, HPK1 inhibitors have defects such as weak immune activation effect, narrow effective window, and cytotoxicity at high concentrations. Therefore, there is a need for further modification and optimization. To meet the huge future clinical needs, by designing and developing selective and highly active HPK1 degraders, new drugs are provided for immune-related diseases, especially cancer treatment, either alone or in combination with cancer chemotherapy, radiotherapy, cancer-targeted drugs, other cancer immunotherapeutic agents (small molecule compounds and antibodies), as well as cancer vaccines and CAR-T immunotherapy. Summary of the Invention

[0005] The object of the present invention is to provide a novel HPK1 degrader with selectivity and high activity, its stereoisomer, tautomer or pharmaceutically acceptable salt, which has not been reported in the literature.

[0006] The present invention relates to a class of HPK1 protein degraders that can degrade HPK1, its stereoisomer, tautomer or pharmaceutically acceptable salt, and their application in the preparation of preventing and / or treating diseases related to the activity or expression level of HPK1 protein, wherein the diseases include solid tumors, hematological diseases or autoimmune diseases.

[0007] The present invention provides a compound represented by the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt:

[0008]

[0009] Wherein:

[0010] Cy 1 is selected from: 5- to 12-membered heteroaryl or 8- to 10-membered fused bicyclic group;

[0011] Cy 2 is selected from: C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6 -C 10 aryl, 5- to 12-membered heteroaryl or 8- to 10-membered fused bicyclic group;

[0012] X 8 、X 9 each independently is selected from: CR a or N;

[0013] L 1 、L 2 each independently is selected from: chemical bond, C 1 -C 8 alkylene, C 3 -C 12 cycloalkylene, 3- to 12-membered heteroalkylene, -O-C1 -C 8 Alkylene, -C 1 -C 8 Alkylene - O -, - NR b -C 1 -C 8 Alkylene -, - C 1 -C 8 Alkylene - NR b -, - O -, - NR b C(O)-, - C(O)-NR b -, - CO -, - SO -, - SO 2 -, C 2 -C 8 Alkenylene or C 2 -C 8 Alkynylene;

[0014] R 1 Selected from: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 3 -C 12 Cycloalkyl, 3 - 12 - membered heterocyclic group, C 6 -C 10 Aryl, 5 - 12 - membered heteroaryl, oxo, - CN, - NO 2 , - OR b , - SO 2 R a , - SO 2 NR 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 CO 2 R c , - NR b SONR c R d , - NR b SO2 NR c R d 、 -NR b SO 2 R c , -SO(=NR b )R c 、 -POR b R c or -Linker - E3, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, 3 - 12 - membered heterocyclic group, C 6 -C 10 aryl, 5 - 12 - membered heteroaryl, halo - C 1 -C 8 alkyl, -C 1 -C 8 alkyl - CONR b R c 、 -C 1 -C 8 alkyl - NR b COR c 、 -C 1 -C 8 alkyl - OR b 、 oxo, -CN, -NO 2 、 -OR b 、 -SO 2 R a 、 -SO 2 NR 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 CO 2 Rc , -NR b SONR c R d , -NR b SO 2 NR c R d , -NR b SO 2 R c , -SO(=NR b )R c , -POR b R c ;

[0015] Or two Rs 1 together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3- to 8-membered ring, said 3- to 8-membered ring containing 0, 1 or 2 heteroatoms selected from N, O, S, P, and said 3- to 8-membered ring being optionally further substituted by one or more substituents selected from halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, amino, hydroxy, oxo, nitro, carboxyl or cyano;

[0016] R 2 is selected from: H, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6 -C 10 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -NO 2 , -OR b , -SO 2 R a , -SO 2 NR 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 CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R 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: halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 3 -C 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6 -C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SO 2 R a 、-SO 2 NR 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 、-NRb CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c ,-SO(=NR b )R c Or-POR b R c ;

[0017] Or two R 2 Together with the one or more atoms to which they are attached (provided that the valence theory is satisfied), they form a 3-8 membered ring, wherein the 3-8 membered ring contains 0, 1 or 2 heteroatoms selected from N, O, S, and P, and the 3-8 membered ring is optionally further substituted with one or more heteroatoms selected from halogen, C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, C 3 -C 12 Cycloalkyl, 3-12 membered heterocyclic group, C 1 -C 8 Alkoxy, C 1 -C 8 substituted by an alkylamino, amino, hydroxy, oxo, nitro, carboxyl or cyano substituent;

[0018] R 3 Selected from: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 3 -C 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6 -C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SO 2 R a 、-SO 2 NR 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 CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R 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: halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 3 -C 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6 -C 10 Aryl, 5-12 membered heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SO 2 R a 、-SO 2 NR 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 CONRc R d 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c ,-SO(=NR b )R c Or-POR b R c ;

[0019] Linker is selected from: -(CH 2 ) r -, one or more of the above CH 2 Optionally, 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-, -SO 2 -、-POR b -、C 3 -C 10 Cycloalkylene, 3-10 membered heterocyclylene, phenylene, 5-6 membered heteroarylene or -CR b R c -substituted by a group; the heterocyclic group may be further replaced by halogen, C 1 -C 3 Alkyl substitution;

[0020] E 3 Selected from: E 3 Ubiquitin ligase ligands;

[0021] R a Selected from: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2-C 8 Alkynyl, C 3 -C 12 Cycloalkyl, 3 - 12 membered heterocyclic group, C 6 -C 10 Aryl, 5 - 12 membered heteroaryl, oxo, -CN, -NO 2 , -OR b , -SO 2 R b , -SO 2 NR 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 CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d , -NR b SO 2 R c , -SO(=NR b )R c or -POR b R c , the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, 3 - 12 membered heterocyclic group, C 6 -C 10 aryl, 5 - 12 membered heteroaryl, oxo, -CN, -NO 2 , -OR b , -SO2 R b 、-SO 2 NR 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 CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c ,-SO(=NR b )R c Or-POR b R c ;

[0022] R b , R c , R d Each independently selected from: H, halogen, C 1 -C 8 Alkyl, C 2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, C 3 -C 12 Cycloalkyl, 3-12 membered heterocyclic group, C 6 -C 10 Aryl, 5-12 membered heteroaryl, halogenated C 1 -C 4 Alkyl, -C 1 -C 4 Alkyl-CONR e R f , -C 1 -C 3 Alkyl-OR e 、-OR eor -NR e R f , the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6 -C 10 aryl, 5- to 12-membered heteroaryl, halo C 1 -C 8 alkyl, -C 1 -C 8 alkyl-CONR e R f , -C 1 -C 8 alkyl-OR e , oxo, -CN, -NO 2 , -OR e , -SO 2 R e , -SO 2 NR 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 CO 2 R f , -NR e SONR f R g , -NR e SO 2 NR f R g , -NR e SO 2 R f , -SO(=NR e )R for -POR e R f ;

[0023] wherein R and R substituted on the same atom c and R b or R d and R c may be linked to form a ring, and the ring may be further substituted by one or more substituents selected from: halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6 -C 10 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -NO 2 , -OR e , -SO 2 R e , -SO 2 NR 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 CO 2 R f , -NR e SONR f R g , -NR e SO 2 NR f R g , -NR e SO 2 R f , -SO(=NR e )R f or -POR e R f ;

[0024] R e, R f , R g are each independently selected from: H, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6 -C 10 aryl, 5- to 12-membered heteroaryl; the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C 1 -C 8 alkyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6 -C 10 aryl, 5- to 12-membered heteroaryl, cyano, hydroxy, amino or nitro;

[0025] m, n, o, p are each independently selected from: 0, 1, 2, 3, 4, 5, 6;

[0026] r is selected from: an integer from 0 to 20.

[0027] r is preferably: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

[0028] A preferred embodiment of the present invention is a compound of the general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0029] where Cy 1 is selected from;

[0030]

[0031] wherein:

[0032] is a single bond or a double bond;

[0033] X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 10 are independently selected from O, S, C, CH, CH 2 , N, NH or CO; provided that the valence theory of the compound is satisfied;

[0034] X 7 selected from: CR a ’ or N;

[0035] R a ’ is selected from: H, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 6 -C 10 aryl, 5- to 12-membered heteroaryl, oxo, -CN, -NO 2 、-OH, -NH 2 、-O-C 1 -C 8 alkyl.

[0036] A preferred embodiment of the present invention is a compound represented by the general formula (IIa) or (IIb), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0037]

[0038] A preferred embodiment of the present invention is a compound represented by the general formula (IIIa) or (IIIb), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0039]

[0040] wherein:

[0041] X 1 is selected from: CH or N;

[0042] X 4 is selected from: NH or S;

[0043] X 8 、X 9 are independently selected from: CH, N or C-Me;

[0044] When is selected from a double bond, X 6 is C, X 5 can be CH, N; when is selected from a single bond, X 6 is N, CH, X 5 is CO, CH 2 ;

[0045] L 1 、L 2Each independently selected from: a chemical bond, -O-, -O-C 1 -C 3 an alkylene group or -C 1 -C 3 an alkylene group -O-;

[0046] Cy 2 Selected from:

[0047]

[0048] R 2 Selected from: H, halogen, C 1 -C 8 an alkyl group, C 2 -C 8 an alkenyl group, C 2 -C 8 an alkynyl group, C 3 -C 12 a cycloalkyl group, a 3- to 12-membered heterocyclic group, -CN, -NO 2 、-OR b 、-SO 2 R a 、-SO 2 NR 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 CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c ,-SO(=NR b )R c 、-POR b R c wherein the above alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclic groups may be further substituted by one or more substituents selected from: halogen, oxo, -CN, -OR b 、-NRb R c ;

[0049] m is selected from: 0, 1, 2, 3, 4, 5;

[0050] n is selected from: 0, 1, 2, 3.

[0051] A preferred embodiment of the present invention is a compound of the general formula (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0052]

[0053] Wherein:

[0054] X 1 is selected from: N or CH;

[0055] X 11 is selected from: N or CH;

[0056] R 1 is selected from: H, halogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclic group, C 6 -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 、SO 2 NR b R c 、cyano, oxo; the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl may be further substituted by halogen, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, halo C 1 -C 3 alkyl, -C 1 -C 3 alkyl-NR b COR c 、-C 1 -C 3 alkyl-CONR b R c 、-C 1 -C3 substituted by alkyl-OR b , hydroxyl, cyano, amino or nitro;

[0057] R 1 ’ is selected from: H, halogen, C 1 -C 4 alkyl, hydroxyl, cyano, amino, nitro;

[0058] or R 1 and R 1 ’ together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3- to 8-membered ring, the 3- to 8-membered ring containing 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3- to 8-membered ring is optionally further substituted by one or more substituents selected from halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, amino, hydroxyl, oxo, nitro, carboxyl or cyano;

[0059] or R 1 ’ and R 1 ’ together with one or more atoms to which they are attached (provided that the valence theory is satisfied) form a 3- to 8-membered ring, the 3- to 8-membered ring containing 0, 1 or 2 heteroatoms selected from N, O, S, P, and the 3- to 8-membered ring is optionally further substituted by one or more substituents selected from halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, amino, hydroxyl, oxo, nitro, carboxyl or cyano;

[0060] R b is selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5- to 7-membered heterocyclic group, C 6 -C 10an aryl or a 5- to 10-membered heteroaryl; the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl may be further substituted by C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxy, cyano, amino or nitro;

[0061] R c is selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, a 5- to 7-membered heterocyclic group, C 6 -C 10 aryl or a 5- to 10-membered heteroaryl; the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl may be further substituted by C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxy, cyano, amino or nitro;

[0062] R 2 is selected from: H or

[0063] n or m' is selected from: 0, 1, 2 or 3.

[0064] A preferred embodiment of the present invention is a compound of the general formula (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

[0065]

[0066] wherein:

[0067] R 1 is selected from: H, C 1 -C 3 alkyl, halogen, halo C 1 -C 3 alkyl, cyano, oxo, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl,

[0068]

[0069] R 1 ' is selected from: H, Cl, F, methyl, ethyl or cyano;

[0070] X 8 、X 9 each independently is selected from CR a or N;

[0071] R aSelected from: H, methyl, ethyl, isopropyl, F, methylamino, ethylamino, methoxy, ethoxy,

[0072]

[0073] n or m' is selected from: 0, 1, 2 or 3.

[0074] A preferred embodiment of the present invention is a compound of the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0075] Wherein:

[0076] Selected from:

[0077]

[0078] R 1 Selected from: H, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, C 6 -C 10 aryl, 5-6 membered heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SO 2 R a 、-SO 2 NR 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 CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d 、-NR b SO 2 R c, -SO(=NR b )R c , -POR b R c or -Linker-E3, where the above alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, 3-6 membered heterocyclic group, C 6 -C 10 aryl, 5-7 membered heteroaryl, halo C 1 -C 3 alkyl, -C 1 -C 3 alkyl-CONR b R c , -C 1 -C 3 alkyl-NR b COR c , -C 1 -C 3 alkyl-OR b , oxo, -CN, -NO 2 , -OR b , -SO 2 R a , -SO 2 NR 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 CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d , -NR b SO 2 R c,-SO(=NR b )R c 、-POR b R c ;

[0079] Or two Rs 1 together with one or more atoms to which they are attached (provided that valence theory is satisfied) form a 3- to 8-membered ring, said 3- to 8-membered ring containing 0, 1 or 2 heteroatoms selected from N, O, S, P, and said 3- to 8-membered ring being optionally further substituted by one or more substituents selected from halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 12 cycloalkyl, 3- to 12-membered heterocyclic group, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, amino, hydroxy, oxo, nitro, carboxy or cyano;

[0080] m is selected from: 0, 1, 2, 3, 4, 5;

[0081] R b 、R c 、R d are each independently selected from: H, halogen, methyl, ethyl, propyl, isopropyl, C 3 -C 6 cycloalkyl, 5- to 7-membered heterocyclic group, C 6 -C 10 aryl, 5- to 6-membered heteroaryl, halo C 1 -C 4 alkyl, -C 1 -C 4 alkyl-CON(CH 3 ) 2 、-C 1 -C 3 alkyl-OCH 3 、-OR e or -NR e R f , and said methyl, ethyl, propyl, isopropyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally further substituted by one or more substituents selected from: halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocyclic group, C 6 -C 10 aryl, 5- to 6-membered heteroaryl, halo C 1-C 4 alkyl, -C 1 -C 4 alkyl-CON(CH 3 ) 2 、-C 1 -C 3 alkyl-OCH 3 、oxo, -CN, -NO 2 、-OH, -NH 2 。

[0082] A preferred embodiment of the present invention is a compound represented by the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0083] Wherein:

[0084] Selected from:

[0085]

[0086]

[0087] R 1 Selected from: H, C 1 -C 3 alkyl, halogen, halo-C 1 -C 3 alkyl, cyano, oxo, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl,

[0088]

[0089] A preferred embodiment of the present invention is a compound represented by the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0090] Wherein:

[0091] Selected from:

[0092]

[0093]

[0094] A preferred embodiment of the present invention is a compound represented by the general formula VI or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0095]

[0096] X 13 Selected from: NH or O;

[0097] X 1Selected from: CH or N;

[0098] R 10 Selected from: H, halogen, C 1 -C 4 alkyl, halo-C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, cyano, amino or nitro;

[0099] R 10’ Selected from: H, halogen, C 1 -C 4 alkyl, C 3 -C 5 cycloalkyl or 3-8 membered heterocyclic group, halo-C 1 -C 4 alkyl, -C 1 -C 4 alkyl-CONR b R c 、-C 1 -C 8 alkyl-OR b 、oxo or -CN, and the alkyl, cycloalkyl or heterocyclic group is optionally further substituted by one or more substituents selected from halogen, C 1 -C 8 alkyl, -CN, -CONR b R c 、-NR b COR c 、-OR b of the substituents.

[0100] Preferably, R 10’ Selected from: H, halogen, cyano, oxo, methyl, ethyl, propyl, isopropyl, isobutyl, -CH 2 F, -CHF 2 、-CF 3 、-CH 2 CH 2 F, -CH 2 CHF 2 、-CH 2 CF 3 、cyclopropyl, cyclobutyl, cyclopentyl,

[0101] R 2 Selected from: H, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group, -CN, -NO 2 、-ORb , -NR b R c , the above-mentioned alkyl, cycloalkyl, and heterocyclic groups may be further substituted by one or more substituents selected from halogen, oxo, -CN, -OR b , -NR b R c ;

[0102] R b is selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5-7 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered heteroaryl; the above-mentioned alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl may be further substituted by halogen, C 1 -C 3 alkyl, hydroxy, cyano, amino or nitro;

[0103] R c is selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5-7 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered heteroaryl; the above-mentioned alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl may be further substituted by halogen, C 1 -C 3 alkyl, hydroxy, cyano, amino or nitro;

[0104] q or q' is selected from: 0, 1, 2 or 3;

[0105] Cy 2 is selected from: 5-membered heteroaromatic rings containing 1-3 heteroatoms.

[0106] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy 2 the above-mentioned 5-membered heteroaromatic ring is preferably selected from:

[0107]

[0108] Preferably, Cy 2 is selected from

[0109] In a preferred embodiment of the present invention, a compound of general formula VII or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

[0110]

[0111] CyA is selected from: phenyl, 5- to 10-membered heteroaryl, or 8- to 10-membered fused bicyclic group;

[0112] The heteroaryl selected from by CyA is preferably selected from:

[0113] The fused bicyclic group is preferably selected from:

[0114]

[0115] R A1 is selected from H, halogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, 3- to 10-membered heterocyclic group, C 6 -C 10 aryl, 5- to 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 group, aryl, and heteroaryl may be further substituted by halogen, C 1 -C 3 alkyl, hydroxyl, cyano, amino, or nitro;

[0116] R B is selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5- to 7-membered heterocyclic group, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl; The alkyl, cycloalkyl, heterocyclic group, aryl, or heteroaryl may be further substituted by C 1 -C 3 alkyl, hydroxyl, cyano, amino, or nitro;

[0117] R C is selected from: H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5- to 7-membered heterocyclic group, C 6 -C 10An aryl or a 5- to 10-membered heteroaryl; the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl may be further substituted by C 1 -C 3 alkyl, hydroxy, cyano, amino or nitro;

[0118] q is selected from: 0, 1, 2 or 3.

[0119] X 1 、X 8 、X 9 、R 2 、n, Linker, E3 are defined as described in formula (I).

[0120] In a preferred embodiment of the present invention, X 8 、X 9 are each independently selected from CRa, N;

[0121] Ra is selected from: H, halogen, methyl, ethyl, isopropyl, methoxy, ethoxy.

[0122] L 1 is selected from: a chemical bond, -O-, -CH 2 -O-.

[0123] In a preferred embodiment of the present invention, the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Linker is selected from:

[0124]

[0125]

[0126]

[0127] In a preferred embodiment of the present invention, Linker is preferably selected from:

[0128]

[0129] In a preferred embodiment of the present invention, the compound or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein E 3 is selected from:

[0130]

[0131]

[0132] wherein,

[0133] q, u or s are each independently selected from: 0, 1 or 2;

[0134] Y 1Independently selected from: CO, methylene, vinyl or ethyl;

[0135] Y 2 Independently selected from: CH or N;

[0136] Y 3 Independently selected from: absent, CH 2 , NH, NMe or O;

[0137] Y 4 Independently selected from: CH or N;

[0138] Y 5 Independently selected from: CH or N;

[0139] R 4 、R 5 、R 6 、R 7 、R 8 、R 9 Each independently selected from: H, halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 5- to 12-membered heterocyclic group, 6- to 10-membered aryl group, 5- to 10-membered heteroaryl group, oxo, -CN, -NO 2 、-OR b 、-SO 2 R a 、-SO 2 NR 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 CO 2 R c 、-NR b SONR c R d 、-NR b SO 2NR c R d 、 -NR b SO 2 R c , -SO(=NR b )R c 、 -POR b R c , The above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl groups may be further substituted by one or more substituents selected from: halogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, 5 - 12 membered heterocyclic, 6 - 10 membered aryl, 6 - 10 membered heteroaryl, oxo, -CN, -NO 2 、 -OR b 、 -SO 2 R b 、 -SO 2 NR 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 CO 2 R c 、 -NR b SONR c R d 、 -NR b SO 2 NR c R d 、 -NR b SO 2 R c , -SO(=NR b )R c or -POR b R c ;

[0140] 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 ;

[0141] R f , R g , R h Each is independently selected from: H, C 1 -C 8 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, C 1 ~C 6 alkyl 3- to 8-membered cycloalkyl, C 1 ~C 6 alkyl 3- to 8-membered heterocyclic group;

[0142] Cy 3 is selected from:

[0143]

[0144] Cy 4 is selected from:

[0145]

[0146] Cy 5 is selected from:

[0147]

[0148] In a preferred embodiment of the present invention, the compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein E3 is selected from:

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] In a preferred embodiment of the present invention, E3 is preferably selected from:

[0155]

[0156] As a more specific option, X 8 and X 9 are each independently selected from: CR a or N; wherein Ra is selected from H, C 1 -C 3 alkyl, -CH 2 N(CH 3 ) 2 , halogen, -NHCH 3 , -O C 1 -C 3 alkyl.

[0157] is selected from

[0158] L 1 and L 2 are each independently selected from a chemical bond, O, -OCH 2 -.

[0159] In a preferred embodiment of the present invention, the compounds of general formula (I) are selected from:

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0176] It should be noted that when specific compounds are involved in the present invention, the numbers corresponding to the compounds below the compounds (such as 115 in the above table) correspond to the corresponding compounds; when the compound numbers are mentioned in the rest of this article, they all refer to the corresponding compounds. For example, "Compound 115" corresponds to the compound structure corresponding to number 115.

[0177] In addition, in the same group, for substituents represented by the same letter at different positions, the substituents corresponding to these different positions are independent of each other and can be the same or different. For example, for the two N atoms before and after "-NR b CONR b -", the Rs on them b can be the same or different, and the above explanation also applies to other similar cases.

[0178] In different groups, when substituents represented by the same letter appear, the same letter in different substituents is independent of each other and has no restrictive effect on each other, and can be the same or different. For example, in R 1 、L 1 、L 2 、R 2 、Linker、R 3 and so on, there are limitations on R b ; in R 1 、L 1 、L 2 、R 2 、Linker、R 3 and so on, the Rs in them b are independent of each other and can be the same or different.

[0179] The present invention provides a pharmaceutical composition, which contains a therapeutically effective dose of a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to any one of general formulas (I), (VI), (IIa), (IIb), (IIIa), (IIIb), (IV), (V) or (VII), and a pharmaceutically acceptable carrier, excipient or a composition thereof.

[0180] The pharmaceutical carrier provided by the present invention can be 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 preparations, preferably having sufficient purity and sufficiently low toxicity, 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, binder, disintegrant, lubricant, aqueous solvent or non-aqueous solvent, etc.

[0181] The pharmaceutical preparation provided by the present invention can be made into any pharmaceutically acceptable dosage form and administered to patients or subjects in need of such treatment by any suitable administration method, such as oral, parenteral, rectal or pulmonary administration. When used for oral administration, it can be made into solid dosage forms, such as capsules, tablets, pills, lozenges, dragees, granules, powders, ointments, creams, drops, etc.; it can also be made into liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays, etc. When used for parenteral administration, it can be made into injections, sterile powders for injection, etc.

[0182] The present invention provides the use of a compound of the general formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V) or (VII), or its stereoisomer, tautomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for degrading HPK1 protein.

[0183] The present invention provides the use of a compound of the general formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V) or (VII), or its stereoisomer, tautomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to the activity or expression level of HPK1 protein, wherein the diseases include solid tumors, hematological diseases or autoimmune diseases.

[0184] The present invention provides the use of a compound of general formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV), (V) or (VII), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for preventing and / or treating a disease related to the activity or expression level of HPK1 protein. The solid tumor diseases include, but are not limited to, one or more of lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, in situ cancer, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testis, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, large intestinal villous adenoma, melanoma, cell tumor and sarcoma; The autoimmune diseases include, but are not limited to, one or more of inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord'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 arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, familial dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma or vulvodynia and chronic graft-versus-host. The hematological diseases include, but are not limited to, one or more of acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelofibrosis, myelodysplastic syndrome, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, multiple myeloma, T-cell lymphoma;

[0185] Term Explanation

[0186] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0187] "Bond" means that the indicated substituent does not exist, and the two ends of the substituent are directly connected to form a bond.

[0188] "Alkyl", when regarded as a group or part of a group, means including C 1 -C 20A straight-chain or branched aliphatic hydrocarbon group. Preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 8 alkyl group. Examples of the alkyl group 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.

[0189] "Alkylene" refers to a divalent alkyl group, where the alkyl group is as defined above. The alkylene preferably has 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably contains 1 to 6 carbon atoms (i.e., C 1-6 alkylene), and further preferably contains 1 to 4 carbon atoms (i.e., C 1-4 alkylene). Non-limiting examples of the alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 ))-), 1,2-ethylene (-CH 2 CH 2 ))-, 1,1-propylene (-CH(CH 2 CH 3 ))-), 1,2-propylene (-CH 2 CH(CH 3 ))-), 1,3-propylene (-CH 2 CH 2 CH 2 -), and 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -). The alkylene may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituents may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclic group, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo group.

[0190] "Alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, which can be straight-chain or branched. It is preferably C 2 -C 10 alkenyl, more preferably C 2 -C 8 alkenyl. Representative examples include, but are not limited to, vinyl,

[0191]

[0192] etc. The alkenyl can be substituted or unsubstituted.

[0193] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight-chain or branched. It is preferably C 2 -C 10 alkynyl, more preferably C 2 -C 8 alkynyl, most preferably C 2 -C 4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl,

[0194] etc. The alkynyl can be substituted or unsubstituted.

[0195] "Alkenylene" refers to a divalent straight-chain or branched aliphatic hydrocarbon group containing one or more carbon-carbon double bonds, which contains a specified number of carbon atoms, such as 2 to 8 carbon atoms, such as -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, etc. The alkenylene can optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0196] "Alkynylene" is a divalent straight-chain or branched hydrocarbon group having one or more carbon-carbon triple bonds, which contains a specified number of carbon atoms, such as 2 to 8 carbon atoms, including but not limited to, etc. The alkynylene can optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

[0197] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused-ring, bridged-ring, and spiro carbon ring. It is preferably C 3 -C 12 cycloalkyl, more preferably C 3 -C 8 cycloalkyl, most preferably C 3 -C 6 cycloalkyl. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. The cycloalkyl can be substituted or unsubstituted.

[0198] "Subcycloalkyl" refers to a divalent saturated or partially saturated monocyclic, fused-ring, bridged-ring, and spiro-ring carbocyclic ring, and is connected to a group through a single bond and to other groups through another single bond, such as C 3-10 Subcycloalkyl A subcycloalkyl having 3 to 10 carbon atoms, C 3-6 Subcycloalkyl A subcycloalkyl having 3 to 6 carbon atoms; common subcycloalkyls 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.

[0199] "Spiroalkyl" refers to a polycyclic group having 5 to 18 members, two or more cyclic structures, and sharing a single carbon atom (called a spiro atom) between monocyclic rings. One or more double bonds may be contained within the rings, but none of the rings is aromatic. It is preferably 6 to 14 members, more preferably 7 to 10 members. Spiropolyalkyls are classified into monospiro, dispiro, or polyspiroalkyls according to the number of spiro atoms shared between rings, preferably monospiro and dispiroalkyls, preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered. 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.

[0200] "Fused-ring alkyl" refers to a fully carbon polycyclic group having 5 to 18 members, 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 is aromatic. It is preferably 6 to 12 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-ring alkyls, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyls. Examples of "fused-ring alkyl" 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 tetradecahydrophenanthryl.

[0201] "Bridged-ring alkyl" refers to a fully carbon polycyclic group having 5 to 18 members, containing two or more cyclic structures sharing two non-adjacent carbon atoms. One or more rings may contain one or more double bonds, but none of the rings is aromatic. It is preferably 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-ring alkyls, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Examples of "bridged-ring alkyl" 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, bicyclo[1.1.1]pentyl.

[0202] "Heterocyclic group", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more ring-forming atoms are heteroatoms such as N, O, S, P, Se, including monocyclic, fused-ring, bridged-ring and spiro-ring, and one or more double bonds may be contained in the ring. It preferably has 3 to 12 ring atoms, more preferably a 4- to 7-membered monocyclic or 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), Se. Examples of "heterocyclic group" 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. The heterocyclic group may be substituted or unsubstituted.

[0203] "Heterocyclylene" refers to a divalent non-aromatic heterocyclic group in which one or more ring-forming atoms are heteroatoms such as N, O, S, P, Se, including monocyclic, fused-ring, bridged-ring and spiro-ring, and one or more double bonds may be contained in the ring, connected to one group through a single bond and to other groups (or ring systems) through another single bond, for example a 3- to 10-membered heterocyclylene, 3- to 7-membered heterocyclylene or 4- to 10-membered heterocyclylene; common heterocyclylenes include (but are not limited to) oxirane-2,2-ylidene, oxirane-2,3-ylidene, azetidine-2,2-ylidene, azetidine-2,3-ylidene, azetidine-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, etc.

[0204] "Spiroheterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and the single rings share one atom with each other, and one or more double bonds may be contained in the ring, but none of the rings has aromaticity, and one or more ring atoms are selected from one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O)m (where m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. It is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclic group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group according to the number of spiro atoms shared between rings, preferably a monospiroheterocyclic group and a dispiroheterocyclic group. 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 monospiroheterocyclic group. Examples of the "spiroheterocyclic group" 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.

[0205] The "fused heterocyclic group" refers to a fully carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings is aromatic, and one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. It is preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of the "fused heterocyclic group" include but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine.

[0206] The "bridged heterocyclic group" refers to a polycyclic group having 5 to 18 members, containing two or more cyclic structures sharing two non-directly connected atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings is aromatic, and one or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1 or 2), P(O) m (where m is selected from 0 or 1), a heteroatom of Se, and the remaining ring atoms are carbon. It is preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, and more preferably a bicyclic or tricyclic group. Examples of the "bridged heterocyclic group" 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.

[0207] "Aryl" means 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 aryl groups, such as phenyl, naphthyl, and the aromatic groups of tetrahydronaphthyl. Preferably, the aryl is C 6 -C 10 aryl, more preferably the aryl is phenyl and naphthyl, and most preferably is phenyl. The aryl may be substituted or unsubstituted.

[0208] "Arylene" refers to an aryl as defined herein, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent aryl. Typical arylenes include, but are not limited to, phenylene and naphthylene.

[0209] "Heteroaryl" and "heteroaromatic ring" are used interchangeably in this application and both 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, 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 may be substituted or unsubstituted.

[0210] "Heteroarylene" refers to a heteroaryl as described above, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent heteroaryl or by removing one hydrogen atom from a carbon atom and one hydrogen atom from a nitrogen atom.

[0211]

[0212] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms. One or more rings may contain one or more double bonds, but at least one ring is not aromatic and at least one ring is aromatic. Among the ring atoms, 0, 1, or more ring atoms are selected from N, O, S(O) n (where n is selected from 0, 1, or 2), P(O) m(where 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, and the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. It is preferably 7 to 14 members, more preferably 9 to 10 members. Examples of the "fused ring" include, but are not limited to:

[0213]

[0214]

[0215] The fused ring may be substituted or unsubstituted.

[0216] "Alkoxy" refers to a group of (alkyl-O-). Among them, the alkyl group is as defined herein. C 1 -C 8 alkoxy is preferred. Examples thereof include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. The alkoxy may be substituted or unsubstituted.

[0217] "Alkenyloxy" refers to a group of (alkenyl-O-). Among them, the alkenyl group is as defined herein. C 2 -C 8 alkenyloxy is preferred. The alkenyloxy may be substituted or unsubstituted.

[0218] "Hydroxyalkyl" is a group of (-alkyl-OH). Among them, the alkyl group is as defined herein. C 1 -C 8 hydroxyalkyl is preferred. Examples thereof include, but are not limited to: hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, etc. The hydroxyalkyl may be substituted or unsubstituted.

[0219] "Alkylamino" refers to a group of (alkyl-NH-). Among them, the alkyl group is as defined herein. C 1 -C 8 alkylamino is preferred. Examples thereof include, but are not limited to: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutoxy, tert-butoxy, etc. The alkylamino may be substituted or unsubstituted, and the substituent may be on the alkyl group or on the N, such as the examples: dimethylamino, diethylamino.

[0220] "Aminoalkyl" refers to a group of (-alkyl-NH 2 ). Among them, the alkyl group is as defined herein. Examples thereof include, but are not limited to: aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminopentyl, etc. The aminoalkyl may be substituted or unsubstituted, and the substituent may be on the alkyl group or on the N, such as the example: dimethylaminoalkyl.

[0221] "Alkylcarbonyl" refers to the group of (alkyl-C(O)-). Among them, the definition of alkyl is as described in this article. Its examples include, but are not limited to: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, etc. Alkylcarbonyl can be substituted or unsubstituted.

[0222] "Alkoxycarbonyl" refers to the group of (alkyl-O-C(O)-). Among them, the definition of alkyl is as described in this article. Its examples include, but are not limited to: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc. Alkoxycarbonyl can be substituted or unsubstituted.

[0223] "Haloalkyl" refers to an alkyl group substituted by a halogen. Among them, the definitions of halogen and alkyl are as described in this article.

[0224] "Haloalkoxy" refers to an alkoxy group substituted by a halogen. Among them, the definitions of halogen and alkoxy are as described in this article.

[0225] "Halo-hydroxyalkyl" refers to a hydroxyalkyl group substituted by a halogen. Among them, the definitions of halogen and hydroxyalkyl are as described in this article.

[0226] "Halo-alkylamino" refers to an alkylamino group substituted by a halogen. Among them, the definitions of halogen and alkylamino are as described in this article.

[0227] "Cycloalkoxy" refers to the group of (cycloalkyl-O-). Among them, the definition of cycloalkyl is as described in this article.

[0228] "Hetero-epoxy" refers to the group of (heterocyclic-O-). Among them, the definition of heterocyclic is as described in this article.

[0229] "Hydroxy" refers to the -OH group.

[0230] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0231] "Amino" refers to -NH 2 。

[0232] "Cyano" refers to -CN.

[0233] "Nitro" refers to -NO 2 。

[0234] "Carboxyl" refers to -C(O)OH.

[0235] "Amide" refers to -C(O)NH 2 。

[0236] "Substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0237] As used herein, the term "substituted" or "substitution", unless otherwise specified, means that a group can be substituted by one or more groups selected from the following: H, deuterium, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkenyloxy, C 3 -C 12 cycloalkyl, C 3 -C 8 cycloalkoxy, 3- to 12-membered heterocyclic group, 3- to 12-membered heterocyclic oxy group, aminosulfonyl, C 6 -C 10 aryl, 5- to 12-membered heteroaryl, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, C 1 -C 8 alkylamino, C 1 -C 8 haloalkylamino, -OR g 、-SR g 、-C 1 -C 8 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(CH 3 )R g 、-N(R x )C(O)R y 、-N(R x )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) 2 NR x R y 、 -N(R x )S(O) 2 R g 、 -S(O)R g 、 -S(O) 2 R g 、 -S(O) 2 NR x R y 、 -P(O)R x R y ; The alkyl, alkylene, alkoxy, alkenyl, alkynyl, alkenyloxy, cycloalkyl, cycloalkoxy, heterocyclic group, heterocyclic oxy group, aryl, heteroaryl, 3 - 12 - membered ring, amino, hydroxyl or amide is optionally further substituted by one or more R o substituents;

[0238] When two R o substitute on the same atom, the two R o together with the atom to which they are attached form a 3 - 6 - membered ring, or when two R o substitute on adjacent atoms, the two R o together with the atoms to which they are attached form a 3 - 12 - membered ring;

[0239] R g 、R x 、R y 、R o are each independently selected from H, deuterium, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 alkenyloxy, C 3 -C 12 cycloalkyl, C 3 -C 8 cycloalkoxy, 3 - 12 - membered heterocyclic group, 3 - 12 - membered heterocyclic oxy group, aminosulfonyl, C 6 -C 10 aryl, 5 - 12 - membered heteroaryl, cyano, amino, nitro, hydroxyl, oxo, carboxyl, amide, hydroxyalkyl, aminoalkyl, alkcarbonyl, alkoxycarbonyl, C1 -C 8 alkylamino, C 1 -C 8 haloalkylamino, -OR s 、-SR s 、-C 1 -C 8 alkylene-R s 、-OC(O)R s 、-C(O)R s 、-C(O)OR s 、-C(O)N(R s )R t 、-NR s R t 、-N(CH 3 )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) 2 NR s R t 、-N(R s )S(O) 2 R t 、-S(O)R s 、-S(O) 2 R s 、-S(O) 2 NR s R t or -P(O)R s R t ,wherein the alkyl, alkylene, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more R r ;

[0240] When two R r are substituted on the same atom, the two R r together with the atom to which they are attached form a 3- to 6-membered ring, or when two R r are substituted on adjacent atoms, the two R r together with the atoms to which they are attached form a 3- to 12-membered ring;

[0241] R r 、R s 、Rt Each independently selected from H, deuterium, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, halogen, cyano, amino, nitro, hydroxy, oxo, C 1 -C 8 alkoxy, C 1 -C 8 haloalkyl, hydroxyalkyl, aminoalkyl, C 1 -C 8 alkylamino, alkylcarbonyl, alkoxycarbonyl, halo-hydroxyalkyl, C 1 -C 8 haloalkylamino, C 3 -C 12 cycloalkyl, 3- to 12-membered heteroaryl, carboxyl, amide, C 6 -C 10 aryl or 5- to 12-membered heteroaryl.

[0242] The compounds of the present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereoisomers, enantiomers, atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0243] Unless otherwise indicated, the structures described in the present invention also include all isomers of such structures (e.g., diastereoisomers, enantiomers, atropisomers and geometric (conformational) isomeric forms; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Thus, individual stereoisomers of the compounds of the present invention, as well as mixtures of enantiomers, mixtures of diastereoisomers and mixtures of geometric (conformational) isomers are within the scope of the present invention.

[0244] C, H, O, S, N, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention all include their isotopic situations. At the same time, C, H, O, S, N, F, Cl, Br, I involved in the groups and compounds of the present invention may optionally be substituted by one or more of their corresponding isotopes, including but not limited to isotopes of carbon 12 C, 13 C, 14 C, the isotopes of hydrogen protium (H), deuterium (D), tritium (T), and the isotopes of oxygen 16 O, 17 O, 18 O, the isotopes of sulfur32 S, 33 S, 34 S, 36 S, isotopes of nitrogen 14 N, 15 N, isotopes of fluorine 17 F, 19 F, isotopes of chlorine 35 Cl, 37 Cl, isotopes of bromine 79 Br, 81 Br, etc.

[0245] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not restrictive of any claims. It should be noted that in the specification and the appended claims, unless otherwise indicated in the text, singular forms such as "a", "an", "the" include plural referents. It should also be noted that unless otherwise stated, "or" means "and / or". In addition, terms such as "comprising", "including" and the like are not restrictive.

[0246] "Pharmaceutically acceptable salts" refer to certain salts of the above compounds that can maintain their original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by formula (I) can be metal salts, salts formed with suitable acids or salts formed with suitable bases. A preferred class of salts are the salts formed by the compounds of the present invention with acids. Acids suitable 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, carbonic acid, etc.; 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, lycium acid, isonicotinic acid, salicylic acid, ascorbic acid, gentisic acid, gluconic acid, pyruvic acid, naphthalenesulfonic acid, stearic acid, phenylacetic acid, p-aminobenzenesulfonic acid, 2-hydroxyethanesulfonic acid, pamoic acid, tannic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. A preferred class of salts are the salts formed by the compounds of the present invention with bases. Bases suitable for forming salts include, but are not limited to: inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, etc.; organic bases such as ammonia, triethylamine, diethylamine, piperazine, guanidine, diethanolamine, etc.

[0247] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, "administration" and "treatment" mean 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 the contact of a reagent with the cells, as well as the contact of a reagent with a fluid that contacts the cells. The terms "administer" and "treat" also mean in vitro and ex vivo treatment of, for example, cells by a reagent, diagnostic agent, binding compound, or by another cell. As used herein, the term "subject" includes any living organism, preferably an animal, more preferably a mammal (e.g., rats, mice, dogs, cats, and rabbits), and most preferably a human.

[0248] "Effective amount" or "therapeutically effective amount" means an amount of an active ingredient, such as a compound, that is sufficient to effect treatment of a disease or at least one clinical symptom of a disease or disorder when the compound is administered to a subject to treat the disease or disorder. The "therapeutically effective amount" can vary with: the compound, the disease, the disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and / or symptom 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 case, the appropriate amount will be apparent to those of ordinary skill 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 and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof disclosed herein that is effective to "treat" (as defined above) a disease or disorder in a subject. In the case of combination therapy, a "therapeutically effective amount" means the total amount of the combination components that is effective to treat a disease, disorder, or condition.

[0249] "Pharmaceutical carrier" means 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, the pharmaceutical carrier can be a filler, binder, disintegrant, lubricant, aqueous solvent, or non-aqueous solvent, etc. The amount of the active ingredient capable of producing a single dosage form by combination with the carrier substance generally refers to the amount of the compound capable of producing a therapeutic effect.

[0250] "Pharmaceutical preparation" refers to any pharmaceutically acceptable dosage form, administered by any suitable route of administration, such as locally, orally, transdermally, rectally, vaginally, parenterally, intranasally, intralungally, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracutaneously, intraperitoneally, subcutaneously, subcuticularly or by inhalation, etc., to a patient or subject in need of such treatment. The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, liquid preparations 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 and a suitable non-toxic pharmaceutically acceptable carrier for mixing and preparing the tablets. For parenteral administration, the pharmaceutical composition may be a solution, aqueous solution, oily suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays or injections, more preferably tablets or capsules. The pharmaceutical composition may be a single unit dosage with an accurate dose. In addition, the pharmaceutical composition may also contain other active ingredients. The dosage forms for local or transdermal administration 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 sterile conditions and may be mixed with any preservatives, buffers or propellants that may be required.

[0251] The term "disease" refers to any disease, discomfort, illness, symptom or indication and may be interchangeable with the terms "condition" or "disorder".

[0252] The experimental verification results show that the compounds of the present invention have good inhibitory activity against HPK1 kinase.

[0253] The experimental verification results show that the compounds of the present invention have a strong ability to degrade HPK1 protein.

[0254] The experimental verification results show that the compounds of the present invention have high selectivity for HPK1 protein degradation.

[0255] The experimental verification results show that the compounds of the present invention have good exposure after oral administration. Detailed implementation mode

[0256] Chemical substances represented by some abbreviations in the present invention: DCM: dichloromethane; DMF: N,N-dimethylformamide; HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; H 2 SO 4 : sulfuric acid; STAB: sodium triacetoxyborohydride; Dioxane: dioxane; Pd(dppf)Cl 2: Dichloropalladium(II) bis(diphenylphosphino)ferrocene; Pd / C: Palladium on carbon.

[0257] Synthesis of Intermediate A1 in Example 1

[0258]

[0259] Synthesis Step 1: Synthesis of A1-1

[0260] Dissolve 4-bromobenzoic acid (3 g, 15.00 mmol) in DCM (30 mL). To the system, successively add dimethylamine (810 mg, 18.00 mmol), HATU (8.55 g, 22.50 mmol), and triethylamine (3.04 g, 30 mmol), and react at room temperature for 5 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 2.2 g of A1-1 is obtained by column chromatography with a yield of 65%. ESI-MS (M+H) + = 228.0.

[0261] Synthesis Step 2: Synthesis of A1

[0262] Dissolve A1-1 (2.00 g, 8.81 mmol) in dioxane (20 mL). To the system, successively add bis(pinacolato)diboron (3.34 g, 13.21 mmol), dichloropalladium(II) bis(diphenylphosphino)ferrocene (644 mg, 0.88 mmol), and potassium acetate (2.60 g, 26.43 mmol), and react at 80 °C under nitrogen protection for 4 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 1.5 g of A1 is obtained by column chromatography with a yield of 67%. ESI-MS (M+H) + = 276.2.

[0263] Refer to the synthetic route and method of Intermediate A1 to synthesize the following intermediate compounds:

[0264]

[0265] Refer to the synthetic method of Synthesis Step 2 of Intermediate A1 to synthesize the following intermediate compounds:

[0266]

[0267] Synthesis of Intermediate A10 in Example 2

[0268]

[0269] Synthesis Step 1: Synthesis of A10-1

[0270] Dissolve tert-butyl 4-(4-bromopyrazol-1-yl)piperidine-1-carboxylate (3 g, 9.09 mmol) in dioxane (30 mL), add 1,4-dioxane solution of HCl (30 ml, 4 mol / L) to the system, and react at room temperature for 5 h. After the reaction is completed, concentrate under reduced pressure to obtain 2.3 g of crude product A10-1, and the yield is 95%. ESI-MS (M+H) + = 230.0

[0271] Synthesis step 2: Synthesis of A10-2

[0272] Dissolve A10-1 (2 g, 8.70 mmol) in DCM (20 mL), add cyclobutanone (1 ml, 13.05 mmol) to the system, stir at room temperature for 0.5 h, add STAB (5.5 g, 26.10 mmol), and react at room temperature for 3 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 1.8 g of A10-2 is obtained by column chromatography, and the yield is 82%. ESI-MS (M+H) + = 284.1

[0273] Synthesis step 3: Synthesis of A10

[0274] The synthesis of A10 refers to the synthesis method in synthesis step 2 of intermediate A1

[0275] Referring to the synthesis method in synthesis step 2 of intermediate A10, the following intermediate compounds are synthesized

[0276]

[0277] Synthesis of intermediate A15 in Example 3

[0278]

[0279] Synthesis step 1: Synthesis of A15-1

[0280] The synthesis of A15-1 refers to the synthesis method in synthesis step 1 of intermediate A10

[0281] Synthesis step 2: Synthesis of A15-2

[0282] Dissolve A15-1 (2 g, 8.70 mmol) in DMF (20 mL), successively add cesium carbonate (5.7 g, 17.4 mmol) and iodoethane (1 ml, 13.05 mmol) to the system, and stir at room temperature for 2 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 1.6 g of A15-2 is obtained by column chromatography, and the yield is 71%. ESI-MS (M+H) += 258.1。

[0283] Synthesis Step 3: Synthesis of A15

[0284] The synthesis of A15 refers to the synthesis method in Step 2 of the synthesis of Intermediate A1.

[0285] Referring to the synthesis method of Intermediate A15, the following intermediate compounds were synthesized:

[0286]

[0287]

[0288] Synthesis of Intermediate B1 in Example 4

[0289]

[0290] Synthesis Step 1: Synthesis of B1-1

[0291] Dissolve 5-bromo-2-iodo-1,3-dimethylbenzene (3 g, 9.71 mmol) in dioxane (30 mL) and water (6 mL). To the system, sequentially add N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (3.6 g, 11.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (710 mg, 0.97 mmol), and sodium carbonate (3.1 g, 29.13 mmol). React at room temperature for 5 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 2.1 g of B1-1 was obtained by column chromatography with a yield of 59%. ESI-MS (M+H) + = 366.1。

[0292] Synthesis Step 2: Synthesis of B1

[0293] Dissolve B1-1 (2.00 g, 5.48 mmol) in dioxane (20 mL). To the system, sequentially add bis(pinacolato)diboron (2.1 g, 8.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (401 mg, 0.55 mmol), and potassium acetate (1.6 g, 16.44 mmol). React at 80 °C under nitrogen protection for 4 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 1.5 g of B1 was obtained by column chromatography with a yield of 66%. ESI-MS (M+H) + = 414.3。

[0294] Referring to the synthesis route and method of Intermediate B1, the following intermediate compounds were synthesized:

[0295]

[0296]

[0297] Synthesis of Intermediate B6 in Example 5

[0298]

[0299] Synthesis Step 1: Synthesis of B6-1

[0300] The synthesis of B6-1 refers to the synthesis method of Step 1 in the synthesis of Intermediate B1.

[0301] Synthesis Step 2: Synthesis of B6-2

[0302] Dissolve B6-1 (2.00 g, 5.48 mmol) in dichloromethane (20 mL). To the system, successively add dimethylamine (370 mg, 8.22 mmol) and STAB (3.5 g, 16.44 mmol), and react at room temperature for 5 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 1.5 g of B6-2 is obtained by column chromatography, and the yield is 70%. ESI-MS (M+H) + = 395.1.

[0303] Synthesis Step 3: Synthesis of B6

[0304] The synthesis of B6 refers to the synthesis method of Step 2 in the synthesis of Intermediate B1.

[0305] Synthesis of Intermediate B7 in Example 6

[0306]

[0307] Synthesis Step 1: Synthesis of B7-1

[0308] The synthesis of B7-1 refers to the synthesis method of Step 1 in the synthesis of Intermediate B1.

[0309] Synthesis Step 2: Synthesis of B7-2

[0310] Dissolve B7-1 (5.00 g, 14.15 mmol) in DMF (20 mL). Slowly add sodium hydride (407 mg, 16.98 mmol) to the system at 0 °C. After stirring at 0 °C for 10 min, add borane trimethylamine complex (1.5 ml, 16.98 mmol) to the system at 0 °C, and react at 80 °C for 2 h. After the reaction is completed, quench with saturated ammonium chloride aqueous solution, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 3.1 g of B7-2 is obtained by column chromatography, and the yield is 81%. ESI-MS (M+H) + = 267.0.

[0311] Synthesis Step 3: Synthesis of B7-3

[0312] Dissolve B7-2 (3.00 g, 11.23 mmol) in dichloromethane (30 mL). At 0 °C, add triethylamine (4.7 mL, 33.68 mmol) and di-tert-butyl dicarbonate (3.8 mL, 16.84 mmol) to the system in sequence, and stir the reaction at room temperature for 2 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 3.3 g of B7-3 is obtained by column chromatography, and the yield is 80%. ESI-MS (M+H) + = 367.1

[0313] Synthesis Step 3: Synthesis of B7

[0314] The synthesis of B7 refers to the synthesis method in Step 2 of the synthesis of Intermediate B1

[0315] Synthesis of Intermediate M1 in Example 7

[0316]

[0317] Synthesis Step 1: Synthesis of M1-1

[0318] Dissolve 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine (3.20 g, 9.93 mmol) in DMF (20 mL). Add p-toluenesulfonyl chloride (2.40 g, 12.90 mmol) and sodium hydride (500 mg, 12.90 mmol) to the system in sequence, and react at room temperature for 3 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. M1-1 is obtained by column chromatography. ESI-MS (M+H) + = 477.9

[0319] Synthesis Step 2: Synthesis of M1-2

[0320] Dissolve M1-1 (3.00 g, 6.29 mmol) in 30 mL of dioxane. Add 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]dichloropalladium (460 mg, 0.63 mmol), potassium carbonate (1.7 g, 12.58 mmol), and water (10 mL) to the system in sequence, and react at 50 °C under nitrogen protection for 4 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. M1-2 is obtained by column chromatography. ESI-MS (M+H) + = 499.0

[0321] Synthesis Step 3: Synthesis of M1-3

[0322] Dissolve M1-2 (2.0 g, 4.01 mmol) in 15 mL of dioxane. Sequentially add 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-methylpropan-2-yl ester (1.9 g, 4.81 mmol), Pd(dppf)Cl 2 (290 mg, 0.40 mmol), potassium carbonate (1.6 g, 12.03 mmol), and water (5 mL) to the system. React at 100 °C under nitrogen protection for 4 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain M1-3 by column chromatography. ESI-MS (M+H) + = 706.3.

[0323] Synthesis Step 4: Synthesis of M1-4

[0324] Dissolve M1-3 (2.3 g, 3.26 mmol) in tetrahydrofuran (15 mL). Add saturated aqueous sodium hydroxide solution (15 mL) to the system and react at 70 °C for 4 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain M1-4 by column chromatography (eluted with dichloromethane / methanol). ESI-MS (M+H) + = 552.3.

[0325] Synthesis Step 5: Synthesis of Intermediate M1

[0326] Dissolve M1-4 (1.4 g, 2.53 mmol) in dichloromethane (10 mL). Add 1,4-dioxane solution of hydrogen chloride (14 mL, 6N) to the system and react at room temperature for 4 h. After the reaction is completed, dilute with dichloromethane, wash with saturated aqueous sodium carbonate solution, combine the organic phases, dry, and concentrate under reduced pressure to obtain Intermediate M1. ESI-MS (M+H) + = 452.2.

[0327] Refer to the synthetic route and method of Intermediate M1 to synthesize the following intermediate compounds:

[0328]

[0329]

[0330]

[0331]

[0332]

[0333] Example 8: Synthesis of Intermediate M27

[0334]

[0335] Synthesis Step 1: Synthesis of M27-1

[0336] Dissolve 3,5-dibromopyrazin-2-amine (2.0 g, 7.91 mmol) in N,N-dimethylformamide (40 mL). To the system, sequentially add 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-ol (1.4 g, 7.91 mmol) and cesium carbonate (5.2 g, 15.82 mmol), and react at 90 °C for 2 h. After the reaction is completed, cool and quench with water, extract with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and purify by column chromatography to obtain M27-1. ESI-MS (M+H) + = 353.1.

[0337] Step 2: Synthesis of Intermediate M27

[0338] Refer to Synthesis Step 3 and Synthesis Step 5 of Intermediate M1 to obtain Intermediate M27. ESI-MS (M+H) + = 460.2.

[0339] Refer to the synthetic route and method of Intermediate M27 to synthesize the following intermediate compounds:

[0340]

[0341] Example 9 Synthesis of Intermediate M31

[0342]

[0343] Synthesis Step 1: Synthesis of M31-1

[0344] Dissolve M1-1 (5.0 g, 10.49 mmol) in DMSO (50 mL). To the system, sequentially add cesium carbonate (10.2 g, 31.47 mmol), copper(I) iodide (200 mg, 1.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (768 mg, 1.05 mmol), evacuate and replace with nitrogen for protection, heat to 80 °C, and add dropwise a DMSO solution of trimethylsilylacetylene (3.7 g, 52.45 mmol). Stir and react at 80 °C for 2 h. After the reaction is completed, quench with water, extract with EA, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain M31-1 by column chromatography. ESI-MS (M+H) + = 448.0.

[0345] Step 2: Synthesis of M31-2

[0346] Dissolve M31-1 (3.9 g, 8.72 mmol) in MeOH (40 mL), add potassium carbonate (414 mg, 26.16 mmol) to the system, and stir the reaction overnight at room temperature. After the reaction is completed, quench with water, concentrate under reduced pressure to a fixed volume, extract with EA, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. M31-2 is obtained by column chromatography. ESI-MS (M+H) + = 376.0

[0347] Step 3: Synthesis of M31-3

[0348] Dissolve M31-2 (3.0 g, 7.92 mmol) in DMF (30 mL), sequentially add methanol (3 mL), trimethylsilyl azide (1.4 g, 11.88 mmol), and copper(I) iodide (75 mg, 0.40 mmol) to the system, evacuate and replace with nitrogen for protection, and heat to 100 °C for reaction for 2 h. After the reaction is completed, quench with water, extract with EA, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. M31-3 is obtained by column chromatography. ESI-MS (M+H) + = 419.0

[0349] Step 4: Synthesis of M31-4

[0350] Dissolve M31-3 (2.7 g, 6.53 mmol) in DCM (30 mL), sequentially add 2,2,2-trifluoroacetaldehyde (961 mg, 9.80 mmol) and STAB (4.2 g, 19.59 mmol) to the system, and react at room temperature for 2 h. After the reaction is completed, quench with water, extract with EA, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. M31-4 is obtained by column chromatography. ESI-MS (M+H) + = 501.0. The structure of the product is confirmed by H-H COSY

[0351] Step 5: Synthesis of M31

[0352] The synthetic methods of M31-5, M31-6 and M31 refer to Steps 3, 4 and 5 of the synthesis of intermediate M1 to obtain intermediate M31. ESI-MS (M+H) + = 454.2

[0353] Example 10 Synthesis of Intermediate M32

[0354]

[0355] Synthesis Step 1: Synthesis of M32-1

[0356] Dissolve M1-1 (5.0 g, 10.49 mmol) in dioxane (50 mL). To the system, sequentially add 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]dichloropalladium (768 mg, 1.05 mmol), water (16 mL), and react at 100 °C under nitrogen protection for 4 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain M32-1 by column chromatography. ESI-MS (M+H) + = 501.9

[0357] Step 2: Synthesis of M32

[0358] The synthesis methods of M32-2, M32-3 and M32 refer to steps 3, 4 and 5 of the synthesis of intermediate M1 to obtain intermediate M32, ESI-MS (M+H) + = 455.1

[0359] Refer to the synthetic route and method of intermediate M32 to synthesize the following intermediate compounds:

[0360]

[0361]

[0362] Example 11 Synthesis of Intermediate M33

[0363]

[0364] Synthesis Step 1: Synthesis of M33-1

[0365] Dissolve 3-bromo-6-cyanoimidazo[1,2-a]pyridine (5.0 g, 22.52 mmol) in tetrahydrofuran (50 mL). Dropwise add a n-hexane solution of n-butyllithium (11.7 mL, 29.28 mmol) to the system at -70 °C and stir for 1 h. Add a tetrahydrofuran solution of zinc chloride (29 mL, 29.28 mmol) at -50 °C and react at 0 °C for 1 h. Directly use for the next step.

[0366] Step 2: Synthesis of M33-2

[0367] Dissolve M1-1 (5.0 g, 10.49 mmol) in tetrahydrofuran (50 mL). Add [2-(2'-amino-1,1'-biphenyl)]palladium(II) dichloride(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (412 mg, 0.52 mmol) to the system, and react with M33-1 (11.54 mmol) at 40 °C for 1 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain M33-2 by column chromatography. ESI-MS (M+H) + = 493.0

[0368] Step 3: Synthesis of M33

[0369] The synthesis methods of M33-3, M33-4 and M33 refer to Steps 3, 4 and 5 of the synthesis of intermediate M1 to obtain intermediate M33. ESI-MS (M+H) + = 446.2

[0370] Refer to the synthetic route and method of intermediate M33 to synthesize the following intermediate compounds:

[0371]

[0372] Synthesis of Intermediate M34 in Example 12

[0373]

[0374] Synthesis Step 1: Synthesis of M34-1

[0375] Dissolve M1-1 (5.0 g, 10.49 mmol) in DMSO (50 mL). Add cesium carbonate (6.8 g, 20.98 mmol), 4-(1H-pyrazol-4-yl)morpholine (2.4 g, 15.74 mmol), and copper(I) oxide (150 mg, 1.05 mmol) to the system in sequence, and react at 100 °C under nitrogen protection for 4 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Obtain M34-1 by column chromatography. ESI-MS (M+H) + = 503.0

[0376] Step 2: Synthesis of M34

[0377] The synthesis methods of M34-2, M34-3 and M34 refer to Steps 3, 4 and 5 of the synthesis of intermediate M1 to obtain intermediate M34. ESI-MS (M+H) + = 456.2

[0378] Refer to the synthetic route and method of intermediate M34 to synthesize the following intermediate compounds:

[0379]

[0380]

[0381] Example 13: Synthesis of Intermediate E71

[0382]

[0383] Synthesis Step 1: Synthesis of E71-1

[0384] Dissolve methyl 6-fluorobenzoate (5.0 g, 32.22 mmol) in 30 mL of N,N-dimethylformamide. Sequentially add 3-(hydroxymethyl)azetidine hydrochloride (4.8 g, 38.67 mmol) and potassium carbonate (13.3 g, 96.66 mmol) to the system, and react at 90 °C for 16 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and obtain E71-1 by column chromatography with a yield of 98%. ESI-MS (M+H) + = 222.1.

[0385] Synthesis Step 2: Synthesis of E71-2

[0386] Dissolve E71-1 (3 g, 13.5 mmol) in dichloromethane (50 mL), stir at room temperature until dissolved clearly, add Dess-Martin periodinane (8.6 g, 20.25 mmol) in 10 batches, and react at room temperature for 1 h. After the reaction is completed, add an appropriate amount of saturated sodium bicarbonate solution, extract with dichloromethane, combine the organic phases, concentrate under reduced pressure, and obtain E71-2 by column chromatography with a yield of 67%. ESI-MS (M+H) + = 220.1.

[0387] Synthesis Step 3: Synthesis of E71-3

[0388] Dissolve E71-2 (1.9 g, 8.63 mol) in methanol (20 mL). Sequentially add trimethoxymethane (1.3 g, 12.94 mmol) to the system, stir at room temperature for 15 minutes, then add p-toluenesulfonic acid (150 mg, 0.86 mmol), and react at 60 °C for 4 h. After the reaction is completed, adjust the pH to 8 with an aqueous sodium bicarbonate solution, concentrate to remove methanol, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain 1.5 g of E71-3 by column chromatography with a yield of 65%. ESI-MS (M+H) + = 266.1.

[0389] Synthesis Step 4: Synthesis of Intermediate E71

[0390] Dissolve E71-3 (800 mg, 3.17 mmol) in N,N-dimethylformamide (10 mL), stir at room temperature until dissolved, add 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), then stir at room temperature for 30 min. Add carbodiimide hydrochloride (1.8 g, 9.51 mmol) and react at room temperature for 3 h. After the reaction is completed, quench with aqueous ammonium chloride solution, extract with ethyl acetate, combine the organic phases, dry and concentrate under reduced pressure, and purify by column chromatography to obtain intermediate E71 with a yield of 49%. ESI-MS (M-H) - = 316.1

[0391] With reference to the synthetic route and method of intermediate E71, the following intermediate compounds were synthesized:

[0392]

[0393] Example 14: Synthesis of intermediate E11

[0394]

[0395] Synthesis step 1: Synthesis of E11-1

[0396] Dissolve 1-fluoro-4-nitrobenzene (2.2 g, 15.60 mmol) in N,N-dimethylformamide (10 mL), sequentially add 3-(hydroxymethyl)azetidine hydrochloride (1.7 g, 15.60 mmol) and potassium carbonate (6.5 g, 46.8 mmol) to the system, and react at room temperature for 16 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry and concentrate under reduced pressure, and obtain 3.1 g of E11-1 by column chromatography. ESI-MS (M+H) + = 209.1

[0397] Synthesis step 2: Synthesis of E11-2

[0398] Dissolve E11-1 (2.5 g, 12.01 mmol) in dichloromethane (50 mL), add Dess-Martin periodinane (7.2 g, 16.93 mmol) to the system in 10 portions, and react at room temperature for 1 h. After the reaction is completed, quench with saturated sodium bicarbonate solution, extract with dichloromethane, combine the organic phases, dry and concentrate under reduced pressure, and obtain E11-2 with a yield of 81% by column chromatography. ESI-MS (M+H) + = 207.1

[0399] Synthesis step 3: Synthesis of E11-3

[0400] Dissolve E11-2 (1.8 g, 8.73 mmol) in methanol (20 mL). Sequentially add trimethyl orthoformate (1.4 g, 13.09 mmol) and p-toluenesulfonic acid (150 mg, 0.87 mmol) to the system, and react at 50 °C for 16 h. After the reaction is completed, add water to quench it. After concentrating the organic solvent, extract with dichloromethane, combine the organic phases, dry, and concentrate under reduced pressure. E11-3 is obtained by column chromatography with a yield of 78%. ESI-MS (M+H) + = 253.1

[0401] Synthesis step 4: Synthesis of E11-4

[0402] Dissolve E11-3 (1.6 g, 6.35 mmol) in tetrahydrofuran (20 mL). Add palladium on carbon (160 mg, 10% Wt) to the system, and react at 50 °C for 16 h under a hydrogen atmosphere. After the reaction is completed, filter quickly. After concentrating the mother liquor, E11-4 is obtained by column chromatography with a yield of 85%. ESI-MS (M+H) + = 223.1

[0403] Synthesis step 5: Synthesis of E11-5

[0404] Dissolve E11-4 (1 g, 4.50 mmol) in N,N-dimethylformamide (10 mL). Sequentially add 3-bromopiperidine-2,6-dione (1.3 g, 6.75 mmol) and sodium bicarbonate (1.1 g, 13.50 mmol) to the system, and react at room temperature for 16 h. After the reaction is completed, add water to quench it. Extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure. E11-5 is purified by column chromatography with a yield of 87%. ESI-MS (M+H) + = 334.2

[0405] Synthesis step 6: Synthesis of intermediate E11

[0406] Dissolve E11-5 (1 g, 3.00 mmol) in tetrahydrofuran (10 mL). Add sulfuric acid aqueous solution (10 mL, 1 mol / L) to the system, and react at 50 °C for 16 h. After the reaction is completed, adjust the pH to 7 with sodium bicarbonate aqueous solution, extract with ethyl acetate, combine the organic phases, dry, and concentrate under reduced pressure. Intermediate E11 is obtained by column chromatography with a yield of 32%. ESI-MS (M+H) + = 288.1

[0407] Using the synthetic route and method of reference intermediate E11, the following intermediate compounds are synthesized:

[0408]

[0409]

[0410] Example 15: Synthesis of Intermediate E23

[0411]

[0412] Synthesis Step 1: Synthesis of E23-1

[0413] Dissolve 4-bromo-2-methylaniline (5.0 g, 27.03 mmol) in toluene (50 mL). Add acrylic acid (3.9 g, 54.06 mmol) to the system and react at 100 °C for 16 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry and concentrate under reduced pressure. E23-1 (5.6 g) is obtained by column chromatography. ESI-MS (M+H) + = 258.0

[0414] Synthesis Step 2: Synthesis of E23-2

[0415] Dissolve E23-1 (5.6 g, 21.78 mmol) in acetic acid (50 mL). Add urea (2.6 g, 43.56 mmol) to the system and react at 110 °C for 16 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry and concentrate under reduced pressure. E23-2 is obtained by column chromatography. ESI-MS (M+H) + = 283.0

[0416] Synthesis Step 3: Synthesis of E23-3

[0417] Dissolve E23-2 (3.5 g, 12.41 mmol) in dichloromethane (30 mL). Add 3-(1,3-dioxolan-2-yl)azetidine (1.9 g, 14.89 mmol) and sodium triacetoxyborohydride (7.9 g, 37.23 mmol) to the system in sequence and react at room temperature for 16 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry and concentrate under reduced pressure. E23-3 is obtained by column chromatography, ESI-MS (M+H) + = 332.2

[0418] Synthesis Step 4: Synthesis of Intermediate E23

[0419] Dissolve E23-3 (2.8 g, 8.45 mmol) in tetrahydrofuran (20 mL). Add sulfuric acid aqueous solution (10 mL, 1 mol / L) to the system and react at 50 °C for 16 h. After the reaction is completed, adjust the pH to 7 with sodium bicarbonate, extract with ethyl acetate, combine the organic phases, dry and concentrate under reduced pressure. E23 is obtained by column chromatography. ESI-MS (M+H) + = 288.1

[0420] Using the synthetic route and method of reference intermediate E23, the following intermediate compounds were synthesized:

[0421]

[0422]

[0423] Example 16: Synthesis of Intermediate E36

[0424]

[0425] Synthesis Step 1: Synthesis of E36-1

[0426] Dissolve 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (1.5 g, 5.68 mmol) in 15 mL of N,N-dimethylformamide. Sequentially add 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) to the system and react at room temperature for 1 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain 1.6 g of E36-1 by column chromatography. The yield is 75%. ESI-MS (M+H) + = 376.1.

[0427] Synthesis Step 2: Synthesis of Intermediate E36

[0428] Dissolve E36-1 (1.5 g, 4.00 mmol) in trifluoroacetic acid (15 mL) and react at 70 °C for 1 h. Add 1 N sulfuric acid to the system and react at 70 °C for 1 h. After the reaction is completed, adjust the pH value to slightly alkaline with saturated sodium carbonate, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain 1.3 g of intermediate E36 by column chromatography. The yield is 98%. ESI-MS (M+H) + = 332.1.

[0429] Using the synthetic route and method of reference intermediate E36, the following intermediate compounds were synthesized:

[0430]

[0431] Example 17 Synthesis of Intermediate D21

[0432]

[0433] Synthesis Step 1: Synthesis of D21-1

[0434] 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 directly use it for the next step. ESI-MS (M+H) + = 244.0

[0435] Synthesis step 2: Synthesis of D21-2

[0436] Dissolve the above residue in acetic acid (50 ml), add urea (2.6 g, 43.56 mmol) to the system, and react at 110 °C for 16 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, dry and concentrate under reduced pressure, and obtain 2.1 g of D21-2 by column chromatography. ESI-MS (M+H) + = 269.0

[0437] Synthesis steps 3-4: Synthesis of D21

[0438] The synthesis of D21 refers to the synthesis route and method of steps 1-2 in the synthesis of intermediate E36

[0439] With reference to the synthesis route and method of intermediate D21, the following intermediate compounds are synthesized

[0440]

[0441] Example 18: Synthesis of intermediate E45

[0442]

[0443] Synthesis step 1: Synthesis of E45-1

[0444] Dissolve 2-bromooxazole-5-carboxylic acid (1.5 g, 7.85 mmol) in tetrahydrofuran (15 mL), sequentially add 3-(1,3-dioxolan-2-yl)azetidine (1.3 g, 10.20 mmol) and cesium carbonate (7.6 g, 23.55 mmol) to the system, react at 50 °C for 5 h. After the reaction is completed, extract with dichloromethane, combine the organic phases, dry and concentrate under reduced pressure, and obtain E45-1 by column chromatography with a yield of 69%. ESI-MS (M+H) + = 241.1

[0445] Synthesis step 2: Synthesis of E45-2

[0446] Dissolve E45-1 (1.2 g, 5.00 mmol) in N,N-dimethylformamide (15 mL). Sequentially add 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) to the system, and react at room temperature for 1 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain E45-2 by column chromatography. ESI-MS (M+H) + = 351.1

[0447] Synthesis step 3: Synthesis of intermediate E45

[0448] Dissolve E45-2 (1.2 g, 3.42 mmol) in trifluoroacetic acid (15 mL), react at 70 °C for 1 h, add 1 N sulfuric acid to the system, and react at 70 °C for 1 h. After the reaction is completed, adjust the pH to slightly alkaline with saturated sodium carbonate, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain E45 by column chromatography. ESI-MS (M+H) + = 307.1

[0449] Using the synthetic route and method of reference intermediate E45, the following intermediate compounds were synthesized:

[0450]

[0451] Example 19: Synthesis of intermediate E48

[0452]

[0453] Synthesis step 1: Synthesis of E48-1

[0454] Dissolve 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) in toluene (30 mL). Sequentially add 3-(1,3-dioxolan-2-yl)azetidine (1.7 g, 13.35 mmol), lithium bis(trimethylsilyl)amide (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) to the system, and react at 100 °C for 4 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain E48-1 by column chromatography. ESI-MS (M+H)+ = 387.2。

[0455] Synthesis Step 2: Synthesis of Intermediate E48

[0456] Dissolve E48-1 (900 mg, 2.33 mmol) in trifluoroacetic acid (10 mL), react at 70 °C for 1 h, add 1 N sulfuric acid to the system, and react at 70 °C for 1 h. After the reaction is completed, adjust the pH to slightly alkaline with saturated sodium carbonate, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain E48 by column chromatography. ESI-MS (M+H) + = 343.1. Using the synthetic route and method of reference intermediate E48, the following intermediate compounds were synthesized:

[0457]

[0458] Example 20: Synthesis of Intermediate E55

[0459]

[0460] Synthesis Step 1: Synthesis of E55-1

[0461] Dissolve 1,4-diiodobenzene (5.0 g, 15.16 mmol) in dimethyl sulfoxide, and successively add 3-(hydroxymethyl)azetidine hydrochloride (5.6 g, 45.48 mmol), L-proline (349 mg, 3.03 mmol), potassium carbonate (10.5 g, 75.80 mmol), and copper(I) iodide (289 mg, 1.52 mmol) to the system. React at 90 °C for 12 h. After the reaction is completed, adjust the system to clarity with hydrochloric acid aqueous solution (2 mol / L), extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain E55-1 by column chromatography. ESI-MS (M+H) + = 290.0.

[0462] Synthesis Step 2: Synthesis of E55-2

[0463] Dissolve E55-1 (2.9 g, 10.12 mmol) in dichloromethane (50 mL), and add Dess-Martin reagent (6.5 g, 15.18 mmol) to the system in 10 batches. React at room temperature for 1 h. After the reaction is completed, quench with saturated sodium bicarbonate solution, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain E55-2 by column chromatography. ESI-MS (M+H) + = 288.0.

[0464] Synthesis Step 3: Synthesis of E55-3

[0465] Dissolve E55-2 (2.7 g, 9.46 mmol) in methanol (30 mL). Sequentially add trimethyl orthoformate (1.5 g, 14.19 mmol) and p-toluenesulfonic acid (164 mg, 0.95 mmol) to the system, and react at 50 °C for 16 h. After the reaction is completed, quench with water. After concentrating to remove methanol, extract with dichloromethane. Combine the organic phases, dry, and concentrate under reduced pressure to obtain E55-3 by column chromatography. ESI-MS (M+H) + = 334.0

[0466] Synthesis step 4: Synthesis of E55-4

[0467] Dissolve E55-3 (1.9 g, 7.57 mmol) in dimethyl sulfoxide (20 mL). Sequentially add 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), tris(dibenzylideneacetone)dipalladium(0) (695 mg, 0.76 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, (±)-BINAP, [1,1′-binaphthalene]-2,2′-bis(diphenylphosphine) (473 mg, 0.76 mmol) to the system, and react at 95 °C for 12 h. After the reaction is completed, quench with water. Extract with dichloromethane. Combine the organic phases, dry, and concentrate under reduced pressure to obtain E55-4 by column chromatography. ESI-MS (M+H) + = 497.2

[0468] Synthesis step 5: Synthesis of E55-5

[0469] Dissolve E55-4 (1.5 g, 3.06 mmol) in tetrahydrofuran (15 mL). Add Pd / C (150 mg, 10% Wt) to the system and react at 50 °C for 16 h under an H 2 atmosphere. After the reaction is completed, filter quickly. Concentrate the mother liquor and obtain E55-5 by column chromatography. ESI-MS (M+H) + = 319.2

[0470] Synthesis step 6: Synthesis of E55

[0471] Dissolve E55-5 (1 g, 3.12 mmol) in tetrahydrofuran (10 mL). Add H 2 SO 4 aqueous solution (10 mL, 1 mol / L) to the system and react at 50 °C for 16 h. After the reaction is completed, adjust the pH to 7 with aqueous sodium bicarbonate solution. Extract with ethyl acetate. Combine the organic phases, dry, and concentrate under reduced pressure to obtain E55 by column chromatography. ESI-MS (M+H) + = 273.1

[0472] Using the synthetic route and method of reference intermediate E55, the following intermediate compounds were synthesized:

[0473]

[0474] Synthesis of Intermediate D16 in Example 21

[0475]

[0476] Synthesis Step 1: Synthesis of D16-1

[0477] Dissolve methyl 2,4-difluorobenzoate (5.0 g, 32.22 mmol) in N,N-dimethylformamide (50 ml). To the system, successively add 3-(hydroxymethyl)azetidine hydrochloride (4.8 g, 38.67 mmol) and potassium carbonate (13.3 g, 96.66 mmol), and react at 90 °C for 16 h. After the reaction is completed, quench with water, extract with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and obtain D16-1 by column chromatography with a yield of 98%. ESI-MS (M+H) + = 240.1. Synthesis Step 2: Synthesis of D16-2

[0478] Dissolve D16-1 (3 g, 13.5 mmol) in dichloromethane (50 ml), stir at room temperature until dissolved clearly, add Dess-Martin reagent (8.6 g, 20.25 mmol) in 10 batches, and react at room temperature for 1 h. After the reaction is completed, add an appropriate amount of saturated sodium bicarbonate solution, extract with dichloromethane, combine the organic phases, concentrate under reduced pressure, and obtain D16-2 by column chromatography with a yield of 67%. ESI-MS (M+H) + = 238.1.

[0479] Synthesis Step 3: Synthesis of D16-3

[0480] Dissolve D16-2 (1.9 g, 8.63 mol) in methanol (20 ml). To the system, successively add trimethoxymethane (1.3 g, 12.94 mmol), stir at room temperature for 15 minutes, then add p-toluenesulfonic acid (150 mg, 0.86 mmol), and react at 60 °C for 4 h. After the reaction is completed, adjust the pH to 8 with an aqueous sodium bicarbonate solution, concentrate to remove methanol, extract with dichloromethane, combine the organic phases, dry and concentrate under reduced pressure, and obtain 1.5 g of D16-3 by column chromatography with a yield of 65%. ESI-MS (M+H) + = 284.1.

[0481] Synthesis Step 4: Synthesis of D16-4

[0482] Dissolve D16-3 (1.4 g, 5.26 mmol) in a mixed solvent (15 mL, methanol / tetrahydrofuran / water = 1:1:1). Add lithium hydroxide (1.2 g, 52.60 mmol) to the system and react at room temperature for 4 h. After the reaction, adjust the pH to 6 with 2N hydrochloric acid. Concentrate the organic solvents, extract with dichloromethane (containing 10% methanol), combine the organic phases, dry, and concentrate under reduced pressure. D16-4 is obtained by column chromatography with a yield of 68%. ESI-MS (M-H) + = 270.1

[0483] Synthesis step 5: Synthesis of intermediate D16-5

[0484] Dissolve D16-4 (800 mg, 3.17 mmol) in N,N-dimethylformamide (10 ml), stir at room temperature until dissolved, add 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). Stir at room temperature for 30 min, add carbodiimide hydrochloride (1.8 g, 9.51 mmol), and react at room temperature for 3 h. After the reaction, quench with an aqueous ammonium chloride solution, extract with ethyl acetate, combine and dry the organic phases, and concentrate. Intermediate D16-5 is obtained by column purification with a yield of 49%. ESI-MS (M-H) + = 380.2

[0485] Synthesis step 6: Synthesis of intermediate D16

[0486] The synthesis of D16 refers to the synthesis operation in step 6 of the synthesis of intermediate E55

[0487] Synthesis of intermediate D17 in Example 22

[0488]

[0489] Synthesis steps 1-2: Synthesis of intermediate D17-2

[0490] The synthesis of D17-2 refers to the synthesis operations in steps 1 and 4 of the synthesis of intermediate E55

[0491] Synthesis step 3: Synthesis of intermediate D17-3

[0492] Dissolve D17-2 (2 g, 4.17 mmol) in a mixed solvent (20 mL, methanol / tetrahydrofuran / water = 1:1:1). Add lithium hydroxide (500 mg, 20.83 mmol) to the system and react at room temperature for 4 h. After the reaction is completed, adjust the pH to 6 with 2N hydrochloric acid. Concentrate the organic solvent, extract with dichloromethane, combine the organic phases, dry, and concentrate under reduced pressure. Obtain D17-3 by column chromatography with a yield of 61%. ESI-MS (M-H) + = 467.2

[0493] Synthesis step 4: Synthesis of intermediate D17

[0494] The synthesis of D17 refers to the synthesis operation in synthesis step 5 of intermediate E55

[0495] Synthesis of intermediate D19 in Example 23

[0496]

[0497] Synthesis step 1: Synthesis of D19-1

[0498] The synthesis of D19-1 refers to the synthesis operation in synthesis step 4 of intermediate E55

[0499] Synthesis steps 2-3: Synthesis of D19-3

[0500] The synthesis of D19-3 refers to the synthesis operations in synthesis steps 1 and 5 of intermediate E55

[0501] Synthesis step 4: Synthesis of D19

[0502] The synthesis of D19 refers to the synthesis operation in synthesis step 2 of intermediate E55

[0503] Synthesis of intermediate D20 in Example 24

[0504]

[0505] Synthesis step 1: Synthesis of D20-1

[0506] Under nitrogen protection, dissolve 3-bromo-2-hydroxyacetophenone (20 g, 93.04 mmol) in chloroform (100 ml) and ethyl acetate (100 ml). Subsequently, add copper bromide (41.54 g, 186 mmol). Heat the reaction mixture to 90 °C and stir for 16 hours. After the reaction is completed, cool to room temperature, filter, and wash the filter cake with dichloromethane (1.5 L) to obtain a solution of D20-1, which is directly used in the next step. ESI-MS (M+H) + = 292.9

[0507] Synthesis step 2: Synthesis of D20-2

[0508] The solution (350 ml) of D20-1 obtained above was cooled to 0 °C, and then triethylamine (14.11 g, 140 mmol) was slowly added dropwise. After the addition was completed, the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After the reaction was completed, water (200 mL) was added for liquid separation, 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 solvent was removed under reduced pressure from the filtrate to obtain D20-2. ESI-MS (M+H) + = 212.9

[0509] Synthesis step 3: Synthesis of D20-3

[0510] Under nitrogen protection, D20-2 (19.8 g, 93.00 mmol) was dissolved in toluene (150 ml), and then ethoxycarbonylmethylenetriphenylphosphine (38.88 g, 112 mmol) was added. The reaction mixture was heated to 130 °C and stirred for 36 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. Methyl tert-butyl ether (700 mL x 3) was added to the resulting residue, and it was 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 under reduced pressure from the filtrate, and the resulting residue was purified by column chromatography to obtain D20-3 with a yield of 32%. ESI-MS (M+H) + = 283.0

[0511] Synthesis step 4: Synthesis of D20-4

[0512] D20-3 (3 g, 10.60 mmol) was added to N,N-dimethylformamide (20 mL), acrylamide (903.79 mg, 12.72 mmol) and potassium tert-butoxide (1.78 g, 15.89 mmol) were added in sequence, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into 1 N hydrochloric acid (15 mL), water (25 mL) was added, and it 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 the solvent was removed by concentration under reduced pressure from the filtrate. The resulting residue was purified by column chromatography to obtain D20-4. The yield was 69%. ESI-MS (M+H) + = 308.0

[0513] Synthesis steps 5-6: Synthesis of D20

[0514] The synthesis of D20 refers to the synthesis route and operation of steps 1-2 in the synthesis of intermediate E55

[0515] Example 25: Synthesis of intermediate E68

[0516]

[0517] Synthesis Step 1: Synthesis of E68-1

[0518] Dissolve 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (3.0 g, 10.86 mmol) in N,N-dimethylformamide (30 mL). Sequentially add 3-(1,3-dioxolan-2-yl)azetidine (1.4 g, 10.86 mmol) and N,N-diisopropylethylamine (2.8 g, 21.72 mmol) to the system, and react at 90 °C for 6 h. After the reaction is completed, quench with water, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain E68-1 through column chromatography. ESI-MS (M+H) + = 386.1

[0519] Synthesis Step 2: Synthesis of Intermediate E68

[0520] Dissolve E68-1 (4.2 g, 8.76 mmol) in hydrochloric acid aqueous solution (200 mL, 3 mol / L), and react at 50 °C for 2 h. After the reaction is completed, adjust the pH to 7 with sodium bicarbonate, extract with dichloromethane, combine the organic phases, dry, concentrate under reduced pressure, and obtain Intermediate E68 through column chromatography. ESI-MS (M+H) + = 342.1

[0521] Using the synthetic route and method of reference Intermediate E68, the following intermediate compounds are synthesized:

[0522]

[0523]

[0524] Example 26: Synthesis of Compound 014

[0525]

[0526] Dissolve M1 (102 mg, 0.22 mmol) in ethanol (5 mL), stir and dissolve at room temperature. Add E23 (65 mg, 0.222 mmol) to the system, and react at room temperature for 1 h. Then add sodium cyanoborohydride (44 mg, 0.66 mmol) to the system, and react at room temperature for 1 h. After the reaction is completed, quench with water, remove ethanol under reduced pressure, extract with ethyl acetate, combine the organic phases, dry, and concentrate to obtain 80 mg of 0014 through column chromatography, with a yield of 48%. ESI-MS (M+H) += 723.2. 1H NMR (400 MHz, DMSO-d) δ 10.54 (s, 1H), 9.11–8.83 (m, 1H), 8.75 (s, 1H), 8.25 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 11.9 Hz, 3H), 7.52 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 5.5 Hz, 2H), 5.44 (s, 1H), 3.98 (d, J = 7.5 Hz, 2H), 3.77 (dt, J = 13.8, 7.1 Hz, 1H), 3.63 (dt, J = 12.7, 6.2 Hz, 1H), 3.53 (d, J = 6.6 Hz, 2H), 3.21–3.10 (m, 6H), 3.07 (s, 2H), 2.84 (d, J = 6.4 Hz, 2H), 2.80–2.71 (m, 4H), 2.35 (m, 6H), 2.27 (m, 3H), 2.23 (m, 3H).

[0527] Using the synthetic route and method of Reference 014, the following compounds were synthesized (the compound numbers in the table follow the compound numbers in the claims and the specification):

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536] Example 27: Synthesis of Compound 006

[0537]

[0538] Dissolve M1 (102 mg, 0.22 mmol) in acetonitrile (5 mL), stir at room temperature until clear, then successively add E65 (66 mg, 0.19 mmol) and cesium carbonate (110 mg, 0.34 mmol) to the system, and react at 70 °C for 1 h. After the reaction, extract with dichloromethane, combine the organic phases, wash with saturated ammonium chloride aqueous solution, dry, concentrate under reduced pressure, and obtain 006 by column chromatography. ESI-MS (M+H) + = 713.2

[0539] Example 28: Synthesis of Compound 009

[0540]

[0541] Dissolve M1 (102 mg, 0.22 mmol) in ethanol (5 mL), stir at room temperature until clear, add E66 (58 mg, 0.21 mmol) to the system, and react at 70 °C for 1 h. After the reaction, extract with dichloromethane, combine the organic phases, wash with saturated ammonium chloride aqueous solution, dry, concentrate under reduced pressure, and obtain 009 by column chromatography. ESI-MS (M+H) + = 725.3

[0542] Example 29: Synthesis of Compound 047

[0543]

[0544] Dissolve E35 (75 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL), successively add M1 (102 mg, 0.22 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (105 mg, 0.27 mmol), and diisopropylethylamine (81 mg, 0.63 mmol) to the system, and react at room temperature for 1 h. After the reaction, quench with water, extract with dichloromethane, combine the organic phases, wash with saturated ammonium chloride aqueous solution, dry, concentrate under reduced pressure, and obtain 047 by column chromatography. ESI-MS (M+H) + = 732.3

[0545] Compound 104 was synthesized by adopting the synthetic route and method of reference 047, and ESI-MS (M+H) + = 722.3

[0546] Biological evaluation

[0547] Test Example 1. HPK1 kinase activity

[0548] The inhibitory effect of the compound on HPK1 kinase was evaluated by Lantha screen Assay

[0549] a) Kinase buffer: 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 4 mM DTT, 0.01% Tween-20, 0.01% BSA.

[0550] b) Compound preparation: Dilute the compound with DMSO. The initial concentration for compound detection is 1 μM, and it is diluted to corresponding concentrations.

[0551] c) Kinase reaction and termination: Prepare the kinase solution by adding kinase buffer. Add the kinase solution and the compound to the test plate and incubate at room temperature for 10 minutes. Form the substrate solution by adding Fluorescein-PKC and ATP to the kinase buffer. Add 5 μl of the substrate solution to the test plate to start the reaction, and incubate at room temperature for 90 minutes. Then add 10 μl of the antibody and EDTA mixture to terminate the reaction, and incubate at room temperature for 60 minutes.

[0552] d) Read data with an Envision instrument. Plot a curve with the Log concentration of the inhibitor on the X-axis and the inhibition rate on the Y-axis. Calculate the IC 50 according to the formula Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)^HillSlope).

[0553] Table 1 HPK1 kinase inhibitory activity of the compounds of the present invention

[0554]

[0555]

[0556] +: IC 50 < 10 nM; ++: 10 nM ≤ IC 50 < 50 nM; +++: 50 nM ≤ IC 50 < 100 nM.

[0557] As can be seen from Table 1, the compounds of the present invention have good inhibitory activity against HPK1 kinase.

[0558] Test Example 2. HPK1 degradation activity

[0559] Experimental procedure:

[0560] 1) Cell seeding: Resuscitate the cells, select the Jurkat cell line with good growth status, collect the cells in the logarithmic growth phase and count them. Inoculate the cell suspension into 12- or 24-well plates and place them in a 37°C, 5% CO 2 incubator for overnight incubation.

[0561] 2) Preparation of the compound to be tested: The compound to be tested was serially diluted with DMSO according to the experimental requirements and added to the corresponding cell wells, and incubated in an incubator at 37 °C and 5% CO 2 for 24 h.

[0562] 3) Sample preparation: After the action of the compound to be tested was completed, the cells were collected in a 1.5 mL EP tube, centrifuged at 1500 rpm for 5 min, and after discarding the supernatant, washed once with PBS, and then subjected to BCA protein quantification and concentration adjustment. The adjusted sample was added to 5*loading buffer and boiled at 100 °C for 10 min, and then loaded after returning to room temperature.

[0563] 4) Sample detection: Electrophoresis was performed using 10% SDS-PAGE, and the sample loading volume was 8 μL / well. After transferring the membrane, it was blocked with 5% BSA at room temperature for 1 h. After washing away the residual blocking solution with TBST, HPK1 and GAPDH antibodies were added and incubated overnight at 4 °C. Then it was washed 3 times with TBST on a shaker, 10 min each time. After the washing was completed, the secondary antibody was added and incubated at room temperature for 1 h, and then washed 3 times with TBST on a shaker, 10 min each time. Finally, ECL exposure solution was used to develop and image the bands to detect the change of HPK1 protein.

[0564] Table 2 Degradation ability of the compounds of the present invention on HPK1 protein

[0565]

[0566] +: DC 50 <10 nM; ++: 10 nM ≤ DC 50 <50 nM; +++: 50 nM ≤ DC 50 <100 nM.

[0567] Compound a is C196 of WO2024 / 125631A1.

[0568]

[0569] As can be seen from Table 2, the compounds of the present invention have a strong degradation ability on HPK1 protein.

[0570] Test Example 3. HPK1 / GLK degradation selectivity

[0571] Experimental procedure:

[0572] 1) Cell seeding: Resuscitate the cells, select the Jurkat cell line with good growth state, collect the cells in the logarithmic growth phase and count, inoculate the cell suspension into a 12- or 24-well plate (20W / well), and place it in an incubator at 37 °C and 5% CO 2 overnight.

[0573] 2) Preparation of the compound to be tested: The compound to be tested was serially diluted with DMSO according to the experimental requirements and added to the corresponding cell wells, and incubated in an incubator at 37 °C and 5% CO 2 for 24 h.

[0574] 3) Sample preparation: After the action of the compound to be tested ended, the cells were collected in a 1.5 mL EP tube, centrifuged at 1500 rpm for 5 min, the supernatant was discarded, washed once with PBS, and subjected to BCA protein quantification and concentration adjustment. The adjusted sample was added to 5*loading buffer, boiled at 100 °C for 10 min, and loaded after returning to room temperature.

[0575] 4) Sample detection: 10% SDS-PAGE was used for electrophoresis, and the sample loading amount was 10 μL / well. After transferring the membrane, it was blocked with 5% skim milk at room temperature for 1 h. After washing away the residual blocking solution with TBST, HPK1 and GLK antibodies were added and incubated overnight at 4 °C. Then it was washed 3 times with TBST on a shaker, 5 min each time. After the washing was completed, the secondary antibody was added and incubated on a shaker at room temperature for 1 h, then washed 3 times with TBST on a shaker, 5 min each time. Finally, the membrane was soaked in TBST for chemiluminescent imaging.

[0576] 5) Data processing: After developing the PVDF membrane, the data was exported, plotted using Imang J, and the gray value of the protein band was analyzed using the Image J software. Using the software Graphpad Prism 9, the DC 50 curve was fitted to obtain the compound's degradation selectivity result for HPK1 / GLK: HPK1 / GLK Fold = DC 50 (HPK1) / DC 50 (GLK).

[0577] Table 3 Degradation selectivity of the compounds of the present invention for HPK1 / GLK

[0578]

[0579]

[0580] +: Fold < 10; ++: 10 ≤ Fold < 100; +++: 100 ≤ Fold < 1000; ++++: 1000 ≤ Fold

[0581] As can be seen from Table 3, in the degradation selectivity test of the compounds of the present invention for HPK1 and GLK proteins, high selectivity for HPK1 degradation was shown.

[0582] Test Example 4. Pharmacokinetic properties

[0583] The test compound was administered to SD rats by intragastric gavage at a dose of 10 mg / kg. Blood samples were collected at 0 h (before dosing) and 0.083, 0.25, 1, 2, 4, 6, 8, and 24 h after oral gavage administration, and placed in anticoagulant tubes containing sodium heparin. The mixture was vortexed thoroughly and centrifuged at 6000 rpm for 3 minutes. The plasma drug concentration was determined by LC-MS / MS method, and the relevant pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 pharmacokinetic software.

[0584] Table 4 Pharmacokinetic properties of the compounds of the present invention

[0585]

[0586] As can be seen from Table 4, the compounds of the present invention have 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 -、 -、-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, hydroxyl, 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, -OC1-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