HPK1 inhibitors and uses thereof

Abstract

The present invention belongs to the field of medical technology, and specifically relates to a class of compounds that can be used as HPK1 inhibitors, their deuterated products, their pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, their deuterated products, their pharmaceutically acceptable salts or isomers thereof, methods for preparing the compounds, their deuterated products, their pharmaceutically acceptable salts or stereoisomers thereof, and uses of the compounds, their deuterated products, their pharmaceutically acceptable salts or stereoisomers thereof.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a class of compounds, deuterated substances, pharmaceutically acceptable salts thereof, and stereoisomers thereof that can be used as HPK1 inhibitors, pharmaceutical compositions and preparations containing the compounds, deuterated substances, pharmaceutically acceptable salts thereof, and stereoisomers thereof, methods for preparing the compounds, deuterated substances, pharmaceutically acceptable salts thereof, and stereoisomers thereof, and uses of the compounds, deuterated substances, pharmaceutically acceptable salts thereof, and stereoisomers thereof. Background Art

[0002] T cell receptor (TCR)-mediated T cell activation plays an important role in the development of thymic T cells, differentiation of T cell subsets, and the function of effector T cells. TCR can recognize MHC (major histocompatibility complex) on the surface of antigen-presenting cells, and then recognize the signal transmitted to the cell interior. Signal transmission causes the activation of downstream signaling pathways. Typical intracellular signals of TCR activation include MAPK (mitogen-activated protein kinase), PKC (protein kinase C), and calcium ion signaling pathways. The activation of these signals ultimately activates the specific gene expression of T cells, causes cell proliferation, and causes T cells to differentiate into effector T cells. Endogenous or adoptively transferred effector T cells are important mediators of anti-tumor immunity. Continuous antigen exposure causes T cells to gradually differentiate into an exhausted state, which is characterized by a hierarchical loss of effector function and proliferation ability, as well as obvious transcriptional, epigenetic and metabolic changes. How to prevent T cell exhaustion and expand the function of effector T cells is one of the most pressing issues in tumor immunology.

[0003] Hematopoietic progenitor kinase HPK1 (Hematopoietic Progenitor Kinase 1) is an immunosuppressive regulatory kinase that is restrictedly expressed in hematopoietic stem cells. HPK1 is a negative signal regulator of the T cell receptor (TCR). After TCR activation, cytoplasmic HPK1 is recruited to the vicinity of the cell membrane, and the activated HPK1 phosphorylates the adaptor protein SLP76, thereby activating SLP76 as a docking site for the negative regulatory protein 14-3-3, ultimately leading to the instability of the TCR signaling complex, thereby downregulating the TCR signal. The literature (Shui et al., Nature Immunology (2007) 8: 84-91) discloses that HPK1 deficiency leads to enhanced TCR-induced SLP-76 and Erk phosphorylation, increased Ca flux, and increased production of cytokines and antigen-specific antibodies, indicating that HPK1 negatively regulates TCR signaling and T cell-mediated immune responses. In addition, Sawasdikosol et al. found that HPK 1(- / -) T cells are resistant to the inhibitory and apoptotic effects of prostaglandin PGE2 (Sawasdikosol et al., Cancer Immunol. Immunother. (2010) 59: 419-429). In 2020, the research group of Liao Xuebin of Tsinghua University reported the functional significance of HPK1 in T cell immunotherapy. [Si et al., Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies, Cancer Cell (2020)] The researchers first analyzed the public tumor database and found that MAP4K1 (encoding HPK1) showed a strong positive correlation with signaling molecules related to T cell exhaustion (such as PDCD1, TIGIT, CTLA4, LAG3, etc.). In tumors such as low-grade glioma (LGG) and invasive breast cancer (BRAC), it is significantly shown that patients with low expression of MAP4K1 have a longer survival. Next, the researchers selected multiple myeloma tissue biopsies and sorted and measured the protein expression of HPK1 and immunosuppressive molecules in T cells. The experimental results showed that in exhausted T cells, the expression of HPK1 was upregulated. This experimental result shows a positive correlation between HPK1 and tumor-infiltrating T cell exhaustion. HPK1 may be an important kinase that regulates T cell exhaustion and inhibits anti-tumor immune response.

[0004] HPK1, also known as MAP4K1, is a member of the MAP4K family. There are five other members in the family, including MAP4K2 (GCK kinase), MAP4K3 (GLK kinase), MAP4K4 (HGK kinase), MAP4K5 (KHS kinase) and MAP4K6 (MINK kinase). The biological effect of GLK kinase is exactly opposite to that of HPK1. GLK can promote the activation of TCR pathway by binding to downstream adaptor proteins. The literature [Huai-Chia Chuang et al., Chapter Seven-MAP4K Family Kinases in Immunity and Inflammation, Advances in Immunology, 2016 (129) 277-314] found that the loss of HGK kinase can lead to spontaneous systemic inflammation and type 2 diabetes in mice. The role of other kinases in the family is currently unknown. In order to ensure better safety, we need to find HPK1 kinase inhibitors that are highly selective for other members of the MAP4K family.

[0005] At present, the research on drugs for this target is still in the clinical trial stage, and no drug has been marketed yet. In order to better meet clinical needs, it is of great clinical significance to develop a highly selective, highly active and highly safe HPK1 kinase inhibitor. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a novel HPK1 inhibitor compound with good inhibitory activity on HPK1. Further, the compound can be used to inhibit the activity of HPK1 kinase, thereby enhancing the body's immune effect on tumors. Furthermore, the compound can also be used to treat or prevent related diseases mediated by HPK1, especially cancer. The compound has a good inhibitory effect on a variety of cancer cells and has good drugability.

[0007] The technical solution of the present invention is as follows:

[0008] In one aspect, the present invention provides a compound represented by the following general formula (I), a deuterated substance thereof, a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0009]

[0010] in,

[0011] X 1 , X 2 are independently selected from -C(R 3 )-or-N-;

[0012] Y 1 , Y 2, Y 3 are independently selected from -C(R 4 ) or -N-;

[0013] L 1 Selected from chemical bonds, -CR a R b -、-C(R a R b )-C(R a R b )-、-O-、-NR a -、-S-、-S(O)2NR a -、-S(O)-、-S(O)NR a -, -C(O)-, -C(O)O-, -C(O)NR a -、-C(O)N(R a )O-、-OC(O)-、-OC(O)NR a -、-N(R a )C(O)O-、-N(R a )C(O)-、-N(R a )S(O)2-、-C(R a R b )-NR a -or-NR a -C(R a R b )-;

[0014] Each R 3 , each R 4 are independently selected from hydrogen, halogen, hydroxyl, thiol, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0015] Ring A is selected from 7-15 membered cycloalkyl, 7-15 membered heterocycloalkyl, 6-15 membered aryl or 5-15 membered heteroaryl, optionally substituted with 1-3 Q1;

[0016] Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b 、-OR a 、-SR a 、-C(O)R a , or the following group optionally substituted by 1-3 Q2: C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) m -3-10 membered cycloalkyl, -(CH2)m -3-10 membered heterocycloalkyl, -(CH2) m -5-10 membered heteroaryl or -(CH2) m -6-10 membered aryl;

[0017] Each Q2 is independently selected from deuterium, halogen, hydroxyl, nitro, -NR c R d , cyano, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl or 6-10 membered aryl;

[0018] R 1 is selected from 6-15 membered aryl or 5-15 membered heteroaryl optionally substituted by 1-3 Q3, wherein Q3 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo 1-6 Alkoxy, halogenated C 1-6 Alkylthio, hydroxyl C 1-6 Alkoxy, hydroxyl C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 Alkylthio;

[0019] R 2 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, -NR a R b 、-OR a 、-SR a 、-NR a -C(O)-R b -、-C(O)R a 、-C(O)NR a or-C(O)OR a ;

[0020] Each R a , each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo 1-6 Alkoxy, halogenated C 1-6 Alkylthio, hydroxyl C 1-6 Alkoxy, hydroxyl C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 Alkylthio or the following groups optionally substituted by substituents: -(CH2) m -3-10 membered cycloalkyl, -(CH2) m -3-10 membered heterocycloalkyl, -(CH2) m -5-10 membered heteroaryl, -(CH2) m -6-10 membered aromatic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0021] Each R c , each R d are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0022] p is selected from 0, 1 or 2;

[0023] Each m is independently selected from 0, 1, 2, 3, 4 or 5.

[0024] In certain embodiments, the compound, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer, wherein:

[0025] X 1 , X 2 are independently selected from -C(R 3 )-or-N-;

[0026] Y 1 , Y 2 , Y 3 are independently selected from -C(R 4 ) or -N-;

[0027] L 1 Selected from chemical bonds, -CR a R b -、-C(R aR b )-C(R a R b )-、-O-、-NR a -、-S-、-S(O)2NR a -、-S(O)-、-S(O)NR a -, -C(O)-, -C(O)O-, -C(O)NR a -、-C(R a R b )-NR a -or-NR a -C(R a R b )-;

[0028] Each R 3 , each R 4 are independently selected from hydrogen, halogen, hydroxyl, thiol, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy;

[0029] Ring A is selected from 5-6 membered heteroaryl, 7-10 membered cycloalkyl or 7-10 membered heterocycloalkyl optionally substituted with 1-3 Q1;

[0030] Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b 、-OR a 、-SR a 、-C(O)R a , or the following group optionally substituted by 1-3 Q2: C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocycloalkyl, -(CH2) m -5-8 membered heteroaryl or -(CH2) m -phenyl;

[0031] Each Q2 is independently selected from deuterium, halogen, hydroxyl, nitro, -NR c R d , cyano or carboxyl;

[0032] R 1 is selected from 5-15 membered heteroaryl optionally substituted by 1-3 Q3, wherein Q3 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo 1-6 Alkoxy, halogenated C 1-6 Alkylthio, hydroxyl C 1-6 Alkoxy, hydroxyl C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 Alkylthio;

[0033] R 2 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, -NR a R b OR a ;

[0034] Each R a , each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo 1-6 Alkoxy, halogenated C 1-6 Alkylthio, hydroxyl C 1-6 Alkoxy, hydroxyl C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 Alkylthio or the following groups optionally substituted by substituents: -(CH2) m -3-10 membered cycloalkyl, -(CH2) m -3-10 membered heterocycloalkyl, -(CH2) m -5-10 membered heteroaryl, -(CH2) m -6-10 membered aromatic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0035] Each R c , each R d are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy;

[0036] p is selected from 0, 1 or 2;

[0037] Each m is independently selected from 0, 1, 2 or 3.

[0038] In certain embodiments, the compound, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer, wherein:

[0039] Ring A is selected from a 5-6 membered nitrogen-containing heteroaryl group, a 7-8 membered monocycloalkyl group, an 8-10 membered fused cyclic group, a 7-8 membered monoheterocyclic group or an 8-10 membered fused heterocyclic group optionally substituted by 1-3 Q1;

[0040] Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b 、-OR a 、-SR a 、-C(O)R a , or the following group optionally substituted by 1-3 Q2: C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocycloalkyl, -(CH2) m -5-8 membered heteroaryl or -(CH2) m -phenyl; each Q2 is independently selected from deuterium, halogen, hydroxyl, nitro, -NR c R d , cyano or carboxyl;

[0041] R 1 is selected from 8-10 membered fused heteroaryl groups optionally substituted by 1-3 Q3, wherein Q3 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxyl C 1-4 Alkoxy, amino C 1-4Alkoxy;

[0042] R 2 is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, -NR a R b OR a ;

[0043] Each R a , each R b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy or -(CH2) optionally substituted by a substituent m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocycloalkyl, -(CH2) m -5-8 membered heteroaryl or -(CH2) m -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl;

[0044] Each R c , each R d are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy;

[0045] p is selected from 0, 1 or 2;

[0046] Each m is independently selected from 0, 1, 2 or 3.

[0047] In certain embodiments, X 1 , X 2 are independently selected from -C(R 3 )-or-N-;Y 1 , Y 2 , Y3 are independently selected from -C(R 4 ) or -N-; each R 3 , each R 4 are independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Alkoxy.

[0048] In certain embodiments, X 1 , X 2 are independently selected from -C(R 3 )-or-N-;Y 1 , Y 2 , Y 3 are independently selected from -C(R 4 ) or -N-; each R 3 , each R 4 Each is independently selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0049] In certain embodiments, X 1 , X 2 are independently selected from -C(R 3 )-or-N-;Y 1 , Y 2 , Y 3 are independently selected from -C(R 4 ) or -N-; each R 3 , each R 4 are independently selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0050] In certain embodiments, X 1 , X 2 are independently selected from -C(R 3 )-or-N-;Y 1 , Y 2 , Y 3 are independently selected from -C(R 4 ) or -N-; each R 3 , each R 4 Each is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0051] In certain embodiments, X 1 , X 2are independently selected from -CH- or -N-; Y 1 , Y 2 , Y 3 are independently selected from -CH- or -N-.

[0052] In certain embodiments, L 1 Selected from chemical bonds, -CR a R b -、-C(R a R b )-C(R a R b )-、-O-、-NR a -, -S-, -S(O)-, -C(O)-, -C(O)NR a -、-C(R a R b )-NR a -or-NR a -C(R a R b )-.

[0053] In certain embodiments, L 1 Selected from chemical bonds, -CR a R b -、-O-、-NR a -, -S-, or -C(O)-.

[0054] In certain embodiments, Ring A is selected from a 5-membered nitrogen-containing heteroaryl or a 7-8-membered monoheterocyclic group optionally substituted by 1-3 Q1; each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR a R b 、-OR a 、-SR a 、-C(O)R a , or the following group optionally substituted by 1-3 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocycloalkyl, -(CH2) m -5-8 membered heteroaryl or -(CH2) m -phenyl; the Q2 are independently selected from deuterium, halogen, hydroxyl, nitro, -NR c R d , cyano or carboxyl; R c , R d are independently selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl.

[0055] In certain embodiments, Ring A is selected from wherein n is selected from 0, 1, 2 or 3.

[0056] In certain embodiments, each Q1 is independently selected from fluoro, chloro, bromo, amino, cyano, hydroxy, carboxyl, nitro, -C(O)R a , or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -Oxetane, -(CH2) m -tetrahydrofuranyl, -(CH2) m -tetrahydropyranyl, -(CH2) m -tetrahydropyrrolyl, -(CH2) m -pyrazolidinyl, -(CH2) m -imidazolidinyl, -(CH2) m -piperazinyl or -(CH2) m -piperidinyl; the Q2 are independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, -NR c R d , cyano, carboxyl, nitro, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, pyrazolidinyl, imidazolidinyl, piperazinyl or piperidinyl; R c , R d Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0057] In certain embodiments, each Q1 is independently selected from cyano, -C(O)R a or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -Oxetane, -(CH2) m-tetrahydrofuranyl or -(CH2) m -tetrahydropyranyl; the Q2 are independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, -NR c R d , cyano, carboxyl or nitro; R c , R d Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0058] In certain embodiments, R 1 is selected from a 9-membered nitrogen-containing fused heteroaryl group optionally substituted by 1-3 Q3, wherein Q3 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxyl C 1-4 Alkoxy or amino C 1-4 Alkoxy.

[0059] In certain embodiments, R 1 is selected from a 9-membered nitrogen-containing fused heteroaryl group optionally substituted by 1-3 Q3, wherein Q3 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy.

[0060] In certain embodiments, R 1 Selected from the following groups optionally substituted by 1-3 Q3: Preferably, R 1 Selected from the following groups optionally substituted by 1-3 Q3:

[0061] In certain embodiments, Q3 is independently selected from fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy or trifluoroethoxy.

[0062] In certain embodiments, each R a , each R b are independently selected from hydrogen, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxyl C 1-4 Alkoxy, amino C 1-4 Alkoxy or -(CH2) optionally substituted by a substituent m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocycloalkyl, -(CH2) m -5-8 membered heteroaryl or -(CH2) m -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl.

[0063] In certain embodiments, each R a are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy or -(CH2) optionally substituted by a substituent m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocycloalkyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Alkyl; each R b are independently selected from hydrogen or C 1-4 alkyl.

[0064] In certain embodiments, each R a are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy; each R b are independently selected from hydrogen or C 1-4 alkyl.

[0065] In certain embodiments, each R aR is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, pyrazolidinyl, imidazolidinyl, piperazinyl or piperidinyl, wherein the substituent is selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0066] In certain embodiments, each R a are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl, trifluoromethoxy or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted by a substituent; the substituent is selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0067] In certain embodiments, each R a Each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl, trifluoromethoxy; b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0068] In certain embodiments, the compound, its deuterated product, its pharmaceutically acceptable salt or its stereoisomer has a structure shown in the following general formula (II-1) or general formula (II-2):

[0069]

[0070] in,

[0071] L 1 Selected from chemical bonds, -CR a R b -、-C(R a R b )-C(R a R b )-、-O-、-NR a -、-S-、-C(O)-、-C(O)NR a -、-C(R a R b )-NR a -or-NR a -C(R a R b )-;

[0072] Each R 2 are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0073] Ring A is selected from

[0074] Each Q1 is independently selected from cyano, -C(O)R a , or the following group optionally substituted by 1-3 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, -(CH2) m -3-6 membered cycloalkyl or -(CH2) m -3-6 membered heterocycloalkyl; preferably, each Q1 is independently selected from cyano, -C(O)R a , or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -Oxetane, -(CH2) m -tetrahydrofuranyl or -(CH2) m -tetrahydropyranyl;

[0075] Each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, -NR c R d , cyano, carboxyl or nitro;

[0076] R c , R d are independently selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, R c , R d are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

[0077] R 1 Selected from the following groups optionally substituted by 1-3 Q3:

[0078] Each Q3 is independently selected from fluorine, chlorine, bromine, iodine, nitro, cyano, amino, hydroxyl, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

[0079] Each R a Each of the following groups is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, oxetanyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

[0080] Each R b are independently selected from hydrogen or C 1-4 alkyl;

[0081] Each m, n, and p is independently selected from 0, 1 or 2.

[0082] In certain embodiments, R 1 Selected from the following groups optionally substituted by 1-3 Q3: The Q3 are independently selected from halogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, the Q3 are independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0083] In certain embodiments, R 1 Selected from the following groups: The Q3 are independently selected from halogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, the Q3 are independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0084] In certain embodiments, the compound, its deuterated product, its pharmaceutically acceptable salt or its stereoisomer has the structure shown in the following general formula (III-1) or general formula (III-2):

[0085]

[0086] Among them, ring A, R 2 , L 1 , Q1, Q2, Q3, R a , Rb , R c , R d , m, n, p are as defined above, and q is selected from 0, 1, 2 or 3.

[0087] In certain embodiments, the compound, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer has a structure shown in the following general formula (III-3) or general formula (III-4):

[0088]

[0089] Among them, ring A, R 2 , L 1 , Q1, Q2, Q3, R a , R b , R c , R d , m, n, p are as defined above, and q is selected from 0, 1, 2 or 3.

[0090] In certain embodiments, the compound, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer has a structure shown in the following general formula (III-5) or general formula (III-6):

[0091]

[0092] Among them, ring A, R 2 , L 1 , Q1, Q2, Q3, R a , R b , R c , R d , m, n, p are as defined above, and q is selected from 0, 1, 2 or 3.

[0093] In certain embodiments, the compound, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer, wherein:

[0094] L 1 Selected from chemical bonds, -CR a R b -, -O- or -NR a -;

[0095] Each R 2 are independently selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, each R 2 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

[0096] Ring A is selected from

[0097] Each Q1 is independently selected from cyano, -C(O)R a , or the following group optionally substituted by 1-3 Q2: C 1-4 Alkyl or -(CH2) m -3-6 membered cycloalkyl; preferably, each Q1 is independently selected from cyano, -C(O)R a , or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, -(CH2) m -cyclopropyl or -(CH2) m - cyclobutyl;

[0098] Each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, -NR c R d , cyano, carboxyl or nitro;

[0099] R c , R d are independently selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, R c , R d are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

[0100] Each Q3 is independently selected from halogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; preferably, each Q3 is independently selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

[0101] Each R a are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy; preferably, each R a Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl, trifluoromethoxy;

[0102] Each R b are independently selected from hydrogen or C 1-4 Alkyl; preferably, each R b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;

[0103] p is selected from 0 or 1;

[0104] Each m and n is independently selected from 0, 1 or 2.

[0105] In certain embodiments, Ring A is selected from Each Q1 is independently selected from cyano, -C(O)R a , C 1-4 Alkyl, deuterated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, halogenated C 1-4 Alkyl or 3-6 membered cycloalkyl.

[0106] In certain embodiments, Q1 is independently selected from cyano, -C(O)-methyl, methyl, ethyl, isopropyl, monofluoromethyl, monofluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl, deuterated methyl, deuterated ethyl, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclobutyl or

[0107] In certain embodiments, each R 2 are each independently H.

[0108] In certain embodiments, R a , R b are each independently H.

[0109] In certain embodiments, R c , R d are each independently H.

[0110] In certain embodiments, L 1 is selected from -NH- or O.

[0111] In the technical solution of the present invention, the hydrogen on the ring nitrogen atom in the ring A can be optionally replaced by Q1.

[0112] In certain embodiments, p is 0.

[0113] In certain embodiments, n is 1.

[0114] The various technical solutions in the present invention can be combined with each other to form new technical solutions, and the formed new technical solutions are also included in the scope of the present invention.

[0115] In certain embodiments, the aforementioned compound, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer is selected from the following compounds:

[0116]

[0117]

[0118] The present invention also provides a pharmaceutical composition, which contains the compounds described in the aforementioned general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (III-5), general formula (III-6), their deuterated products, pharmaceutically acceptable salts or their stereoisomers, and one or more pharmaceutical carriers and / or diluents; the pharmaceutical composition can be prepared into any clinically or pharmaceutically acceptable dosage form, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays, etc.

[0119] In certain embodiments of the present invention, the above-mentioned pharmaceutical preparations can be administered to patients or subjects who need such treatment by oral, parenteral, rectal or transpulmonary administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When made into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the above-mentioned pharmaceutical preparations can also be made into injections, including injections, sterile powders for injection and concentrated solutions for injection. When making injections, conventional methods in the existing pharmaceutical field can be used for production. When preparing injections, additives can be omitted or appropriate additives can be added according to the properties of the drugs. When used for rectal administration, the pharmaceutical composition can be made into suppositories, etc. When used for transpulmonary administration, the pharmaceutical composition can be made into inhalants or sprays, etc.

[0120] The pharmaceutically acceptable carrier and / or diluent used in the pharmaceutical composition or pharmaceutical preparation of the present invention can be any conventional carrier and / or diluent in the field of pharmaceutical preparations, and the selection of a specific carrier and / or diluent will depend on the mode of administration or the type and state of disease used to treat a specific patient. The preparation method of a suitable pharmaceutical composition for a specific mode of administration is completely within the knowledge of a person skilled in the art of medicine.

[0121] On the other hand, the present invention also relates to the use of the compounds of the aforementioned general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (III-5), general formula (III-6), their deuterated products, their pharmaceutically acceptable salts or stereoisomers in the preparation of drugs for preventing and / or treating diseases mediated by HPK1 and related diseases, and the drugs can be used in combination with one or more other drugs to prevent or treat diseases mediated by HPK1 and related conditions. The diseases and related conditions are selected from cancer or benign tumors, and the cancer includes carcinoma in situ and metastatic cancer. Furthermore, the cancer includes, but is not limited to, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female reproductive tract cancer, lymphoma, neurofibroma, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma or sarcoma, etc.

[0122] Furthermore, the present invention also relates to the use of pharmaceutical preparations containing the compounds of the aforementioned general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (III-5), general formula (III-6), their deuterated substances, pharmaceutically acceptable salts or stereoisomers thereof in the preparation of drugs, which can be used in combination with one or more drugs to treat and / or prevent diseases mediated by HPK1 and related conditions.

[0123] On the other hand, the drug comprising the compound of the aforementioned general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (III-5), general formula (III-6), its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer can be administered alone or used in combination with one or more second therapeutically active agents, which are used in combination with the HPK1 inhibitor compound of the present application to treat and / or prevent diseases and related conditions mediated by HPK1. Therefore, in certain embodiments, the pharmaceutical composition further contains one or more second therapeutically active agents. In certain embodiments, the second therapeutically active agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors, targeted antibodies, HMG-CoA reductase inhibitors and prenyl protein transferase inhibitors.

[0124] In certain embodiments, the components to be combined (e.g., a compound of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a second therapeutically active agent) may be administered simultaneously or sequentially separately. For example, the second therapeutically active agent may be administered before, simultaneously with, or after the administration of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. In addition, the components to be combined may also be administered in combination in the form of the same preparation or in the form of separate different preparations.

[0125] On the other hand, the present invention also provides a method for treating diseases and related conditions mediated by HPK1, which comprises administering to a patient in need thereof an effective amount of a compound of the aforementioned general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (III-3), general formula (III-4), general formula (III-5), general formula (III-6), its deuterated product, its pharmaceutically acceptable salt or its stereoisomer, the aforementioned preparation or pharmaceutical composition; the diseases and related conditions mediated by HPK1 are as defined above.

[0126] The "effective amount" is a dose of a drug that can alleviate, delay, inhibit or cure the condition of a subject. The size of the dose is determined by the drug administration method, the pharmacokinetics of the drug, the severity of the disease, the individual characteristics of the subject (gender, weight, height, age), etc. [Detailed description of the invention]

[0128] In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art, but in order to better understand the present invention, the definitions of some terms are provided below. When the definitions and explanations of the terms provided by the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided by the present invention shall prevail.

[0129] The "halogen" described in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0130] The "C 1-6 "Alkyl" means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example, "C 1-4 Alkyl", "C 1-3 Alkyl", "C 1-2 Alkyl", "C 2-6 Alkyl", "C 2-5 Alkyl", "C 2-4 Alkyl", "C 2-3 Alkyl", "C 3-6 Alkyl", "C 3-5 Alkyl", "C 3-4 Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The “C 1-4 "Alkyl" refers to C 1-6 Specific examples of alkyl groups contain 1 to 4 carbon atoms.

[0131] The "C 1-6 "Alkoxy" refers to "C 1-6 Alkyl-O-", the "C 1-6 "C alkyl" is as defined above. 1-4 "Alkoxy" refers to "C 1-4 Alkyl-O-", the "C 1-4 "Alkyl" is as defined above.

[0132] The "C 1-6 "Alkylthio" refers to "C 1-6 Alkyl-S-", the "C 1-6 "C alkyl" is as defined above. 1-4 "Alkylthio" refers to "C1-4 Alkyl-S-", the "C 1-4 "Alkyl" is as defined above.

[0133] The "hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 "Alkyl" refers to C 1-6 One or more hydrogen atoms in the alkyl group are replaced by one or more hydroxyl groups, amino groups or halogen groups. 1-6 Alkyl is as defined above

[0134] The "hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, halogenated C 1-6 "Alkoxy" refers to "C 1-6 One or more hydrogen atoms in the "alkoxy" group are replaced by one or more hydroxyl groups, amino groups or halogen groups.

[0135] The "hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, halo 1-6 "Alkylthio" refers to "C 1-6 One or more hydrogen atoms in the "alkylthio" group are replaced by one or more hydroxyl groups, amino groups or halogen groups.

[0136] The "C 1-6 Alkylamino, di(C 1-6 "alkyl)amino" refers to C 1-6 Alkyl-NH-,

[0137] The "3-15 membered cycloalkyl group" mentioned in the present invention includes "3-8 membered monocycloalkyl group" and "7-15 membered condensed cycloalkyl group".

[0138] The “3-8 membered monocycloalkyl” described in the present invention refers to a saturated or partially saturated monocyclic alkyl group containing 3-8 carbon atoms and not aromatic, including “3-8 membered saturated monocycloalkyl” and “3-8 membered partially saturated monocycloalkyl”; preferably “3-4 membered monocycloalkyl”, “3-5 membered monocycloalkyl”, “3-6 membered monocycloalkyl”, “3-7 membered monocycloalkyl”, “4-5 membered monocycloalkyl”, “4-6 membered monocycloalkyl”, “4-7 membered monocycloalkyl”, “4-8 membered monocycloalkyl”, “5-6 membered monocycloalkyl”, “5-7 membered monocycloalkyl”, “5-8 membered monocycloalkyl”, “6-7 membered monocycloalkyl”, “6-8 membered monocycloalkyl”, “7-8 membered monocycloalkyl”, “3-6 membered saturated monocycloalkyl”, “5-8 membered saturated monocycloalkyl”, “5-7 membered saturated monocycloalkyl”, “5-6 membered saturated monocycloalkyl”, etc. Specific examples of the “3-8 membered saturated monocyclic alkyl” include, but are not limited to, cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentanyl (cyclopentyl), cyclohexanyl (cyclohexyl), cycloheptanyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the “3-8 membered partially saturated monocyclic alkyl” include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl, cyclooctenyl, cyclooct-1,3-dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0139] The "7-15 membered fused cycloalkyl" described in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-15 ring atoms, which is formed by two or more cyclic structures sharing two adjacent carbon atoms. One ring in the fused ring can be an aromatic ring, but the fused ring as a whole does not have aromaticity; it includes "8-9 membered fused ring group", "9-10 membered fused ring group", etc., and the fusion mode can be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl, etc. Examples include, but are not limited to, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrenyl, bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydropentalenyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl and the like.

[0140] The "3-10 membered cycloalkyl group" described in the present invention refers to a specific example of the "3-15 membered cycloalkyl group" containing 3 to 10 carbon atoms.

[0141] The "7-15 membered cycloalkyl group" described in the present invention refers to a specific example of the "3-15 membered cycloalkyl group" containing 7 to 15 carbon atoms.

[0142] The "3-15 membered heterocyclic group" described in the present invention includes "3-8 membered monoheterocyclic group" and "7-15 membered condensed heterocyclic group".

[0143] The "3-8 membered monoheterocyclic group" of the present invention refers to a saturated or partially saturated monocyclic group without aromaticity, containing at least one heteroatom (e.g., 1, 2, 3, 4 or 5) and having 3-8 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure may be oxidized. The "3-8 membered monoheterocyclic group" of the present invention includes "3-8 membered saturated monoheterocyclic group" and "3-8 membered partially saturated monoheterocyclic group". Preferably, the "3-8 membered monoheterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered monoheterocyclic group" of the present invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-8 membered monoheterocyclic group" of the present invention contains 1 nitrogen atom. The “3-8 membered monoheterocyclic group” is preferably a “3-7 membered monoheterocyclic group”, “3-6 membered monoheterocyclic group”, “4-7 membered monoheterocyclic group”, “4-6 membered monoheterocyclic group”, “6-8 membered monoheterocyclic group”, “7-8 membered monoheterocyclic group”, “5-7 membered monoheterocyclic group”, “5-6 membered monoheterocyclic group”, “3-6 membered saturated monoheterocyclic group”, “5-6 membered saturated monoheterocyclic group”, “3-6 membered nitrogen-containing monoheterocyclic group”, “3-6 membered saturated nitrogen-containing monoheterocyclic group”, “5-6 membered nitrogen-containing monoheterocyclic group”, “5-6 membered saturated nitrogen-containing monoheterocyclic group”, etc. For example, it contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and other 1 or 2 heteroatoms (such as oxygen atoms and / or sulfur atoms). Specific examples of the "3- to 8-membered monoheterocyclic group" include, but are not limited to, aziridine, 2H-aziridine, diaziridine, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl, etc.

[0144] The "7-15 membered fused heterocyclic group" of the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-15 ring atoms formed by two or more cyclic structures sharing two adjacent atoms, and at least one ring atom is a heteroatom, wherein one of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxidized, including but not limited to "8-9 membered fused heterocyclic group" The condensed form can be 5-6-membered heterocyclic group and 5-6-membered heterocyclic group, 5-6-membered heterocyclic group and 5-6-membered cycloalkyl, benzo 5-6-membered heterocyclic group, benzo 5-6-membered saturated heterocyclic group, benzo 6-7-membered heterocyclic group, benzo 6-7-membered saturated heterocyclic group, 5-6-membered heteroaryl and 5-6-membered heterocyclic group, 5-6-membered heteroaryl and 5-6-membered saturated heterocyclic group; 5-6-membered heteroaryl is as defined above; specific examples of the "8-10-membered condensed heterocyclic group" include but are not limited to: pyrrol pyrrolidinyl, cyclopropyl, cyclopentylaziridinyl, pyrrolidinyl, cyclobutyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, morpholinyl, piperidyl, morpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridocyclopentyl, pyridocyclohexyl, pyridotetrahydrofuranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidothiazolidinyl, pyrimidothiazolidinyl, pyrimidotmorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl;tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H- Furano[3,4-d]imidazolyl, 4,6-dihydro-1H-thieno[3,4-d]imidazolyl, 4,6-dihydro-1H-pyrrolo[3,4-d]imidazolyl, octahydro-benzo[d]imidazolyl, decahydroquinolinyl, hexahydrothienoimidazolyl, hexahydrofuranoimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, 4H-1,3-benzoxazinyl, etc. ;

[0145] The "3-10 membered heterocyclic group" described in the present invention refers to a specific example of a "3-15 membered heterocyclic group" containing 3 to 10 ring atoms.

[0146] The "7-15 membered heterocyclic group" described in the present invention refers to a specific example of the "3-15 membered heterocyclic group" containing 7 to 15 ring atoms.

[0147] The term "benzocyclopentyl" refers to the structure (also known as 2,3-dihydro-1H-indenyl); the term "benzopyrrolidine" includes etc.; the term "pyridotetrahydrofuranyl" includes Other specific examples of the "other defined fused heterocyclic groups" defined above have similar ring structures.

[0148] The “6-15 membered aryl group” described in the present invention includes “6-8 membered monocyclic aryl group” and “8-15 membered condensed ring aryl group”.

[0149] The "6-8 membered monocyclic aromatic group" described in the present invention refers to a monocyclic aromatic group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0150] The "8-15 membered fused ring aromatic group" described in the present invention refers to an unsaturated aromatic cyclic group containing 8-15 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms, preferably a "9-10 membered fused ring aromatic group", and specific examples include naphthyl and the like.

[0151] The “5-15 membered heteroaryl group” described in the present invention includes “5-8 membered single heteroaryl group” and “8-15 membered fused heteroaryl group”.

[0152] The "5-8 yuan single heteroaryl" of the present invention refers to a monocyclic cyclic group with aromaticity containing 5-8 ring atoms (wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxo-substituted. "5-8 yuan single heteroaryl" includes, for example, "5-7 yuan single heteroaryl", "5-6 yuan single heteroaryl", "5-6 yuan nitrogen-containing single heteroaryl", "6 yuan nitrogen-containing single heteroaryl", etc., and the heteroatom in the "nitrogen-containing heteroaryl" contains at least one nitrogen atom, for example, only 1 or 2 nitrogen atoms, or, one nitrogen atom and other 1 or 2 heteroatoms (such as oxygen atoms and / or sulfur atoms), or, 2 nitrogen atoms and other 1 or 2 heteroatoms (such as oxygen atoms and / or sulfur atoms). Specific examples of “5-8 membered monocyclic heteroaryl” include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, and the like. The "5- to 6-membered monoheteroaryl" refers to a specific example of a 5- to 8-membered heteroaryl containing 5 to 6 ring atoms.

[0153] The "8-15 membered fused heteroaryl" described in the present invention refers to an unsaturated aromatic cyclic structure formed by two or more cyclic structures sharing two adjacent atoms, containing 8-15 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxo-substituted. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., and the fusion mode can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furathiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0154] The "carbon atom, nitrogen atom or sulfur atom is substituted with oxygen" mentioned in the present invention refers to the formation of a structure of C=O, N=O, S=O or SO2.

[0155] The "C(R a )(R b )" refers to R a , R b The groups formed by replacing two hydrogen atoms on the methylene group are specifically connected in the following manner:

[0156] The term "optionally substituted" used in the present invention refers to two situations in which one or more hydrogen atoms on the substituted group may be "substituted" or "not substituted" by one or more substituents.

[0157] The "deuterated compound" of the present invention refers to one or more 1 H is 2 H (also denoted as "D") substituted to form the structure.

[0158] The "pharmaceutically acceptable salt" of the present invention refers to a salt formed by an acidic functional group (e.g., -COOH, -OH, -SO3H, etc.) present in a compound and a suitable inorganic or organic cation (base), including a salt formed with an alkali metal or alkaline earth metal, an ammonium salt, and a salt formed with a nitrogen-containing organic base; and a salt formed by a basic functional group (e.g., -NH2, etc.) present in a compound and a suitable inorganic or organic anion (acid), including a salt formed with an inorganic acid or an organic acid (e.g., carboxylic acid, etc.). Examples thereof include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, bismuth salts, hydrochlorides, sulfates, nitrates, phosphates, hydrobromides, hydroiodides, formates, acetates, propionates, oxalates, malonates, succinates, maleates, fumarates, lactates, malates, citrates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, tetrafluoroborate, arginine salts, aspartates, and glutamic acid, etc.

[0159] The "isomer" of the present invention refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of the present invention may have asymmetric centers, and such asymmetric centers each independently produce two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefin double bonds, unless otherwise specified, cis isomers and trans isomers are included. The compounds of the present invention may exist in the form of tautomers (a kind of functional group isomers), which have different hydrogen connection points through one or more double bond displacements, for example, ketones and their enol forms are keto-enol tautomers. The compounds of the present invention contain a spirocyclic structure, and under the influence of the three-dimensional spatial structure of the ring, the substituents on the ring may exist on both sides of the ring to form relative cis (cis) and trans (trans) isomers. Each tautomer and its mixture are included in the scope of the present invention. All enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds are included in the scope of the present invention.

[0160] The compounds of the present invention can be prepared by enantiospecific synthesis or by resolution from a mixture of enantiomers to give individual enantiomers. Conventional resolution techniques include the use of optically active acids to form salts of the free bases of each isomer of an enantiomeric pair (followed by fractional crystallization and regeneration of the free base), the use of optically active amines to form salts of the acid forms of each enantiomer of an enantiomeric pair (followed by fractional crystallization and regeneration of the free acid), the use of optically pure acids, amines or alcohols to form esters or amides of each of the enantiomers of an enantiomeric pair (followed by chromatographic separation and removal of the chiral auxiliary), or the use of various well-known chromatographic methods to resolve the enantiomeric mixture of the starting material or final product.

[0161] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Optical purity wt% is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

[0162] The "dosage form" mentioned in the present invention refers to a form of a drug suitable for clinical use, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections, sterile powders for injection and concentrated solutions for injection), sprays, aerosols, powder sprays, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.

[0163] Advantageous Effects of the Invention

[0164] 1. The compound of the present invention, its deuterated product, its pharmaceutically acceptable salt or its stereoisomer has excellent and highly selective HPK1 activity inhibition effect.

[0165] 2. The compounds of the present invention, their deuterated products, their pharmaceutically acceptable salts or their stereoisomers have good pharmacokinetic properties in vivo, long-lasting effects, good exposure and bioavailability, and can treat and / or prevent diseases mediated by HPK1.

[0166] 3. The compounds of the present invention, their deuterated products, their pharmaceutically acceptable salts or their stereoisomers have a good therapeutic effect on HPK1-mediated cancers. Specific implementation plan

[0167] The technical solution of the present invention will be described below in conjunction with specific implementation methods, and the above content of the present invention will be further described in detail, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0168] The abbreviations used in the following experiments have the following meanings:

[0169] CuCl2·2H2O: Copper chloride dihydrate Boc2O: Di-tert-butyl dicarbonate DIEA: N,N-diisopropylethylamine

[0170] DCM: dichloromethane THF: tetrahydrofuran PE: petroleum ether

[0171] EA: ethyl acetate MeOH: methanol TBSCl: tert-butyldimethylsilyl chloride

[0172] CuI: iodide MeCN: acetonitrile SiO2: silicon dioxide

[0173] Pd2(dba)3: tris dibenzylideneacetone dipalladium TFA: trifluoroacetic acid

[0174] Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene LDA: lithium diisopropylamide

[0175] XPhos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)

[0176] RuPhosPdG3: methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)

[0177] Pd(dppf)Cl2:1,1'-bis(diphenylphosphinoferrocene)palladium dichloride m-CPBA:m-chloroperbenzoic acid

[0178] Example 1: Preparation of 7-((7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one (Compound 1)

[0179]

[0180] 1. Preparation of 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepine-2-amine trifluoroacetate

[0181] 2-(tert-Butylamino)-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylic acid tert-butyl ester (1.0 g) was dissolved in trifluoroacetic acid (10 mL). The system was reacted at 80° C. for 2 hours and then concentrated and used directly in the next reaction.

[0182] 2. Preparation of tert-butyl 2-amino-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylate

[0183] The crude product of the previous step was dissolved in dichloromethane (10 mL), and triethylamine (1.0 g, 9.89 mmol) and Boc2O (680 mg, 3.11 mmmol) were added. The system was reacted at 25°C for 1 hour and then concentrated. The residue was purified by column chromatography (EA / PE=50%) to obtain 100 mg of the target compound.

[0184] 3. Preparation of tert-butyl 2-((2-(tert-butoxycarbonyl)-7-chloro-3-oxoisoindolin-4-yl)amino)-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylate

[0185] 2-Amino-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylic acid tert-butyl ester (100 mg, 0.38 mmol), 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (134 mg, 0.39 mmol), Pd2(dba)3 (40 mg, 0.05 mmol), Xantphos (29 mg, 0.05 mmol) and cesium carbonate (260 mg, 0.80 mmol) were dissolved in 10 ml of dioxane, and the system was reacted at N2100°C for 5.5 hours. After concentration, the residue was purified by column chromatography (EA / PE=50%) to obtain 85 mg of the target product with a yield of 42.5%.

[0186] 4. Preparation of tert-butyl 2-((2-(tert-butyloxycarbonyl)-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-4-yl)amino)-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylate

[0187] 2-((2-(tert-butoxycarbonyl)-7-chloro-3-oxoisoindolin-4-yl)amino)-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylic acid tert-butyl ester (75 mg, 0.14 mmol), bis-boronic acid pinacol ester (75 mg, 0.30 mmol), potassium acetate (35 mg, 0.36 mmol) and XPhos-Pd-G2 (20 mg, 0.03 mmol) were dissolved in dioxane (5 mL) and reacted at 90° C. for 2 hours. After concentration, the residue was subjected to column chromatography (EA / PE=35%) to obtain 80 mg of the target product with a yield of 90.9%.

[0188] 5. Preparation of tert-butyl 2-((2-(tert-butoxycarbonyl)-7-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxoisoindolin-4-yl)amino)-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylate

[0189] 2-((2-(tert-Butyloxycarbonyl)-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-4-yl)amino)-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylic acid tert-butyl ester (80 mg, 0.13 mmol), 3-bromo-6-methylpyrazolo[1,5-a]pyridine (35 mg, 0.16 mmol), potassium phosphate (65 mg, 0.31 mmol) and XPhos-Pd-G2 (28 mg, 0.03 mmol) were dissolved in dioxane (7 mL) and water (1.3 mL) and reacted at 90° C. for 2 hours. After concentration, the residue was subjected to column chromatography (EA / PE=50%) to obtain 30 mg of the target product with a yield of 37.3%.

[0190] 6. Preparation of 4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-7-((6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-2-yl)amino)isoindolin-1-one hydrochloride

[0191] 2-((2-(tert-Butyloxycarbonyl)-7-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxoisoindolin-4-yl)amino)-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepine-6-carboxylic acid tert-butyl ester (25 mg) was dissolved in 5 mL of hydrochloric acid and ethyl acetate solution, reacted at 25°C for 1 hour, concentrated, and directly used in the next reaction.

[0192] 7. Preparation of 7-((7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one

[0193] The crude product from the previous step was dissolved in methanol (5.0 mL), and 37% formaldehyde (30 mg, 0.37 mmol), acetic acid (24 mg, 0.40 mmol) and sodium cyanoborohydride (30 mg, 0.48 mmol) were added, and the reaction was completed at 25°C for 1.0 hour. After concentration, the residue was subjected to column chromatography (EA / PE=60%) to obtain 2 mg of the target product.

[0194] Molecular formula: C 26 H 26 N6O molecular weight: 438.5 LC-MS (M / e): 438.2 (M+H + )

[0195] 1H-NMR(400MHz,DMSO)δ:9.70(s,1H),8.81-8.8(m,1H),8.32(s,1H),7.96(s,1H),7.65-7.61(d,1H),7.59-7.57(d,1H),7.35(s,1H),7.15-7. 05(d,1H),6.75-6.73(d,1H),6.08(s,1H),4.61-6.59(s,2H),3.3-3.2 (m,2H),2.9-2.85(m,2H),2.75-2.6(m,4H),2.41(s,3H),2.39(s,3H).

[0196] Example 2: Preparation of 7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one (Compound 2)

[0197]

[0198]

[0199] 1. Preparation of 7,8-dihydroquinoline-5(6H)-monoxime

[0200] Dissolve 7,8-dihydroquinolin-5(6H)-one (10 g, 67.9 mmol), hydroxylamine hydrochloride (7.08 g, 101.9 mmol), and pyridine (10.74 g, 135.8 mmol) in ethanol (150 mL), react at 80 ° C for 2 h, cool down, add water (600 mL), filter, and dry the filter cake to obtain the target compound (11 g, 99.8%).

[0201] 2. Preparation of 7,8-dihydroquinolin-5(6H)-one o-toluenesulfonyl oxime

[0202] Dissolve 7,8-dihydroquinoline-5(6H)-monoxime (11 g, 67.8 mmol), triethylamine (13.7 g, 135.6 mmol) and p-toluenesulfonyl chloride (15.5 g, 81.4 mmol) in dichloromethane (150 mL), react at 20°C for 2 hours, add water (200 mL) for washing after the reaction, separate the liquids, and the organic phase is spin-dried and purified by column chromatography (ethyl acetate / n-heptane = 50%) to obtain the target compound (19 g, 88.5%).

[0203] 3. Preparation of 5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepine-6-one

[0204] Dissolve 7,8-dihydroquinolin-5(6H)-one o-toluenesulfonyl oxime (19 g, 60 mmol) and potassium acetate (17.66 g, 180 mmol) in ethanol (100 mL) and water (200 mL), react at 95°C for 16 hours, remove ethanol, extract with ethyl acetate (100 mL x 5), combine the organic phases, dry them, and chromatograph them (ethyl acetate / n-heptane = 0-100%) to obtain the target compound (4.4 g, 45.2%).

[0205] 4. Preparation of 5-methyl-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepine-6-one

[0206] 5,7,8,9-Tetrahydro-6H-pyrido[3,2-b]azepin-6-one (3.4 g, 21.0 mmol) was dissolved in tetrahydrofuran (100 mL), 60% sodium hydride (1 g, 25.0 mmol) was added at 0°C, and the mixture was reacted at 0°C for 1 hour. Iodomethane (3.55 g, 25.0 mmol) was added at 0°C, and the mixture was reacted at 25°C for 4 hours. The mixture was cooled to 0°C, quenched with water, the solvent was spin-dried, and the target compound (3.3 g, 89.2%) was obtained by column chromatography (0-100% ethyl acetate).

[0207] 5. Preparation of 5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine-1-oxide

[0208] Dissolve 5-methyl-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-one (3.3 g, 18.8 mmol) in dichloromethane (100 mL), add m-chloroperbenzoic acid (4.8 g, 28.1 mmol), and react at 25°C for 2 hours. LCMS detection shows that the reaction is complete. Dilute the reaction solution with dichloromethane, wash with saturated sodium bicarbonate aqueous solution, and dry and concentrate the organic phase for direct use in the next step.

[0209] 6. Preparation of 2-(tert-butylamino)-5-methyl-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepine-6-one

[0210] Dissolve 5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine 1-oxide (N / A, 18.8 mmol) in dichloromethane (50 mL), add p-toluenesulfonic anhydride (12.3 g, 37.6 mmol) and tert-butylamine (6.9 g, 94.0 mmol), and react at 25°C for 2 hours. LCMS detection of the reaction is complete. Wash with water, extract with dichloromethane, dry the organic phase, spin dry, and separate by silica gel column chromatography (methanol: dichloromethane = 1:10) to obtain 700 mg of the target compound, with a yield of 15.1% (two steps).

[0211] 7. Preparation of N-(tert-butyl)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine-2-amine

[0212] Dissolve 2-(tert-butylamino)-5-methyl-5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepine-6-one (700.0 mg, 2.8 mmol) in tetrahydrofuran (20 mL), add lithium aluminum hydride (538.5 mg, 14.2 mmol) at 0°C, and react at 25°C for 4 hours. LCMS detected that the reaction was complete. At 0°C, water was added to quench the reaction, filtered through diatomaceous earth, the filtrate was concentrated, and separated by silica gel column chromatography (methanol: dichloromethane = 1:20) to obtain 420 mg of the target compound with a yield of 63.6%.

[0213] 8. Preparation of 5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine-2-amine

[0214] Dissolve N-(tert-butyl)-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine-2-amine (420.0 mg, 1.80 mmol) in trifluoroacetic acid (10 mL) and react at 80°C for 6 hours. LCMS detected that the reaction was complete. Concentrate the solvent, dissolve the solid in dichloromethane, wash with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, spin dry, and separate by silica gel column chromatography (methanol: dichloromethane = 1:10) to obtain 300 mg of the target compound with a yield of 94.0%.

[0215] 9. Preparation of tert-butyl 4-chloro-7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-2-yl)amino)-1-oxoisoindoline-2-carboxylate

[0216] 5-Methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine-2-amine (297.7 mg, 1.7 mmol), tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (581.9 mg, 1.7 mmol), Pd2(dba)3 (155.6 mg, 0.17 mmol), XantPhos (196.8 mg, 0.34 mmol) and cesium carbonate (1.1 g, 3.4 mmol) were dissolved in 1,4-dioxane (22 mL) and reacted at 100°C for 2 hours under nitrogen protection. The reaction was completed by LCMS. The temperature was lowered to 25°C, filtered through diatomaceous earth, and the filtrate was concentrated. The target compound (700 mg) was obtained by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) with a yield of 94.0%.

[0217] 10. Preparation of tert-butyl 7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3-dioxaborol-2-yl)isoindoline-2-carboxylate

[0218] Dissolve tert-butyl 4-chloro-7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine-2-yl)amino)-1-oxoisoindole-2-carboxylate (479.0 mg, 1.1 mmol) in 1,4-dioxane (50 mL), add bis(pinacol) borate (558.8 mg, 2.2 mmol), potassium acetate (215.8 mg, 2.2 mmol) and Xphos Pd G2 (85.8 mg, 0.11 mmol), and react at 90° C. for 4 hours under nitrogen protection. LCMS detected the completion of the reaction. Concentrate the solvent, separate by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 470 mg of the target compound, with a yield of 81.2%.

[0219] 11. Preparation of tert-butyl 7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-2-yl)amino-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate

[0220] 7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3-dioxaborin-2-yl)isoindoline-2-carboxylic acid tert-butyl ester (470.0 mg, 0.88 mmol), 3-bromo-6-methylpyrazolo[1,5-a]pyridine (139.7 mg, 0.66 mmol), Xphos Pd G2 (177.8 mg, 0.23 mmol), potassium phosphate (483.4 mg, 2.28 mmol) were dissolved in 1,4-dioxane (20 mL) and water (2 mL), and the mixture was reacted at 90° C. under nitrogen protection for 6 hours. The reaction was completed by LCMS. The solvent was concentrated and separated by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain 210 mg of the target compound in a yield of 59.1%.

[0221] 12. Preparation of 7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one hydrochloride

[0222] Dissolve tert-butyl 7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate (200.0 mg, 0.37 mmol) in ethyl acetate (10 mL), add hydrogen chloride / ethyl acetate (5 mL), and react at 25° C. for 30 minutes. LCMS detected that the reaction was complete. Filter to obtain a solid, and dry the solid to obtain 160 mg of the target compound with a yield of 90.7%.

[0223] 13. Preparation of 7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one

[0224] 7-((5-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one hydrochloride (60 mg, 0.13 mmol) was dissolved in ethyl acetate (10 mL) and saturated sodium bicarbonate aqueous solution (10 mL) and reacted at 25°C for 30 minutes. The organic phase was concentrated and purified on a Pre-TLC plate (dichloromethane:methanol=20:1) to obtain 24.0 mg of the target compound with a yield of 43.3%.

[0225] Molecular formula: C 26 H26 N6O molecular weight: 438.5 LC-MS (M / e): 439.1 (M+H + )

[0226] 1 H-NMR(400MHz,DMSO)δ:9.77(s,1H),8.74(s,1H),8.52-8.57(m,2H),8.23(s, 1H),7.76(d,J=8.8Hz,1H),7.66(d,J=8.4Hz,1H),7.31(d,J=8.8Hz,1H),7.17 (d,J=8.4Hz,1H),6.80(d,J=8.4Hz,1H),4.49(s,2H),2.92-2.95(m,2H),2.83 -2.85(m,2H),2.78(s,3H),2.33(s,3H),1.71-1.82(m,2H),1.55-1.68(m,2H).

[0227] Example 3: Preparation of 7-((7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-ylisoindolin-1-one (Compound 4)

[0228]

[0229] 1. Preparation of tert-butyl 5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0230] Propargylamine (20.0 g, 0.36 mol) was dissolved in isopropanol (500 mL), the system was heated to 60°C, tert-butyl 4-oxoazepane-1-carboxylate (50.0 g, 0.23 mol) and CuCl2·2H2O (4.0 g, 23.0 mmol) were added, and the system temperature was raised to 84°C for 16.0 hours. After the reaction was completed, the mixture was concentrated and the residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain compound 17g with a yield of 29.8%.

[0231] 2. Preparation of 7-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-1-oxide

[0232] 5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylic acid tert-butyl ester (17.0 g, 68.5 mmol) was dissolved in dichloromethane (200 mL), and m-chloroperbenzoic acid (14.3 g, 82.9 mmol) was added to the system, and the mixture was reacted at 25° C. for 2.0 hours. After the reaction, the mixture was washed with a saturated sodium bicarbonate solution, separated, and the organic phase was concentrated to obtain compound 17 g, with a yield of 94.0%.

[0233] 3. Preparation of tert-butyl 2-(tert-butylamino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0234] 7-(tert-Butoxycarbonyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-1-oxide (17.0 g, 68.5 mmol) was dissolved in dichloromethane (300 mL). p-Toluenesulfonic anhydride (14.3 g, 82.9 mmol) and tert-butylamine (21.0 g, 287.3 mmol) were added to the system at 20°C. The reaction was terminated after 3.0 hours. The organic phase residue was washed with water, separated and concentrated, and subjected to column chromatography (ethyl acetate / petroleum ether = 10%) to obtain 900 mg of the target compound. The yield was 4.0%.

[0235] 4. Preparation of 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-2-amine trifluoroacetate

[0236] Dissolve tert-butyl 2-(tert-butylamino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (420 mg, 1.31 mmol) in trifluoroacetic acid (10 mL), heat to 80°C and react for 2 hours. After the reaction is completed, the solution is concentrated and used directly in the next reaction.

[0237] 5. Preparation of tert-butyl 2-amino-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0238] The crude product from the previous step was dissolved in dichloromethane (10 mL), and triethylamine (300 mg, 2.96 mmol) and Boc2O (370 mg, 1.69 mmol) were added to react at 25°C for 1 hour. After the reaction, the reaction solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 50%) to obtain 300 mg of the target compound, with a two-step yield of 86.7%.

[0239] 6. Preparation of tert-butyl 2-((2-(tert-butoxycarbonyl)-7-chloro-3-oxidoisoindolin-4-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0240] 2-Amino-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylic acid tert-butyl ester (290 mg, 1.10 mmol), 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (400 mg, 1.15 mmol), Pd2(dba)3 (120 mg, 0.13 mmol), Xantphos (70 mg, 0.12 mmol) and cesium carbonate (700 mg, 2.15 mmol) were dissolved in 10 ml of dioxane, and the temperature was raised to 100° C. under N2 protection to react for 6.0 hours. After the reaction, the target product was concentrated and purified by column chromatography (ethyl acetate / petroleum ether=50%) to obtain 180 mg of the yield of 30.9%.

[0241] 7. Preparation of tert-butyl 2-((2-(tert-butyloxycarbonyl)-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-4-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0242] 2-((2-(tert-butoxycarbonyl)-7-chloro-3-oxidoisoindolin-4-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylic acid tert-butyl ester (160 mg, 0.30 mmol), bis-boronic acid pinacol ester (155 mg, 0.61 mmol), potassium acetate (60 mg, 0.61 mmol) and XPhos-Pd-G2 (25 mg, 0.03 mmol) were dissolved in dioxane (10 mL) and reacted at 90° C. for 2 hours. After the reaction was completed, the target product was concentrated and purified by column chromatography (ethyl acetate / petroleum ether=35%) to obtain 150 mg of the target product with a yield of 80.0%.

[0243] 8. Preparation of tert-butyl 2-((2-(tert-butoxycarbonyl)-7-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxoisoindolin-4-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0244] 2-((2-(tert-Butyloxycarbonyl)-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-4-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylic acid tert-butyl ester (140 mg, 0.23 mmol), 3-bromo-6-methylpyrazolo[1,5-a]pyridine (50 mg, 0.23 mmol), potassium phosphate (110 mg, 0.52 mmol) and XPhos-Pd-G2 (50 mg, 0.06 mmol) were dissolved in dioxane (10 mL) and water (2 mL) and reacted at 90°C for 2 hours. After the reaction, the target product (100 mg) was obtained by concentration and column chromatography (ethyl acetate / petroleum ether = 50%) with a yield of 70.0%.

[0245] 9. Preparation of 4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-7-((6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)isoindolin-1-one hydrochloride

[0246] Dissolve tert-butyl 2-((2-(tert-butoxycarbonyl)-7-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxoisoindolin-4-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (90 mg, 0.14 mmol) in 5 mL of hydrochloric acid and ethyl acetate solution, react at 25°C for 1 hour, and use it directly in the next reaction after concentration.

[0247] 10. Preparation of 7-((7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-ylisoindolin-1-one

[0248] The crude product from the previous step was dissolved in methanol (5.0 mL), and 37% formaldehyde (40 mg, 0.49 mmol), acetic acid (90 mg, 1.50 mmol) and sodium cyanoborohydride (120 mg, 1.91 mmol) were added, and the mixture was reacted at 25°C for 1.0 hour. After the reaction was completed, the target product (11 mg) was obtained by concentration and column chromatography (ethyl acetate / petroleum ether = 60%), and the yield of the two steps was 17.4%.

[0249] Molecular formula: C 26 H 26 N6O molecular weight: 438.5 LC-MS (M / e): 439.0 (M+H+)

[0250] 1H-NMR(400MHz,DMSO)δ:9.70(s,1H),8.81-8.8(m,1H),8.32(s,1H),7.96(s,1H),7.65-7.61(d,1H),7.59-7.57(d,1H),7.35(s 1H),7.15-7.05(d,1H),6.75-6.73(d,1H),6.08(s,1H),4.61-6.59(s,2H),3 .3-3.2(m,2H),2.9-2.85(m,2H),2.75-2.6(m,4H),2.41(s,3H),2.39(s,3H).

[0251] Example 4: Preparation of 7-((7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepin-3-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one (Compound 5)

[0252]

[0253] 1. Preparation of N-(5-bromo-4-methylpyridin-2-yl)-pivalamide

[0254] Dissolve 5-bromo-4-methyl-2-aminopyridine (50 g, 0.27 mol) in DCM (500 mL), add triethylamine (35 g, 0.35 mol) and pivaloyl chloride (39 g, 0.32 mol) at 0°C, and move to 35°C for 4 hours. Add dichloromethane and water to the reaction solution, separate and extract three times, spin dry the organic phase, separate on a silica gel column (PE:EA=5:1), and obtain 52 g of the product with a yield of 72%.

[0255] 2. Preparation of N-(5-bromo-4-(2-hydroxyethyl)pyridin-2-yl)-pivalamide

[0256] N-(5-bromo-4-methylpyridin-2-yl)-pivalamide (44g, 0.16mol) was dissolved in THF (300mL), and LDA tetrahydrofuran solution (2M, 200mL, 0.4mol) was added dropwise under nitrogen protection at zero degrees. After 1 hour, paraformaldehyde (29g, 0.96mol) was added. After the addition was completed, the mixture was moved to 30°C for reaction for 16 hours. After the reaction was completed, the reaction solution was quenched by adding saturated sodium bicarbonate solution, and then EA and water were added for three times of liquid extraction. The organic phase was dried and spin-dried, and the product 22.5g was obtained by forward preparative separation (PE:EA=5:1-1:1), with a yield of 46%.

[0257] 3. Preparation of N-(5-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)pivalamide

[0258] Dissolve N-(5-bromo-4-(2-hydroxyethyl)pyridin-2-yl)-pivalamide (22 g, 73.3 mmol) in DCM (200 mL), add imidazole (10 g, 146.6 mmol) and TBSCl (16.7 g, 110.0 mmol) at 0°C, and react at 30°C for 1 h. After the reaction is complete, add DCM and dilute hydrochloric acid to separate and extract three times, and the organic phase is spin-dried to obtain 28.1 g of the product with a yield of 92.7%.

[0259] 4. Preparation of (E)-N-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(2-ethoxyvinyl)pyridin-2-yl)pivalamide

[0260] N-(5-bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)tivalamide (28g, 67.6mmol), (Z)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (16g, 81.1mmol), tetrakis(triphenylphosphine)palladium (7.9g, 6.8mmol) and sodium carbonate (14.3g, 135.2mmol) were dissolved in dioxane (300mL), water (50mL) was added, and the mixture was reacted at 80°C for 4h under nitrogen protection. After the reaction was completed, EA and water were added to the reaction solution for three times of liquid extraction, the organic phase was spin-dried, and the product was obtained by normal phase preparative separation (PE:EA=10:1) with a yield of 32.8%.

[0261] 5. Preparation of N-(4-(2-hydroxyethyl)-5-(2-oxoethyl)pyridin-2-yl)-pivalamide

[0262] Dissolve (E)-N-(4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(2-ethoxyvinyl)pyridin-2-yl)tivalamide (8.9 g, 21.9 mmol) in acetonitrile (200 mL), add 1M hydrochloric acid solution (109.6 mL, 109.6 mmol), and react at 80°C for 2 h. After the reaction is completed. Add saturated sodium bicarbonate solution to adjust pH to 8-9, add EA and water for three times of liquid extraction, the organic phase is spin-dried, and separated by reverse phase preparation (water: acetonitrile = 1:2) to obtain 3 g of the product with a yield of 51.9%.

[0263] 6. Preparation of N-(4,5-bis(2-hydroxyethyl)pyridin-2-yl)-pivalamide

[0264] N-(4-(2-hydroxyethyl)-5-(2-oxoethyl)pyridin-2-yl)-tivalamide (3g, 11.4mmol) was dissolved in THF (5mL), methanol (5mL) was added, sodium borohydride (0.8g, 22.8mmol) was added at 0°C, and the mixture was reacted at 30°C for 2h. After the reaction was completed, water was added to quench the mixture, and EA and water were added for three times of liquid extraction. The organic phase was spin-dried and separated by normal phase preparative separation (DCM:MeOH=20:1) to obtain 1.5g of the product with a yield of 50%.

[0265] 7. Preparation of 6-pivalamidopyridine-3,4-bisethoxymethanesulfonate

[0266] Dissolve N-(4,5-bis(2-hydroxyethyl)pyridin-2-yl)-pivalamide (1.5 g, 5.6 mmol) in DCM (20 mL), add triethylamine (1.7 g, 16.8 mmol) and methanesulfonyl chloride (1.9 g, 16.8 mmol) at 0°C, and move to 30°C to react for 2 h. After the reaction is completed, add DCM and water for three times of liquid extraction, and the organic phase is spin-dried to obtain 2.3 g of crude product.

[0267] 8. Preparation of N-(6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepin-3-yl)-pivalamide

[0268] 6-pivalamidopyridine-3,4-bisethoxymethanesulfonate (2.3 g crude product) was dissolved in acetonitrile (6 mL), and aqueous ammonia (15 mL) was added, and the tube was sealed and reacted at 90° C. for 2 h. After the reaction was completed, the mixture was spin-dried and separated by normal phase preparative separation (DCM:MeOH=10:1) to obtain 860 mg of the product, with a two-step yield of 30.7%.

[0269] 9. Preparation of N-(7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepin-3-yl)-pivalamide

[0270] Dissolve N-(6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine-3-yl)-tivalamide (840 mg, 3.4 mmol) in methanol (30 mL), add formaldehyde aqueous solution (1.4 g, 17.0 mmol) and acetic acid (304 mg, 3.4 mmol), react at 30°C for 1 h, then add sodium cyanoborohydride (1.1 g, 17.0 mmol), and continue to react for 2 h. After the reaction is completed, add EA and water for three times of liquid extraction, spin dry the organic phase, and separate by normal phase preparative separation (DCM:MeOH=20:1) to obtain 530 mg of the product with a yield of 59.7%.

[0271] 10. Preparation of 7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine-3-amine

[0272] N-(7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine-3-yl)-pivalamide (510 mg, 1.9 mmol) was dissolved in 6M HCl (40 mL, 240 mmol) and reacted at 80°C for 16 h. After the reaction was completed, the reaction solution was dried to obtain 500 mg of a crude product.

[0273] 11. Preparation of 3-chloro-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine

[0274] Dissolve 7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine-3-amine (250 mg, 1.2 mmol) in concentrated hydrochloric acid, add an aqueous solution (1 mL) of sodium nitrite (248 mg, 3.6 mmol) at 0°C, and react for 1 h at 0°C. After the reaction is completed, add saturated sodium bicarbonate solution to adjust the pH to 8-9, spin dry the solvent, and separate by reverse phase C18 preparative chromatography (water: methanol = 4:1-2:1) to obtain 110 mg of the product.

[0275] 12. Preparation of tert-butyl 7-((7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepin-3-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate

[0276] 3-Chloro-7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine (90 mg, 0.46 mmol), tert-butyl 7-amino-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate (146 mg, 0.46 mmol), RuPhosPdG3 (38 mg, 0.046 mmol), cesium carbonate (299 mg, 0.92 mmol) were dissolved in 1,4-dioxane (5 mL), and reacted at 100°C for 4 h under nitrogen protection. After the reaction was completed, the solvent was dried and separated by reverse phase C18 preparative chromatography (water: methanol = 1:8) to obtain 110 mg of the product with a yield of 44.5%

[0277] 13. Preparation of 7-((7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepin-3-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one

[0278] Dissolve tert-butyl 7-((7-methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepin-3-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate (100 mg, 0.2 mmol) in ethyl acetate (2 mL), add ethyl acetate solution of hydrochloric acid (10 mL), and react at 30° C. for 1 h. After the reaction is completed, filter with suction, wash the filter cake three times with ethyl acetate, and spin dry to obtain 70 mg of the product with a yield of 86.0%.

[0279] Molecular formula: C 26 H 26 N6O molecular weight: 438.5 LC-MS (M / e): 439.2

[0280] 1 H-NMR(400MHz,d-DMSO)δ:11.4(s,1H),10.3(s,1H),8.8(s,1H),8.6(s,1H),8.3(s,1H),8.2(d,1H),8.1(s,1H ),7.8(d,2H),7.2(d,1H),7.1(s,1H),4.5(s,2H),3.5(m,2H),3.3(m,2H),3.0(m,4H),2.8(s,3H),2.3(s,3H).

[0281] Example 5: Preparation of 7-((7-cyclopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]-pyridin-3-yl)isoindolin-1-one hydrochloride (Compound 6)

[0282]

[0283] 1. Preparation of 7-cyclopropyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine

[0284] At 30°C, 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (890 mg, 5.0 mmol) and (1-ethoxycyclopropyloxy)trimethylsilane (1.8 g, 10.0 mmol) were dissolved in methanol (10 mL). After stirring for 10 min, sodium cyanoborohydride (1.0 g, 15.0 mmol) was added. After the addition was complete, the reaction was stirred for 3 h. The reaction was detected to be complete. Diluted with water, extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified on a silica gel column (ethyl acetate: petroleum ether = 2:5) to obtain 1.0 g of the title compound, with a yield of 91.7%.

[0285] 2. Preparation of 7-cyclopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-2-ol

[0286] 7-Cyclopropyl-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (1.0 g, 4.6 mmol) and hydrobromic acid in acetic acid (33%) (8 mL) were reacted at 100°C for 16 hours. The mixture was concentrated and the crude product was used directly in the next step.

[0287] 3. Preparation of 7-cyclopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-2-oxyl-trifluoromethanesulfonate

[0288] Dissolve 7-cyclopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-2-ol (crude product, 4.6mmol) in dichloromethane (25mL), add triethylamine (930mg, 9.2mmol). Cool to 0℃, add trifluoromethanesulfonic anhydride (1.5g, 5.5mmol) dropwise, and react at 0℃ for 1 hour. LCMS detection of the reaction is complete. Concentrate and purify by silica gel column chromatography (n-heptane: ethyl acetate = 1:2) to obtain 1.0g of the target compound, with a two-step yield of 66.7%.

[0289] 4. Preparation of tert-butyl 7-((7-cyclopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl-1-oxoisoindoline-2-carboxylate

[0290] 7-Cyclopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-2-oxy-trifluoromethanesulfonate (120 mg, 0.36 mmol) was dissolved in 1,4-dioxane (12 mL), and tert-butyl 7-amino-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate (169 mg, 0.45 mmol), RuPhos-Pd-G3 (39 mg, 0.047 mmol) and cesium carbonate (293 mg, 0.90 mmol) were added. Under N2 protection, the reaction was carried out at 100°C for 5 h. After the reaction was completed, the reaction was concentrated and purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:4) to obtain 100 mg of the product with a yield of 49.2%.

[0291] 5. Preparation of 7-((7-cyclopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]-pyridin-3-yl)isoindolin-1-one hydrochloride

[0292] At 30°C, tert-butyl 7-((7-cyclopropyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl-1-oxoisoindoline-2-carboxylate was dissolved in ethyl acetate hydrochloric acid solution (10 mL) and stirred for 1 hour. LCMS detected the completion of the reaction. Filtered and evaporated to dryness under reduced pressure to obtain 70 mg of the title compound, yield: 69.4%.

[0293] Molecular formula: C 28 H 29 ClN6O molecular weight: 500.2 LC-MS (M / e): 465.2 (M+H + )

[0294] 1 H-NMR(400MHz,DMSO-d6)δ:11.10(s,1H),10.07(s,1H),8.85(s,1H),8.59(s, 1H),8.51(m,1H),8.27(s,1H),7.78-7.70(m,2H),7.62-7.60(m,1H),7.20-7.1 8(m,1H),6.95-6.93(m,1H),3.77-3.71(m,3H),3.67-3.39(m,2H),3.36-3.22 (m,2H),2.99-2.89(m,2H),2.49(s,3H),1.26-1.23(m,2H),0.87-0.85(m,2H).

[0295] Example 6: Preparation of 7-(7-(2-hydroxyethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one (Compound 8)

[0296]

[0297] 1. Preparation of 6-methoxy-2,3-bis(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine

[0298] 2,3-Dibromo-6-methoxypyridine (1.5 g, 5.6 mmol) and potassium 2-(tetrahydro-2H-pyran-2-oxy)ethyl trifluoroborate (4.0 g, 16.9 mmol) were dissolved in 1,4-dioxane / water (60 mL / 20 mL), palladium acetate (380 mg, 1.7 mmol), n-butyldi(1-adamantyl)phosphine (400 mg, 1.1 mmol) and cesium carbonate (11.0 g, 33.8 mmol) were added, purged with nitrogen, and reacted at 100°C for 16 hours under nitrogen protection. Extracted with water (20 mL) and ethyl acetate (30 mL), the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 7:1) to obtain 1.5 g of the product, with a yield of 73.0%.

[0299] 2. Preparation of 2,2'-(6-methoxypyridine-2,3-diyl)bis(ethane-1-ol)

[0300] Dissolve 6-methoxy-2,3-bis(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine (1.5 g, 4.1 mmol) in methanol (50 mL), add p-toluenesulfonic acid (750 mg, 4.3 mmol). React at 25°C for 16 hours. Add saturated sodium bicarbonate (20 mL), extract with dichloromethane (50 mL), wash the organic phase with water (20 mL) and saturated brine (20 mL), dry, and concentrate to obtain 700 mg of crude product.

[0301] 3. Preparation of (6-methoxypyridine-2,3-diyl)bis(ethane-2,1-diyl) dimethanesulfonate

[0302] Dissolve 2,2'-(6-methoxypyridine-2,3-diyl)bis(ethane-1-ol) (700 mg, crude product) in dichloromethane (50 mL), add triethylamine (1.9 g, 18.8 mmol) and methanesulfonyl chloride (1.4 g, 12.2 mmol) at 0°C. React at 0°C for 0.5 hours. Add saturated sodium bicarbonate (20 mL), extract with dichloromethane (70 mL), wash the organic phase with saturated brine (30 mL), dry, concentrate, and use the crude product directly in the next step.

[0303] 4. Preparation of 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine

[0304] Dissolve (6-methoxypyridine-2,3-diyl)bis(ethane-2,1-diyl) dimethanesulfonate (crude product) in dimethyl sulfoxide (10 mL), add ammonia water (25%) (10 mL). React at 40°C for 5 hours. Add water (30 mL) and ethyl acetate (50 mL) for extraction, wash the organic phase with saturated brine, dry, and concentrate to obtain 240 mg of crude product. Concentrate the aqueous phase and add (dichloromethane / methanol 50 mL / 5 mL), filter to remove the solid, and concentrate to obtain 300 mg of crude product.

[0305] 5. Preparation of 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-2-ol

[0306] Add 2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (220 mg, 1.2 mmol) and hydrobromic acid in acetic acid (33%) (8 mL) to the sealed tube. React at 100°C for 16 hours. Concentrate and use the crude product directly in the next step.

[0307] 6. Preparation of tert-butyl 2-hydroxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0308] Dissolve 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine-2-ol (crude product) in tetrahydrofuran (15 mL), add triethylamine (1.3 g, 12.8 mmol) and di-tert-butyl dicarbonate (550 mg, 2.5 mmol). React at 25°C for 1 hour. Add water (10 mL) and ethyl acetate (15 mL) for extraction, concentrate, and purify on a C18 column (methanol = 0-70%) to obtain 200 mg of the target compound.

[0309] 7. Preparation of tert-butyl 2-(((trifluoromethyl)sulfonyl)oxy)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0310] Dissolve tert-butyl 2-hydroxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (180 mg, 0.68 mmol) in dichloromethane (15 mL), add triethylamine (210 mg, 2.1 mmol). Cool to 0°C, add trifluoromethanesulfonic anhydride (290 mg, 1.0 mmol) dropwise, and react at 0°C for 1 hour. Concentrate and purify by silica gel column chromatography (n-heptane: ethyl acetate = 1:2) to obtain 180 mg of the target compound, yield: 66.7%.

[0311] 8. Preparation of tert-butyl 2-((2-(tert-butoxycarbonyl)-7-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxoisoindolin-4-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate

[0312] Dissolve tert-butyl 2-(((trifluoromethyl)sulfonyl)oxy)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (180 mg, 0.45 mmol) in 1,4-dioxane (12 mL), add tert-butyl 7-amino-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate (169 mg, 0.45 mmol), RuPhos-Pd-G3 (39 mg, 0.047 mmol) and cesium carbonate (293 mg, 0.90 mmol). Under N2 protection, react at 100°C for 5 h. After the reaction is complete, concentrate and purify by silica gel column chromatography (n-heptane:ethyl acetate=1:4) to obtain 120 mg of the product with a yield of 43.0%.

[0313] 9. Preparation of 4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-7-((6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)isoindolin-1-one hydrochloride

[0314] Dissolve tert-butyl 2-((2-(tert-butoxycarbonyl)-7-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxoisoindolin-4-yl)amino)-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (50 mg, 0.11 mmol) in dichloromethane (2 mL), add ethyl acetate solution of hydrogen chloride (4 M) (1 mL). React at 25°C for 1 hour. Concentrate, and the crude product is used directly in the next step.

[0315] 10. Preparation of 7-((7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one

[0316] Dissolve 4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-7-((6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)isoindolin-1-one hydrochloride (crude product) and tert-butyldimethylsilyl acetaldehyde (55 mg, 0.32 mmol) in methanol (5 mL), add acetic acid (50 mg, 0.83 mmol). Stir at 25°C for 10 min. Add sodium cyanoborohydride (25 mg, 0.40 mmol). React at 25°C for 1 hour. Part of the product is deionized with TBS, and the reaction solution is directly used in the next step.

[0317] 11. Preparation of 7-(7-(2-hydroxyethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one

[0318] Hydrochloric acid (2 mL) was added to the reaction solution of 7-((7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one. The mixture was reacted at 25°C for 1 hour. Saturated sodium bicarbonate was added to adjust the pH to about 8, and the mixture was extracted with dichloromethane / methanol = 10:1 (20 mL), concentrated, and purified on a preparative silica gel plate (dichloromethane / methanol = 8:1) to obtain 50 mg of a crude product, which was purified on a C18 column (methanol / water (0.05% HCl) = 3:2) to obtain 30 mg of a crude product. Saturated sodium bicarbonate (10 mL) was added, and the mixture was extracted with (dichloromethane / methanol = 10:1) (20 mL), and concentrated to obtain 19 mg of the target compound.

[0319] Molecular formula: C 27 H 28 N6O2 molecular weight: 468.6 LC-MS (M / e): 469.2 (M+H + )

[0320] 1H NMR (400MHz, CDCl3) δ: 9.71 (s, 1H), 8.81 (d, J = 8.8Hz, 1H), 8.33 (s, 1H), 7.9 7(s,1H),7.64(d,J=8.4Hz,1H),7.57-7.54(m,1H),7.33-7.31(m,1H),7.07- 7.04(m,1H),7.69(d,J=8.0Hz,1H),6.03(s,1H),4.47(s,2H),3.69-3.66(m ,2H),3.20-3.18(m,2H),2.95-2.80(m,4H),2.76-2.71(m,4H),2.40(s,3H).

[0321] Example 7: Preparation of 7-((8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepin-2-yl)amino)-4-(6-methylpyrazol[1,5-a]pyridin-3-yl)isoindolin-1-one (Compound 11)

[0322]

[0323] 1. Preparation of methyl 3-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)picolinate

[0324] Methyl 3-bromopicolinate (24.0 g, 0.11 mol), tert-butyl propylcarbamate (25.6 g, 0.16 mol), CuI (2.1 g, 0.011 mol), Pd(dppf)Cl2 (8.0 g, 0.011 mol), DIEA (42.6 g, 0.33 mol) and acetonitrile (500 mL) were weighed in sequence, replaced with nitrogen three times, reacted at 85 ° C for 14 h, LC-MS showed the reaction was complete, the reaction solution was filtered, the filtrate was spin-dried, and the residue was separated by column chromatography (SiO2, PE:EA=5:1-3:1-2:1) to obtain 23.0 g of product with a yield of 71.3%.

[0325] 2. Preparation of methyl 3-(3-((tert-butyloxycarbonyl)amino)propyl)picolinate

[0326] Pd / C (12.0 g) was added to a solution of methyl 3-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)picolinate (23.0 g, 79.2 mmol) in methanol (400 mL). The mixture was replaced with hydrogen three times and reacted at 20°C for 15 h. LC-MS showed that the reaction was complete. The reaction solution was filtered and the filtrate was dried to give 23.0 g of a crude product.

[0327] 3. Preparation of 3-(3-aminopropyl)picolinic acid methyl ester hydrochloride

[0328] To a solution of methyl 3-(3-((tert-butoxycarbonyl)amino)propyl)picolinate (23.0 g crude product) in methanol (100 mL) was added HCl / dioxane solution (4 M, 200 mL, 800.0 mmol), and the mixture was reacted at 25 °C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was spin-dried to obtain 16.0 g of a crude product.

[0329] 4. Preparation of 5,6,7,8-tetrahydro-9H-pyrido[2,3-c]azepine-9-one

[0330] To a solution of methyl 3-(3-aminopropyl)picolinate hydrochloride (16.0 g crude product) in methanol (100 mL) and dioxane (300 mL) was added cesium carbonate (45.2 g, 0.14 mol), and the mixture was reacted at 100° C. for 15 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=98:2-95:5) to obtain 11.0 g of the product.

[0331] 5. Preparation of 8-(methyl-d3)-5,6,7,8-tetrahydro-9H-pyrido[2,3-c]azepine-9-one

[0332] At 0°C, sodium hydride (60%, 2.2 g, 55.0 mmol) was added to a tetrahydrofuran (80 mL) solution of 5,6,7,8-tetrahydro-9H-pyrido[2,3-c]azepine-9-one (6.0 g, 37.0 mmol), and the mixture was reacted at 0°C for 0.5 h. Deuterated iodomethane (5.4 g, 37.2 mmol) was then added, and the mixture was reacted at 25°C for 13 h. LC-MS showed that the reaction was complete. Methanol and a small amount of water were added to the reaction solution to quench the reaction, and the reaction solution was spin-dried. The residue was separated by column chromatography (SiO2, DCM: MeOH = 98:2-96:4) to obtain 6.3 g of the product with a yield of 95.0%.

[0333] 6. Preparation of 8-(methyl-d3)-9-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepine-1-oxide

[0334] To a solution of 8-(methyl-d3)-5,6,7,8-tetrahydro-9H-pyrido[2,3-c]azepine-9-one (6.3 g, 35.2 mmol) in dichloromethane (200 mL) was added m-CPBA (85%, 10.7 g, 52.7 mmol), and the mixture was reacted at 20°C for 13 h. LC-MS showed that the reaction was complete. A small amount of saturated sodium bicarbonate solution was added to the reaction solution, the reaction solution was spin-dried, the residue was slurried with DCM / MeOH (10:1), filtered, the filtrate was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=30:1-10:1) to obtain 7.0 g of a crude product.

[0335] 7. Preparation of 2-(tert-butylamino)-8-(methyl-d3)-5,6,7,8-tetrahydro-9H-pyrido[2,3-c]azepine-9-one

[0336] To a solution of 8-(methyl-d3)-9-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepine-1-oxide (7.0 g crude product) and tert-butylamine (18.4 g, 0.25 mol) in dichloromethane (300 mL) at 0°C, p-toluenesulfonic anhydride (35.2 g, 0.12 mol) was added, and the mixture was reacted at 25°C for 14 h. LC-MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=98:2-95:5) to obtain 3.5 g of the product.

[0337] 8. Preparation of N-(tert-butyl)-8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepine-2-amine

[0338] To a solution of 2-(tert-butylamino)-8-(methyl-d3)-5,6,7,8-tetrahydro-9H-pyrido[2,3-c]azepine-9-one (3.5 g, 14.0 mmol) in tetrahydrofuran (80 mL) was added lithium aluminum hydride (1.6 g, 42.1 mmol) at 0°C, and the mixture was reacted at 80°C for 4 h. LC-MS showed that the reaction was complete. Water (1.6 mL) and sodium hydroxide solution (10%, 1.6 mL) were added dropwise to the reaction solution at 0°C, and the mixture was stirred at 25°C for 1 h. The mixture was filtered and the filtrate was dried. The residue was separated by column chromatography (SiO2, DCM:MeOH=98:2-96:4) to give 1.7 g of the product with a yield of 51.4%.

[0339] 9. Preparation of 8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepine-2-amine

[0340] N-(tert-Butyl)-8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepine-2-amine (1.7 g, 7.2 mmol) was dissolved in trifluoroacetic acid (30 mL) and reacted at 80°C for 5 h. LC-MS showed that the reaction was complete. The reaction solution was dried by rotation, and the residue was diluted with DCM. A small amount of saturated sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was dried by rotation. The residue was separated by column chromatography (SiO2, DCM:MeOH=10:1) to obtain 1.5 g of a crude product.

[0341] 10. Preparation of tert-butyl 4-chloro-7-((8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyridin[2,3-c]azepin-2-yl)amino)-1-oxoisoindoline-2-carboxylate

[0342] 8-(Methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepine-2-amine (600 mg crude product), tert-butyl 7-bromo-4-chloro-1-oxoisoindoline-2-carboxylate (1.2 g crude product), Pd2(dba)3 (300 mg, 0.33 mmol), XantPhos (191 mg, 0.33 mmol), cesium carbonate (3.2 g, 9.9 mmol) and dioxane (20 mL) were weighed in sequence, nitrogen was replaced three times, the reaction was carried out at 100 ° C for 13 h, LC-MS showed that the reaction was completed, the reaction solution was filtered, the filtrate was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=98:2-94:6) to obtain 960 mg of the product.

[0343] 11. Preparation of tert-butyl 7-((8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)isoindoline-2-carboxylate

[0344] Weigh tert-butyl 4-chloro-7-((8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyridin[2,3-c]azepine-2-yl)amino)-1-oxoisoindoline-2-carboxylate (900 mg, 2.0 mmol), potassium acetate (589 mg, 6.0 mmol), bipyraclostrobin (1.0 g, 3.9 mmol), XPhos-Pd-G2 (157 mg, 0.20 mmol) and dioxane (30 mL) in sequence, replace with nitrogen three times, react at 90 ° C for 2 h, LC-MS showed that the reaction was complete, the reaction solution was spin-dried, and the residue was separated by column chromatography (SiO2, DCM:MeOH=95:5-92:8) to obtain 820 mg of the product with a yield of 76.0%.

[0345] 12. Preparation of tert-butyl 7-((8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepin-2-yl)amino)-4-(6-methylpyrazolyl[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate

[0346] tert-Butyl 7-((8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepin-2-yl)amino)-1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)isoindoline-2-carboxylate (800 mg, 1.5 mmol), 3-bromo-6-methylpyrazolo[1,5-a]pyridine (380 mg, 1.8 mmol), XPhos-Pd-G2 (118 mg, 0.15 mmol), potassium phosphate (955 mg, 4.5 mmol), dioxane (20 mL) and water (4 mL) were weighed in sequence, the atmosphere was replaced with nitrogen three times, the reaction was carried out at 100°C for 2 h, and LC-MS showed that the reaction was complete. The reaction solution was spin-dried and the residue was separated by column chromatography (SiO2, DCM:MeOH=98:2-95:5) to obtain 670 mg of the product with a yield of 82.6%.

[0347] 13. Preparation of 7-((8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepin-2-yl)amino)-4-(6-methylpyrazol[1,5-a]pyridin-3-yl)isoindolin-1-one

[0348] To a solution of tert-butyl 7-((8-(methyl-d3)-6,7,8,9-tetrahydro-5H-pyrido[2,3-c]azepin-2-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate (650 mg, 1.2 mmol) in methanol (5 mL) was added HCl / dioxane solution (4M, 10 mL, 40.0 mmol), and the reaction was carried out at 30 ° C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was dried by spin-drying, the residue was dissolved with DCM / MeOH, washed with saturated sodium bicarbonate solution, the organic phase was dried by spin-drying, and the residue was separated by column chromatography (SiO2, DCM:MeOH=96:4-94:6) to give a crude product, which was then slurried with DCM / MeOH, filtered, and the filter cake was dried to give 260 mg of the product with a yield of 49.1%.

[0349] Molecular formula: C 26 H 23 D3N6O molecular weight: 441.6 LC-MS (m / z): 442.3 (M+H + )

[0350] 1H-NMR(400MHz,DMSO-d6)δ:9.91(s,1H),8.79(s,1H),8.60(d,J=8.4,1H), 8.57(s,1H),8.24(s,1H),7.77(d,J=9.0,1H),7.68(d,J=8.4,1H),7.44(d, J=8.0,1H),7.17(d,J=8.0,1H),6.75(d,J=8.0,1H),4.50(s,2H),3.87(s, 2H),2.95-2.92(m,2H),2.79-2.75(m,2H),2.33(s,3H),1.70-1.63(m,2H).

[0351] Example 8: Preparation of 7-((1-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one hydrochloride (hydrochloride salt of compound 15)

[0352]

[0353] 1. Preparation of tert-butyl (2-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)ethyl)carbamate

[0354] 5-Bromo-1H-pyrrolo[2,3-c]pyridine (1.1 g, 5.58 mmol) was dissolved in DMF (25 mL). Potassium tert-butoxide (813 mg, 7.25 mmol) was added at 0°C. After 10 min, 1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide (1.5 g, 6.70 mmol) was added. The reaction was continued at 25°C for 16 h. After LCMS detection, the reaction was complete. Water was added to quench the reaction. The mixture was extracted with ethyl acetate. The organic phase was spin-dried and purified by silica gel column chromatography (EA:PE=1:1) to obtain 1.5 g of the product with a yield of 79.0%.

[0355] 2. Preparation of tert-butyl (2-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)ethyl)(methyl)carbamate

[0356] Tert-butyl (2-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)ethyl)carbamate (900 mg, 2.65 mmol) was dissolved in DMF (15 mL), and NaH (159 mg, 3.98 mmol) was added at 0°C. After 10 min, iodomethane (451 mg, 3.18 mmol) was added, and the reaction was continued at 25°C for 2 h. LCMS detected that the reaction was complete, and the reaction was quenched with water. The reaction was extracted with ethyl acetate, and the organic phase was spin-dried. The product was purified by silica gel column chromatography (EA:PE=1:1) to obtain 900 mg of the product with a yield of 95.8%.

[0357] 3. Preparation of 2-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-methylethane-1-amine trifluoroacetate

[0358] Dissolve tert-butyl (2-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)ethyl)(methyl)carbamate (900 mg, 2.54 mmol) in DCM (8 mL), add TFA (2 mL) at 25 °C, and continue to react at 25 °C for 2 h. LCMS detection shows that the reaction is complete. The reaction solution is spin-dried to obtain 1.8 g of a crude product, which is directly used in the next step.

[0359] 4. Preparation of 2-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-dimethylethane-1-amine

[0360] 2-(5-Bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-N-methylethane-1-amine trifluoroacetate (1.8 g, crude product) was dissolved in methanol (25 mL), acetic acid (1.5 g, 24.7 mmol) was added, sodium cyanoborohydride (666 mg, 10.6 mmol) and formaldehyde (1.1 g, 13.6 mmol) were added at 0°C, and the reaction was completed after LCMS detection. The reaction solution was dried by rotation, the pH was adjusted to 8-9 with saturated sodium hydroxide aqueous solution, and the mixture was extracted with dichloromethane. The organic phase was dried by rotation, and 350 mg of the product was separated by silica gel column chromatography (MeOH:DCM=1:10). The yield of the two steps was 51.2%.

[0361] 5. Preparation of tert-butyl 7-((1-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate

[0362] 7-amino-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylic acid tert-butyl ester (100 mg, 0.26 mmol) and 2-(5-bromo-1H-pyrrolo[2,3-c]pyridin-1-yl)-N,N-dimethylethane-1-amine (78 mg, 0.29 mmol) were dissolved in 1,4-dioxane (10 mL), and RuPhos-Pd-G3 (42 mg, 0.05 mmol) and cesium carbonate (169 mg, 0.52 mmol) were added. Under N2 protection, the reaction was carried out at 100°C for 16 hours. LCMS detected that the reaction was complete, and water was added to quench the reaction. Dichloromethane and water were added for liquid extraction. The organic phase was spin-dried and separated by silica gel column chromatography (MeOH:DCM=1:10) to obtain 80 mg of the product with a yield of 54.2%.

[0363] 6. Preparation of 7-((1-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)isoindolin-1-one hydrochloride

[0364] Dissolve tert-butyl 7-((1-(2-(dimethylamino)ethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)amino)-4-(6-methylpyrazolo[1,5-a]pyridin-3-yl)-1-oxoisoindoline-2-carboxylate (30 mg, 0.053 mmol) in dichloromethane (2 mL), and add a solution of hydrogen chloride in ethyl acetate (2 mL). React at 25°C for 3 hours. The reaction solution is concentrated and dried to obtain 17.5 mg of the target compound, with a yield of 65.8%.

[0365] Molecular formula: C 27 H 28 ClN7O molecular weight: 502.0 LC-MS (M / e): 466.3 (M+H + )

[0366] 1 H-NMR(400MHz, DMSO)δ:9.71(d,J=6.4Hz,1H),9.00-9.20(m,1H),9.13(d,J=3.5Hz,1H),8.86(s,1H),8.61(s,1H),8.00-8.20(m,1H),7 .70-7.90(m,3H),7.20(d,J=9.3Hz,2H),6.71(s,1H),4.80(s,2H),4.55(s,2H),3.60-3.70(m,2H),2.83(d,J=4.6Hz,6H),2.33(s,3H).

[0367] The compounds shown in the following table were prepared using the same or similar methods as the above preparation examples:

[0368]

[0369]

[0370] Experimental protocol

[0371] The following provides exemplary experimental schemes of some compounds of the present invention to show the beneficial activity and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental schemes are merely examples of the content of the present invention, rather than limitations on the scope of the present invention.

[0372] Experimental Example 1 Inhibition experiment of the compounds of the present invention on in vitro enzymatic activity

[0373] Test substances: some compounds of the present invention, whose structural formula and preparation methods are shown in the preparation examples of the present invention.

[0374] The abbreviations used in the following experiments have the following meanings:

[0375] DMSO: dimethyl sulfoxide;

[0376] HEPES: Hydroxyethylpiperazine ethyl sulfonic acid

[0377] Experimental Methods: The compounds were evaluated on six kinases in vitro using the Lantha screen assay.

[0378] Experimental steps:

[0379] 1. Prepare 1× kinase buffer containing 50 mM HEPES solution, 10 mM MgCl2, 4 mM dithiothreitol, 0.01% bovine serum albumin, and 0.01% Tween-20:

[0380] 2. Compound dilution:

[0381] 1) Take 90μl of 100% DMSO and add 10μl of 10mM compound solution to prepare a 1mM compound solution. Add 90μl of 100% DMSO to the second well of the 96-well plate and add 10μl of 1mM compound solution to prepare a 100μM compound solution. Add 60μl of 100% DMSO to the other wells. Take 30μl of compound from the second well and add it to the third well. Make 3-fold dilutions one by one, for a total of 10 concentrations.

[0382] Transfer 40 μl of the 100 μM compound solution prepared above to a 384-well Echo plate;

[0383] 2) Transfer 40 μl of 100% DMSO to two empty wells as a positive control without compound and a negative control without enzyme;

[0384] 3) Use Echo 550 to transfer 100 nl of compound to a 384-well assay plate. The starting concentration of the compound is 1 μM.

[0385] 3. Prepare 2× kinase solution with 1× kinase buffer, transfer 5 μl of 2× kinase solution to the reaction wells of the 384-well plate, add 1× kinase buffer to the negative control wells, shake at 450 rpm to mix, and incubate at room temperature for 10 minutes.

[0386] 4. Prepare 2× substrate solution with 1× kinase buffer, transfer 5 μl of 2× substrate solution to the reaction wells of the 384-well plate, and shake at 450 rpm to mix.

[0387] 5. The reaction was carried out at room temperature for 90 minutes.

[0388] 6. Prepare 2× stop reaction solution containing antibodies, transfer 10 μl of 2× stop reaction solution to the reaction wells of 384-well plate, centrifuge at 1000 rpm for 1 minute, leave at room temperature for 60 minutes, and detect.

[0389] 7. Data reading: The data were read on Envision2104 Multilable Reader with excitation at 340 nm and emission at 520 nm and 495 nm.

[0390] 8. Data calculation

[0391] 1) The numerical ratio of the fluorescence readings (Lantha signal (520nm / 495nm)) was converted into the inhibition percentage using the formula:

[0392] Inhibition percentage = (maximum value - Lantha signal) / (maximum value - minimum value) * 100

[0393] The “minimum value” is the reading of the negative control well without enzyme; the “maximum value” is the reading of the positive control well without compound.

[0394] 2) Import data into MS Excel, IC 50 The results were curve fitted using XLFit excel add-in version 5.4.0.8.

[0395] Experimental Results

[0396] Table 1 In vitro enzyme inhibition activity of the compounds of the present invention

[0397]

[0398] Experimental conclusion

[0399] The compounds of the present invention have good inhibitory activity on MAP4K1 / HPK1, and have excellent selectivity for HPK1.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, X 1 , X 2 are each independently selected from -CH-; Y 1 , Y 2 are independently selected from -CH- or -N-; Y 3 Selected from -C(R 4 )-; L 1 Selected from -NR a -; R 4 is selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 Alkoxy; Ring A is selected from n is selected from 0, 1, 2 or 3; Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, -NR a R b 、-OR a 、-SR a 、-C(O)R a , or the following group optionally substituted by 1-3 Q2: C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) m -3-8 membered cycloalkyl; Each Q2 is independently selected from deuterium, halogen, hydroxyl, nitro, NR c R d or cyano; R 1 Selected from the following groups optionally substituted by 1-3 Q3: The Q3 are independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy; R 2 Selected from hydrogen or C 1-6 alkyl; Each R a , each R b are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; Each R c , each R d are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 Alkoxy; p is selected from 0, 1 or 2; Each m is independently selected from 0, 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from n is selected from 0, 1, 2 or 3; Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, -NR a R b 、-OR a 、-SR a 、-C(O)R a , or the following group optionally substituted by 1-3 Q2: C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) m -3-8 membered cycloalkyl; Each Q2 is independently selected from deuterium, halogen, hydroxyl, nitro, -NR c R d or cyano; R 1 Selected from the following groups optionally substituted by 1-3 Q3: The Q3 are independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy; R 2 Selected from hydrogen or C 1-4 alkyl; Each R a , each R b are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy; Each R c , each R d are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; p is selected from 0, 1 or 2; Each m is independently selected from 0, 1, 2 or 3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: X 1 , X 2 are each independently selected from -CH-; Y 1 , Y 2 are independently selected from -CH- or -N-; Y 3 Selected from -C(R 4 )-; L 1 Selected from -NR a -; R 4 is selected from hydrogen, halogen, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy; Ring A is selected from n is selected from 0, 1, 2 or 3; Each Q1 is independently selected from fluorine, chlorine, bromine, amino, cyano, hydroxyl, nitro, -C(O)R a , or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl or -(CH2) m -cyclohexyl; Each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, -NR c R d , cyano or nitro; R c , R d are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy; R 1 Selected from the following groups optionally substituted by 1-3 Q3: Each Q3 is independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy or trifluoroethoxy; Each R a are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 Alkoxy; Each R b are independently selected from hydrogen or C 1-4 alkyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, which has a structure represented by the following general formula (II-1) or general formula (II-2): in, L 1 Selected from -NR a -; Each R 2 are independently selected from hydrogen or C 1-4 alkyl; Ring A is selected from Each Q1 is independently selected from cyano, -C(O)R a , or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl; Each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, -NR c R d , cyano or nitro; R c , R d are independently selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 1 Selected from the following groups optionally substituted by 1-3 Q3: Each Q3 is independently selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy; Each R a Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy; Each m, n, and p is independently selected from 0, 1 or 2.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein L 1 Selected from -NR a -; Each R 2 are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; Ring A is selected from Each Q1 is independently selected from cyano, -C(O)R a , or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, -(CH2) m -cyclopropyl or -(CH2) m - cyclobutyl; Each Q2 is independently selected from deuterium, fluorine, chlorine, bromine, hydroxyl, -NR c R d , cyano or nitro; R c , R d are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl; Each R a are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl or trifluoromethoxy; p is selected from 0 or 1; Each m and n is independently selected from 0, 1 or 2.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds:

7. A pharmaceutical preparation containing the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that: Containing one or more pharmaceutically acceptable excipients, the pharmaceutical preparation is in any pharmaceutically acceptable dosage form.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that: The invention comprises one or more second therapeutically active agents, wherein the second active therapeutic agent is selected from mitotic inhibitors, alkylating agents, anti-metabolites, antisense DNA or RNA, anti-tumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibitors, targeted antibodies, HMG-CoA reductase inhibitors and prenyl protein transferase inhibitors.

9. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease or related condition mediated by HPK1, wherein the disease or related condition mediated by HPK1 is selected from cancer or benign tumor.

10. Use of the pharmaceutical preparation according to claim 7 in the preparation of a medicament for treating and / or preventing diseases and related conditions mediated by HPK1, wherein the diseases and related conditions mediated by HPK1 are selected from cancer or benign tumors.

11. Use of the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing a disease mediated by HPK1 and related conditions, wherein the disease mediated by HPK1 and related conditions are selected from cancer or benign tumors.

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