CN116888127A - Tri-fused ring HPK1 inhibitor and application thereof - Google Patents

Abstract

The invention belongs to the field of medical technology, and specifically relates to a class of tricyclic HPK1 inhibitor compounds, pharmaceutically acceptable salts thereof or stereoisomers thereof, containing the compounds, pharmaceutically acceptable salts thereof or isomers thereof. Pharmaceutical compositions and preparations thereof, methods for preparing the compounds, pharmaceutically acceptable salts or stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts or stereoisomers thereof.

Description

Tricyclic HPK1 inhibitors and their uses Technical field

The present invention belongs to the field of medical technology, and specifically relates to tricyclic HPK1 compounds represented by general formula (I), pharmaceutically acceptable salts thereof, and stereoisomers thereof. Pharmaceutical compositions and preparations of salts and stereoisomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts thereof and stereoisomers thereof, and said compounds, pharmaceutically acceptable salts and stereoisomers thereof Uses of isomers.

Background technique

T cell receptor (TCR)-mediated T cell activation plays an important role in thymic T cell development, T cell subset differentiation, and effector T cell function. TCR can recognize MHC (major histocompatibility complex) on the surface of antigen-presenting cells, and then recognize the signal transmitted to the interior of the cell. After signal transmission, it causes the activation of downstream signaling pathways. Typical intracellular signals for 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, causing cell proliferation and differentiation of T cells into effector T cells. Endogenous or adoptively transferred effector T cells are important mediators of anti-tumor immunity. Sustained antigen exposure causes T cells to gradually differentiate into an exhausted state, characterized by a hierarchical loss of effector function and proliferative capacity, as well as significant transcriptional, epigenetic, and metabolic changes. How to prevent T cell exhaustion and expand effector T cell function is one of the most pressing issues in tumor immunology.

Hematopoietic Progenitor Kinase1 (HPK1) 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 adapter 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 TCR signaling. Literature (Shui et al., Nature Immunology (2007) 8:84-91) disclosed that HPK1 deficiency resulted in 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 HPK1(-/-) T cells were 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, [Siet 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.). It has been significantly shown in tumors such as low-grade glioma (LGG) and invasive breast cancer (BRAC) that patients with low MAP4K1 expression have longer survival times. Next, the researchers selected multiple myeloma tissue biopsies, sorted and measured the protein expression of HPK1 and immunosuppressive molecules in T cells. The experimental results showed that the expression of HPK1 was up-regulated in exhausted T cells. The results of this experiment indicate the 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 responses.

HPK1, also known as MAP4K1, is a member of the MAP4K family. There are five other members in the family: MAP4K2 (GCK kinase), MAP4K3 (GLK kinase), MAP4K4 (HGK kinase), MAP4K5 (KHS kinase) and MAP4K6 (MINK kinase). . The biological role of GLK kinase is exactly opposite to that of HPK1. GLK can promote the activation of the TCR pathway by binding to downstream adapter 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 roles of other kinases in the family are currently unknown. In order to ensure better safety, HPK1 kinase inhibitors with high selectivity for other members of the MAP4K family need to be found.

At present, the research on this target drug is still in the clinical trial stage, and no drug has yet been launched. In order to better meet clinical needs, it is of great clinical significance to develop a HPK1 kinase inhibitor with high selectivity, high activity and strong safety. .

Contents of the invention

The technical problem to be solved by the present invention is to provide a HPK1 inhibitor compound with a novel structure and good inhibitory activity against HPK1. Furthermore, this type of compound can be used to inhibit HPK1 kinase activity, thereby enhancing the body's immunity against tumors. Furthermore, this type of compounds can also be used to treat or prevent related diseases mediated by HPK1, especially cancer. This type of compound has good inhibitory effect on various cancer cells and has good drug potential.

The technical solution of the present invention is as follows:

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

in,

X ¹ and Y ¹ are each independently selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-;

X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )- or -S-;

Y ² and Y ⁴ are independently selected from -C(R ² ) or -N-;

Y ³ is selected from -C(R ⁵ ) or -N-;

Y ⁵ is selected from -C(R ⁶ );

Y ⁶ is selected from -C(R ⁷ ) or -N-;

Each R ² , R ³ , and each R ⁴ are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, C _{1- 6} alkoxy or halo C _1-6 alkoxy;

One of R ⁵ and R ⁷ together with R ⁶ and the ring atoms connected to each of them form a 3-10-membered cycloalkyl group optionally substituted by 1-5 Q1, a 3-10-membered heterocyclyl group, a 6-10 Aryl or 5-10-membered heteroaryl; uncyclic R ⁵ or R ⁷ is selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, halogenated C _{1- 6} alkyl, C _1-6 alkoxy or halo C _1-6 alkoxy;

R ¹ 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 , -C(O)OR ^a or any Select the following groups substituted by substituents: -(CH ₂ ) _p -3-10-membered cycloalkyl, -(CH ₂ ) _p -3-10-membered heterocyclyl, -(CH ₂ ) _p -5-10 Heteroaryl, -(CH ₂ ) _p -6-10 aryl; the substituent _is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 Alkoxy or halo C _1-6 alkyl;

Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR ^a R ^b , -OR ^a , -SR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-3 Q2: C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, -(CH ₂ ) _m -3-10-membered cycloalkyl, -(CH ₂ ) _m -3-10-membered heterocyclyl, -(CH ₂ ) _m -5-10-membered heteroaryl or -( CH ₂ ) _m -6-10 yuan aryl _; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen Substituted C _1-6 alkyl group, halogenated C _1-6 alkoxy group, hydroxyl C _1-6 alkyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclyl group, 5-10 membered heteroaryl group or 6-10 yuan aryl group;

Each R ^a and 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, halo C _1-6 alkyl, hydroxyl C 1-6 _{alkyl, amino C 1-6 alkyl, C 1-6 alkylthio ,} halo C _{1- 6} alkoxy group, halogenated C _1-6 alkylthio group, hydroxyl C _1-6 alkoxy group, hydroxyl C _1-6 alkylthio group, amino C _1-6 alkoxy group, amino C _1-6 alkylthio group Or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-10-membered cycloalkyl, -(CH ₂ ) _m -3-10-membered heterocyclyl, -(CH ₂ ) _m -5 -10-membered heteroaryl, -(CH ₂ ) _m -6-10-membered aryl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _{1 -6} alkoxy or halo C _1-6 alkyl;

Each m and each p are independently selected from 0, 1, 2, 3, 4 or 5.

In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt or its stereoisomer has the following general formula (II-1) or general formula (II-2): The structure shown

in,

X ¹ and Y ¹ are each independently selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-;

X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )- or -S-;

Y ² and Y ⁴ are independently selected from -C(R ² ) or -N-;

Y ³ is selected from -C(R ⁵ ) or -N-;

Y ⁶ is selected from -C(R ⁷ ) or -N-;

Each R ² , each R ³ , each R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, halogenated C _{1- 6} alkyl, C _1-6 alkoxy or halo C _1-6 alkoxy;

R ¹ 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 , -C(O)OR ^a or any Select the following groups substituted by substituents: -(CH ₂ ) _p -3-10-membered cycloalkyl, -(CH ₂ ) _p -3-10-membered heterocyclyl, -(CH ₂ ) _p -5-10 Heteroaryl, -(CH ₂ ) _p -6-10 aryl; the substituent _is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 Alkoxy or halo C _1-6 alkyl;

Ring A is selected from 3-10-membered cycloalkyl, 3-10-membered heterocyclyl, 6-10-membered aryl or 5-10-membered heteroaryl;

Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR ^a R ^b , -OR ^a , -SR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-3 Q2: C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, -(CH ₂ ) _m -3-10-membered cycloalkyl, -(CH ₂ ) _m -3-10-membered heterocyclyl, -(CH ₂ ) _m -5-10-membered heteroaryl or -( CH ₂ ) _m -6-10 yuan aryl _; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen Substituted C _1-6 alkyl group, halogenated C _1-6 alkoxy group, hydroxyl C _1-6 alkyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclyl group, 5-10 membered heteroaryl group or 6-10 yuan aryl group;

Each R ^a and 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, halo C _1-6 alkyl, hydroxyl C 1-6 _{alkyl, amino C 1-6 alkyl, C 1-6 alkylthio ,} halo C _{1- 6} alkoxy group, halogenated C _1-6 alkylthio group, hydroxyl C _1-6 alkoxy group, hydroxyl C _1-6 alkylthio group, amino C _1-6 alkoxy group, amino C _1-6 alkylthio group Or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-10-membered cycloalkyl, -(CH ₂ ) _m -3-10-membered heterocyclyl, -(CH ₂ ) _m -5 -10-membered heteroaryl, -(CH ₂ ) _m -6-10-membered aryl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _{1 -6} alkoxy or halo C _1-6 alkyl;

Each m, each n and each p are independently selected from 0, 1, 2, 3, 4 or 5.

In certain embodiments, the compound represented by general formula (I), general formula (II-1) or general formula (II-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein,

X ¹ and Y ¹ are each independently selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-;

X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )- or -S-;

Y ² and Y ⁴ are independently selected from -C(R ² ) or -N-;

Y ³ is selected from -C(R ⁵ ) or -N-; Y ⁶ is selected from -C(R ⁷ ) or -N-;

Each R ² , R ³ , each R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-4 alkyl, and halogenated C _1-4 Alkyl, C _1-4 alkoxy or halogenated C _1-4 alkoxy;

R ¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, hydroxy C _1-4 alkyl, amino C _1-4 alkyl, -NR ^a R ^b , -OR ^a , -SR ^a , -NR ^a -C(O)-R ^b -, -C(O)R ^a , -C(O)NR ^a , -C(O)OR ^a or any Select the following groups substituted by substituents: -(CH ₂ ) _p -3-6-membered cycloalkyl, -(CH ₂ ) _p -3-6-membered heterocyclyl, -(CH ₂ ) _p -5-8 Metaheteroaryl, -(CH ₂ ) _p -phenyl; 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;

Ring A is selected from 5-10-membered cycloalkyl, 5-10-membered heterocyclyl, 6-10-membered aryl or 5-10-membered heteroaryl;

Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR ^a R ^b , -OR ^a , -SR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-3 Q2: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 Alkyl, -(CH ₂ ) _m -3-8-membered cycloalkyl, -(CH ₂ ) _m -3-8-membered heterocyclyl, -(CH ₂ ) _m -5-8-membered heteroaryl or -( CH ₂ ) _m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _{1- 4-} alkyl, halogenated C _1-4 alkoxy, hydroxyl C _1-4 alkyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclyl, 5-8-membered heteroaryl or phenyl;

Each R ^a and 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, halo C _1-4 alkyl _{, hydroxyl C 1-4 alkyl, amino C 1-4 alkyl, C 1-4 alkylthio ,} halo C _{1- 4} alkoxy group, halogenated C _1-4 alkylthio group, hydroxyl C _1-4 alkoxy group, hydroxyl C _1-4 alkylthio group, amino C _1-4 alkoxy group, amino C _1-4 alkylthio group Or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-8-membered cycloalkyl, -(CH ₂ ) _m - 3-8-membered heterocyclyl, -(CH ₂ ) _m -5 -8-membered heteroaryl, -(CH ₂ ) _m -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy base or halo C _1-6 alkyl;

Each m, each n and each p are independently selected from 0, 1, 2 or 3.

In certain embodiments, the compound represented by general formula (II-1) or general formula (II-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein,

X ¹ and Y ¹ are each independently selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-;

X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )- or -S-;

Y ² and Y ⁴ are independently selected from -C(R ² )- or -N-;

Y ³ is selected from -C(R ⁵ ) or -N-;

Y ⁶ is selected from -C(R ⁷ ) or -N-;

Each R ² , R ³ , each R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, halogen, C _1-4 alkyl or halogenated C _1-4 alkyl;

R ¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, -NR ^a -C(O)-R ^b -, -NR ^a R ^b , -OR ^a or the following groups optionally substituted by substituents: -(CH ₂ ) _p -3-6-membered cycloalkyl, -(CH ₂ ) _p -3-6-membered heterocyclyl; the substituents Selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy or halogenated C _1-6 alkyl;

Ring A is selected from 5-10 membered cycloalkyl or 5-10 membered heterocyclyl;

Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR ^a R ^b , -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C( O) NR ^a or the following groups optionally substituted by 1-3 Q2: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl, - (CH ₂ ) _m -3-6-membered cycloalkyl, -(CH ₂ ) _m -3-6-membered heterocyclyl, -(CH ₂ ) _m -5-6-membered heteroaryl or -(CH ₂ ) _m -Phenyl; the Q2 are independently selected from halogen, nitro, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl, halogenated C _1-4 alkoxy group, hydroxy C _1-4 alkyl group, 3-8 membered cycloalkyl group, 3-8 membered heterocyclyl group, 5-8 membered heteroaryl group or phenyl group;

Each R ^a and _each R ^b are independently selected from hydrogen, halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, and halogenated C _1-4 alkyl. group, halogenated C _1-4 alkoxy group or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-8-membered cycloalkyl, -(CH ₂ ) _m -3-8-membered hetero Ring group; the substituent is selected from halogen, nitro, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy or halogenated C _1-4 alkyl _;

Each m, each n and each p are independently selected from 0, 1, 2 or 3.

In certain embodiments, X ¹ and Y ¹ are each independently selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-; each R ² , each R ³ and each R ⁴ are independently selected from hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl.

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

In certain embodiments, X ¹ , Y ¹ are each independently selected from CH ₂ , O, or NH.

In certain embodiments, Y ² and Y ⁴ are each independently selected from -C(R ² ) or -N-; each R ² is independently selected from hydrogen, halogen, C _1-6 alkyl or haloC _1-6 alkyl.

In certain embodiments, Y ² and Y ⁴ are independently selected from -C(R ² ) or -N-; each R ² is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, Propyl, isopropyl or trifluoromethyl.

In certain embodiments, R ⁷ is selected from hydrogen, halogen, C _1-6 alkyl, or haloC _1-6 alkyl.

In certain embodiments, R ^is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, or trifluoromethyl.

In certain embodiments, ^R5 is hydrogen.

In certain embodiments, ^Y2 is N.

In certain embodiments, Y ³ and Y ⁴ are each independently selected from CH or N.

In certain embodiments, X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )-, or -S-; each R ^2. Each R ⁴ is independently selected from hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl.

In certain embodiments, X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )-, or -S-; each R ^2. Each R ⁴ is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

In certain embodiments, one of X ² , X ³ , and X ⁴ is selected from S, O, N, or -N(R ⁴ )-, and the other two are independently -C(R ² )-; each R ² and each R ⁴ are independently selected from hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl.

In certain embodiments, one of X ² , X ³ , and X ⁴ is selected from S, O, N, or -N(R ⁴ )-, and the other two are independently -C(R ² )-; each R ² and each R ⁴ are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

In certain embodiments, one of X ² , X ³ , and X ⁴ is selected from -C(R ² )-, and the other two are independently S, O, N, or -N(R ⁴ )-; each R ² and each R ⁴ are independently selected from hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl.

In certain embodiments, one of X ² , X ³ , and X ⁴ is selected from -C(R ² )-, and the other two are independently S, O, N, or -N(R ⁴ )-; each R ² and each R ⁴ are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

In certain embodiments, one of X ² , X ³ , and X ⁴ is selected from S or O, and the other two are independently -C(R ² )-; each R ² is independently selected from hydrogen, halogen , C _1-6 alkyl or halogenated C _1-6 alkyl.

In certain embodiments, one of X ² , X ³ , and X ⁴ is selected from S or O, and the other two are independently -C(R ² )-; each R ² is independently selected from hydrogen, fluorine , chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

In ^{certain embodiments ,} In certain embodiments, one of X ² , X ³ , and X ⁴ is selected from -C(R ² )-, and the other two are independently N or -N(R ⁴ )-; each R ⁴ is independently is selected from hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl.

In certain embodiments, X ³ is N, one of X ² and X ⁴ is -N(R ⁴ )-, and the other is -C(R ² )-; R ² and R ⁴ are each independently selected from Hydrogen, halogen, C _1-6 alkyl or halogenated C _1-6 alkyl.

In certain embodiments, R ¹ is selected from hydrogen, halogen, nitro, cyano, C _1-4 alkyl, haloC _1-4 alkyl, -(CH ₂ ) _p -3-6 membered cycloalkyl base, -(CH ₂ ) _p -3-6 membered heterocyclic group, -NR ^a -C(O)-R ^b -, -NR ^a R ^b or -OR ^a ; each p is independently selected from 0, 1 , 2 or 3.

In certain embodiments, ^R1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl Methyl, -NR ^a -C(O)-R ^b -, -NR ^a R ^b , -OR ^a , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridyl, oxetane Propyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl or tetrahydrothienyl.

In certain embodiments, Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered heterocyclyl.

In certain embodiments, Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered nitrogen-containing heterocyclyl.

In certain embodiments, Ring A is selected from 5-8 membered monocycloalkyl, 5-8 membered monoheterocyclyl, 6-8 membered fused heterocyclyl, 6-8 membered bridged heterocyclyl, or 6-8 One-membered spiroheterocyclyl.

In certain embodiments, Ring A is selected from 7-8 membered monocycloalkyl, 7-8 membered monoheterocyclyl, or 8-membered nitrogen-containing bridged heterocyclyl.

In certain embodiments, Ring A is selected from 7-8 membered nitrogen-containing monoheterocyclyl or 7-8 membered oxygen-containing monoheterocyclyl.

In certain embodiments, each Q1 is independently selected from halogen, hydroxy, nitro, hydroxy, amino, cyano, carboxyl, -C(O)R ^a , -C(O)OR ^a , -C(O )NR ^a or the following groups optionally substituted by 1-3 Q2: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl, -( CH ₂ ) _m -3-6-membered cycloalkyl, -(CH ₂ ) _m -3-6-membered heterocyclyl, -(CH ₂ ) _m -5-8-membered heteroaryl or -(CH ₂ ) _m - Phenyl; the Q2 are 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, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl.

In certain embodiments, each Q1 is independently selected from -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a , or the following groups optionally substituted by 1-3 Q2 Group: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl, -(CH ₂ ) _m -3-6-membered cycloalkyl, -(CH ₂ ) _m -3-6 membered heterocyclyl, -(CH ₂ ) _m -5-6 membered heteroaryl or -(CH ₂ ) _m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitrogen group, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl or hydroxy C _1-4 alkyl.

In certain embodiments, each Q1 is independently selected from fluorine, chlorine, bromine, amino, cyano, hydroxy, carboxyl, nitro, -C(O)R ^a , -C(O)OR ^a , -C (O)NR ^a or the following groups optionally substituted by 1-3 Q2: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxy Ethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl base, isopropoxyethyl, -(CH ₂ ) _m -cyclopropyl, -(CH ₂ ) _m -cyclobutyl, -(CH ₂ ) _m -cyclopentyl, -(CH ₂ ) _m -cyclo Hexyl, -(CH ₂ ) _m -oxetanyl, -(CH ₂ ) _m -oxetanyl _, -(CH ₂ ) _m -tetrahydrofuryl, -(CH ₂ ) m -oxetanyl, -(CH ₂ ) _m -tetrahydropyranyl, -(CH ₂ ) _m -azetidinyl, -(CH ₂ ) _m -azetidinyl, -(CH ₂ ) _m -pyrrolidinyl, -(CH ₂ ) _m -piperidinyl, -(CH ₂ ) _m -piperazinyl, -(CH ₂ ) _m -tetrahydropyrrolyl, -(CH ₂ ) _m -pyrazolidinyl, -(CH ₂ ) _m -imidazolidinyl, -(CH ₂ ) _m -piperazinyl, -(CH ₂ ) _m -piperidinyl, -(CH ₂ ) _m -pyrazolyl, -(CH ₂ ) _m -pyrrolyl, -(CH ₂ ) _m -imidazolyl, -(CH ₂ ) _m -pyridyl, -(CH _{2 )} m -pyrimidinyl, -(CH ₂ ) _m -pyridazinyl, -(CH ₂ ) _m -pyrazine group or -(CH ₂ ) _m -phenyl; the Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl , methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl or trifluoromethyl.

In certain embodiments, each Q1 is independently selected from -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a , or the following groups optionally substituted by 1-3 Q2 Group: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxy Ethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH ₂ ) _m -cyclopropyl base, -(CH ₂ ) _m -cyclobutyl, -(CH ₂ ) _m -cyclopentyl, -(CH ₂ ) _m -cyclohexyl, -(CH ₂ ) _m -oxanyl, -(CH ₂ ) _m -oxetanyl, -(CH ₂ ) _m -tetrahydrofuryl, -(CH ₂ ) _m -oxetanyl, -(CH ₂ ) _m -tetrahydropyranyl, -(CH ₂ ) _m -Azetidinyl, -(CH ₂ ) _m -azetidinyl, -(CH ₂ ) _m -pyrrolidinyl, -(CH ₂ ) _m -piperidinyl, -(CH ₂ ) _m - Piperazinyl, -(CH ₂ ) _m -pyridyl, -(CH ₂ ) _m -pyrimidinyl, -(CH ₂ ) _m -pyridazinyl, -(CH _{2 )} m -pyrazinyl; the Q2 respectively Independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoro Methyl, difluoromethyl or trifluoromethyl.

In certain embodiments, each R ^a and each R ^b are independently selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di(C _1-4 Alkyl) amino, halo C _1-4 alkyl, hydroxy C 1-4 alkyl _, amino C _1-4 alkyl, halo C _1-4 alkoxy, hydroxy C _1-4 alkoxy, amino C _1-4 alkoxy group or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-8-membered cycloalkyl group, -(CH ₂ ) _m -3-8-membered heterocyclyl group, - (CH ₂ ) _m -5-8-membered heteroaryl or -(CH ₂ ) _m -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano group, carboxyl, C _1-4 alkyl , C _1-4 alkoxy or halogenated C _1-4 alkyl.

In certain embodiments, each ^Ra is independently selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy Or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-8-membered cycloalkyl, -(CH ₂ ) _m -3-8-membered heterocyclyl; the substituents are selected from halogen, Hydroxy, nitro, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy or halo C _1-4 alkyl; each R ^b is independently selected from hydrogen or C _1-4 alkyl.

In certain embodiments, each R ^a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl Methyl, trifluoromethoxy, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopropyl Pentyl, cyclohexyl, oxetanyl, oxetanyl, tetrahydrofuranyl, azetidinyl, aziridyl, tetrahydropyrrolyl, pyrazolidinyl, imidazolidinyl, piperazinyl Or piperidinyl; the substituent is selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl group; each R ^b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

In certain embodiments, each R ^a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, or any The following groups are selected to be substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl or pyrrolidinyl; the substituents are selected from fluorine, chlorine , bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R ^b is independently selected from hydrogen, methyl , ethyl, propyl or isopropyl.

In certain embodiments, the compounds described in general formula (I), general formula (II-1), general formula (II-2), their pharmaceutically acceptable salts or their stereoisomers have the following general formula: The structure represented by formula (III-1) or general formula (III-2):

Among them, Y ¹ is selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-;

Y ⁴ is selected from -C(R ² ) or -N-;

Y ³ is selected from -C(R ⁵ ) or -N-;

Y ⁶ is selected from -C(R ⁷ ) or -N-;

X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )- or -S-;

Each R ² , R ³ , R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, halogen, C _1-4 alkyl or halogenated C _1-4 alkyl;

R ¹ is selected from hydrogen, halogen, nitro, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -NR ^a - C(O)-R ^b -, -NR ^a R ^b , -OR ^a or the following groups optionally substituted by substituents: -(CH ₂ ) _p -3-6-membered cycloalkyl, -(CH ₂ ) _p -3-6 membered heterocyclyl; 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;

Ring A is selected from Wherein, each ring atom in ring A is optionally oxo-substituted;

Each Q1 is independently selected from halogen, nitro, amino, cyano, carboxyl, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or optionally 1-2 The following groups substituted by Q2: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl, -(CH ₂ ) _m -3-6-membered cycloalkyl base, -(CH ₂ ) _m -3-6-membered heterocyclyl, -(CH ₂ ) _m -5-6-membered heteroaryl or -(CH ₂ ) _m -phenyl; the Q2 are independently selected from Halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl or hydroxyl C _1-4 alkyl;

Each R ^a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl base, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiryl , oxetanyl, aziridyl, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from Halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

Each R ^b is independently selected from hydrogen or C _1-4 alkyl;

Each m, each n and each p are independently selected from 0, 1, 2 or 3.

In certain embodiments, the compound represented by general formula (I), general formula (II-1), general formula (II-2), general formula (III-1) or general formula (III-2), its Pharmaceutically acceptable salts or stereoisomers thereof, wherein,

Y ¹ is selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-;

Y ⁴ is selected from -C(R ² ) or -N-;

Y ³ is selected from -C(R ⁵ ) or -N-;

Y ⁶ is selected from -C(R ⁷ ) or -N-;

X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )- or -S-;

Each R ² , R ³ , each R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

R ¹ is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl , -NR ^a -C(O)-R ^b -, -NR ^a R ^b or -OR ^a , preferably selected from -NR ^a R ^b ;

Ring A is selected from Wherein, each ring atom in ring A is optionally oxo-substituted;

Each Q1 is independently selected from halogen, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-2 Q2: methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxy Propyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH ₂ ) _m -cyclopropyl, -(CH ₂ ) _m -cyclobutyl, -(CH ₂ ) _m -cyclopentyl, -(CH ₂ ) _m -cyclohexyl, -(CH ₂ ) _m -oxanyl, -(CH ₂ ) _m -oxy Heterocyclylbutyl, -(CH ₂ ) _m -azetidinyl, -(CH ₂ ) _m -azetidinyl, -(CH ₂ ) _m -tetrahydrofuranyl, -(CH ₂ ) _m -oxa Cyclohexyl, -(CH ₂ ) _m -tetrahydropyranyl, -(CH ₂ ) _m -pyrrolidinyl, -(CH ₂ ) _m -piperidinyl, -(CH ₂ ) _m -piperazinyl, - (CH ₂ ) _m -pyridyl, -(CH ₂ ) _m -pyrimidinyl, -(CH ₂ ) _m -pyridazinyl, -(CH _{2 )} m -pyrazinyl; the Q2 are independently selected from fluorine , chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoro Methyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl; each R ^a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl group, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; The substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

Each R ^b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;

Each m and each n are independently selected from 0, 1, 2 or 3.

In certain embodiments, Ring A is selected from Wherein, each ring atom in ring A is optionally oxo-substituted;

Each Q1 is independently selected from -C(O)R ^a , -C(O)OR ^a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, Propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH ₂ ) _m -cyclopropyl, -(CH ₂ ) _m -cyclobutyl, -( CH ₂ ) _m -cyclopentyl, -(CH ₂ ) _m -cyclohexyl, -(CH ₂ ) _m -oxetanyl, -(CH ₂ ) _m -oxetanyl, -(CH ₂ ) _m -tetrahydrofuryl, -(CH ₂ ) _m -oxanyl, -(CH ₂ ) _m -tetrahydropyranyl, -(CH ₂ ) _m -aziridyl, -(CH ₂ ) _m - Azetidinyl, -(CH ₂ ) _m -pyrrolidinyl, -(CH ₂ ) _m -piperidinyl, -(CH ₂ ) _m -piperazinyl, -(CH ₂ ) _m -pyridyl, - (CH ₂ ) _m -pyrimidinyl, -(CH ₂ ) _m -pyridazinyl, -(CH ₂ ) _m -pyrazinyl; the Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyanide base, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;

Each m and each n are independently selected from 0, 1, 2 or 3.

In certain embodiments, Ring A is selected from Preferably selected from Preferably selected from Wherein, each ring atom in ring A is optionally oxo-substituted;

Each Q1 is independently selected from halogen, -C(O)R ^a , -C(O)OR ^a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl base, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl base, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH ₂ ) _m -cyclopropyl, -(CH ₂ ) _m -cyclobutyl, -(CH ₂ ) _m -cyclopentyl, -(CH ₂ ) _m -cyclohexyl, -(CH ₂ ) _m -oxetanyl, -(CH ₂ ) _m -oxetanyl, -(CH ₂ ) _m -tetrahydrofuryl, -(CH ₂ ) _m -oxanyl, -(CH ₂ ) _m -tetrahydropyranyl, -(CH ₂ ) _m -aziridyl, -(CH ₂ ) _m -azetidinyl, -(CH ₂ ) _m -pyrrolidinyl, -(CH ₂ ) _m -piperidinyl, -(CH ₂ ) _m -piperazinyl, -(CH ₂ ) _m -pyridinyl , -(CH ₂ ) _m -pyrimidinyl, -(CH ₂ ) _m -pyridazinyl, -(CH ₂ ) _m -pyrazinyl; the Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino , cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyl Ethyl or hydroxypropyl;

Each m and each n are independently selected from 0, 1, 2 or 3.

In certain embodiments, each Q1 is independently selected from -C(O)R ^a , -C(O)OR ^a , or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, Propyl, isopropyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, propoxyethyl, cyclopropyl, cyclobutyl , oxetanyl, oxetanyl, tetrahydrofuranyl, oxetanyl, tetrahydropyranyl, aziridyl, azetidinyl, pyridyl or pyridazinyl; the Q2 respectively Independently selected from fluorine, chlorine, bromine, hydroxy, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl.

In certain embodiments, compounds of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), their Pharmaceutically acceptable salts or stereoisomers thereof have a structure represented by the following general formula (IV-1) or general formula (IV-2):

Among ^them , ^{the definitions of X2 , X3 ,}

In certain embodiments, Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (IV- 1) or a compound described in general formula (IV-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, having a structure represented by the following general formula (V-1) or general formula (V-2) :

^{Among them , X 3 and _} described in the plan.

In certain embodiments, Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), Formula (IV- 1) or a compound described in general formula (IV-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, having a structure represented by the following general formula (V-3) or general formula (V-4) :

^{Among them , X 2 and _ _} Any of the options mentioned above.

In certain embodiments, Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), or Formula (III-2), Formula (IV- 1) or a compound described in general formula (IV-2), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, having a structure represented by the following general formula (VI-1) or general formula (VI-2) :

^{Among them , X 2 and _} described in the plan.

In certain embodiments, Formula (V-1), Formula (V-2), Formula (V-3), Formula (V-4), Formula (VI-1) or Formula ( The compound represented by VI-2), its pharmaceutically acceptable salt or its stereoisomer, wherein,

X ² , X ³ and X ⁴ are each independently selected from -C(R ² )-;

Each R ² and each R ⁴ are independently selected from hydrogen, halogen, C _1-4 alkyl or halogenated C _1-4 alkyl;

R ¹ is selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, -NR ^a R ^b , -OR ^a , -SR ^a , -NH-C(O)-R ^b -, Or the following groups optionally substituted by substituents: -(CH ₂ ) _p -3-6-membered cycloalkyl, -(CH ₂ ) _p -3-6-membered heterocyclyl; the substituents are selected from halogen, C _1-4 alkyl or halo C _1-4 alkyl;

Ring A is selected from Preferably selected from Preferably selected from Wherein, each ring atom in ring A is optionally oxo-substituted;

Each Q1 is independently selected from halogen, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-2 Q2: C _{1- 4} alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl, -(CH ₂ ) _m -3-6 membered cycloalkyl, -(CH ₂ ) _m -3 -6-membered heterocyclyl, -(CH ₂ ) _m -5-6-membered heteroaryl or -(CH ₂ ) _m -phenyl; the Q2 are independently selected from halogen, hydroxyl, C _1-4 alkyl , C _1-4 alkoxy group, halogenated C _1-4 alkyl group or hydroxyl C _1-4 alkyl group;

Each R ^a is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy, or optionally The following groups substituted by substituents: -(CH ₂ ) _m -3-6-membered cycloalkyl, -(CH ₂ ) _m -3-6-membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C _{1 -6} alkyl or halo C _1-6 alkyl;

Each R ^b is independently selected from hydrogen or C _1-4 alkyl;

Each m, each n and each p are independently selected from 0, 1 or 2.

In certain embodiments, the compound, its pharmaceutically acceptable salt or its stereoisomer has a structure represented by the following general formula (VII-1) or general formula (VII-2):

Among them, the definitions of ring A, R ¹ , Q1, Q2, R ^a , R ^b , m, n, and p are as described in any of the previous solutions.

In certain embodiments, the compound, its pharmaceutically acceptable salt or its stereoisomer has a structure represented by the following general formula (VII-3) or general formula (VII-4):

Among them, the definitions of ring A, R ¹ , Q1, Q2, R ^a , R ^b , m, n, and p are as described in any of the previous solutions.

In certain embodiments, the compound, its pharmaceutically acceptable salt or its stereoisomer has a structure represented by the following general formula (VII-5) or general formula (VII-6):

Among them, the definitions of ring A, R ¹ , R ⁴ , Q1, Q2, R ^a , R ^b , m, n, and p are as described in any of the previous solutions.

In certain embodiments, the compound, its pharmaceutically acceptable salt or its stereoisomer has a structure represented by the following general formula (VII-7) or general formula (VII-8):

Among them, the definitions of ring A, R ¹ , R ⁴ , Q1, Q2, R ^a , R ^b , m, n, and p are as described in any of the previous solutions.

In certain embodiments, Formula (VII-1), Formula (VII-2), Formula (VII-3), Formula (VII-4), Formula (VII-5), Formula ( VII-6), a compound represented by general formula (VII-7) or general formula (VII-8), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein,

R ¹ is selected from -NR ^a R ^b , -OR ^a , -SR ^a , -NH-C(O)-R ^b -, or the following groups optionally substituted by substituents: -(CH ₂ ) _p -3 -6-membered cycloalkyl, -(CH ₂ ) _p -3-6-membered heterocyclyl; the substituent is selected from halogen, C _1-4 alkyl or halogenated C _1-4 alkyl;

Each R ⁴ is independently selected from hydrogen, halogen, C _1-4 alkyl or halogenated C _1-4 alkyl;

Ring A is selected from Wherein, each ring atom in ring A is optionally oxo-substituted;

Each Q1 is independently selected from -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-2 Q2: C _1-4 alkane base, C _1-4 alkoxy group, C _1-4 alkoxy-C _1-4 alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclyl group, 5-6 membered heteroaryl group or benzene base; the Q2 are independently selected from halogen, hydroxyl, C _1-4 alkyl or halogenated C _1-4 alkyl;

Each R ^a is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy, or optionally The following groups substituted by substituents: 3-6-membered cycloalkyl, 3-6-membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C _1-6 alkyl or halogenated C _1-6 alkyl;

Each R ^b is independently selected from hydrogen or C _1-4 alkyl;

Each n and each p are independently selected from 0, 1 or 2.

In certain embodiments, ^R1 is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl group, azetidinyl, oxetanyl, -NR ^a -C(O)-R ^b -, -NR ^a R ^b or -OR ^a , preferably selected from -NR ^a R ^b .

In certain embodiments, Formula (VII-1), Formula (VII-2), Formula (VII-3), Formula (VII-4), Formula (VII-5), Formula ( VII-6), a compound represented by general formula (VII-7) or general formula (VII-8), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein,

R ¹ is selected from azetidinyl, oxetanyl, -NR ^a -C(O)-R ^b -, -NR ^a R ^b or -OR ^a , and each R ^a is independently selected from hydrogen, methane base, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or optionally substituted by a substituent The following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or Imidazolidinyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl; each R ^b is independently selected from Hydrogen, methyl, ethyl, propyl or isopropyl.

Each R ⁴ is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

Ring A is selected from Wherein, each ring atom in ring A is optionally oxo-substituted;

Each Q1 is independently selected from -C(O)R ^a , -C(O)OR ^a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, cyclopropyl, cyclobutyl, oxanyl, oxetanyl, Tetrahydrofuryl, oxanyl, tetrahydropyranyl, azetidinyl, azetidinyl, pyrrolidinyl, pyridinyl or pyridazinyl; the Q2 are independently selected from fluorine, chlorine, bromine , hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl;

Each R ^a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoroethyl, Fluoromethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl , tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

Each R ^b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

In certain embodiments, R ¹ is selected from -NH ₂ ,

In the technical solution of the present invention, the hydrogen on the ring nitrogen atom in the ring A may be optionally replaced by Q1. In certain embodiments, Q1 substitutes one or more hydrogens on the ring nitrogen atom in Ring A.

In certain embodiments, each Q1 is independently selected from methyl, ethyl, cyclopropyl, cyclobutyl,

Each technical solution in the present invention can be combined with each other to form a new technical solution, and the formed new technical solution is also included in the scope of the present invention.

In certain embodiments, the compound described in the aforementioned general formula (I), its pharmaceutically acceptable salt or its stereoisomer is selected from the following compounds:

The present invention also provides a pharmaceutical composition, which contains a compound of the present invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and one or more pharmaceutical carriers and/or diluents; the medicine The composition can be made into any clinically or pharmaceutically acceptable dosage form, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powder for injection and concentrated solutions for injection), suppositories, inhalants or sprays, etc.

In certain embodiments of the invention, the pharmaceutical formulations described above may be administered to patients or subjects in need of such treatment by oral, parenteral, rectal or pulmonary administration. When used for oral administration, the pharmaceutical composition can be made into oral preparations, for example, it can be made into 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 making oral preparations, appropriate fillers, binders, disintegrants, lubricants, etc. can be added. When used for parenteral administration, the above pharmaceutical preparations can also be made into injections, including injection liquids, sterile powders for injection and concentrated solutions for injection. When making injections, conventional methods in the existing pharmaceutical field can be used. When preparing injections, no additives may be added, or appropriate additives may be added according to the properties of the drug. When used for rectal administration, the pharmaceutical composition can be made into suppositories and the like. When used for transpulmonary administration, the pharmaceutical composition can be made into inhalants or sprays.

The pharmaceutical carrier and/or diluent usable in the pharmaceutical composition or pharmaceutical preparation of the present invention can be any conventional carrier and/or diluent in the field of pharmaceutical preparation. The selection of the specific carrier and/or diluent will depend on the use. Mode of administration or disease type and condition to treat a specific patient. Methods for the preparation of suitable pharmaceutical compositions for a particular mode of administration are well within the knowledge of those skilled in the pharmaceutical art.

In another aspect, the present invention also relates to the use of the compounds of the present invention, pharmaceutically acceptable salts thereof or stereoisomers thereof in the preparation of medicaments for preventing and/or treating diseases mediated by HPK1 and related diseases, 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, including carcinoma in situ and metastatic cancer. Further, the cancers include but are 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.

Further, the present invention also relates to the use of pharmaceutical preparations containing the compounds of the present invention, pharmaceutically acceptable salts or stereoisomers thereof in the preparation of medicines, which can be used in combination with one or more medicines to Treat and/or prevent HPK1-mediated diseases and related conditions.

In another aspect, the invention relates to a medicament containing a compound of the invention, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which may be administered alone or in combination with one or more second therapeutically active agents, The second therapeutically active agent is used in combination with the HPK1 inhibitor compounds of the present application to treat and/or prevent diseases and related disorders mediated by HPK1. Accordingly, 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 anti-cancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, anti-tumor antibiotics, growth factor inhibitors, signaling Conduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormone drugs, angiogenesis inhibitors, cell growth inhibition agents, targeted antibodies, HMG-CoA reductase inhibitors and isoprenyl protein transferase inhibitors.

In certain embodiments, the components to be combined (e.g., a compound of the invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a second therapeutically active agent) may be administered simultaneously or separately and sequentially. . For example, the second therapeutically active agent may be administered before, simultaneously with, or after administration of a compound of the invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Furthermore, the ingredients to be combined can also be administered jointly in the same formulation or in separate different formulations.

On the other hand, the present invention also provides a method for treating HPK1-mediated diseases and related conditions, which method includes administering an effective amount of the compound described in the aforementioned general formula (I), its pharmaceutical composition, to a patient in need. The above acceptable salts or stereoisomers thereof, the aforementioned preparations or pharmaceutical compositions; the diseases and related disorders mediated by HPK1 are as defined above.

The "effective dose" refers to the dose of drug that can reduce, delay, inhibit or cure the subject's disease. The size of the dosage is determined by the method of drug administration, the pharmacokinetics of the drug, the severity of the disease, the subject's personal signs (gender, weight, height, age), etc.

[Detailed description of the invention]

In the present invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of the present invention, definitions of some terms are provided below. When the definitions and explanations of terms provided in the present invention are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided in the present invention shall prevail.

The "halogen" mentioned in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C _1-6 alkyl" as used in the present invention refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, including, for example, "C _1-4 alkyl" and "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 alkyl", etc. Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The "C _1-4 alkyl group" used in the present invention refers to specific examples of C _1-6 alkyl groups containing 1 to 4 carbon atoms.

The "C _1-6 alkoxy group" mentioned in the present invention refers to "C _1-6 alkyl-O-", and the "C _1-6 alkyl group" is as defined above. The "C _1-4 alkoxy group" mentioned in the present invention refers to "C _1-4 alkyl-O-", and the "C _1-4 alkyl group" is as defined above.

The "C _1-6 alkylthio group" mentioned in the present invention refers to "C _1-6 alkyl-S-", and the "C _1-6 alkyl group" is as defined above. The "C _1-4 alkylthio group" mentioned in the present invention refers to "C _1-4 alkyl-S-", and the "C _1-4 alkyl group" is as defined above.

The "hydroxy C _1-6 alkyl group, amino C _1-6 alkyl group, and halo C _1-6 alkyl group" referred to in the present invention means that one or more hydrogens in the C _1-6 alkyl group are respectively replaced by one or Substituted by multiple hydroxyl groups, amino groups or halogens. C _1-6 alkyl is as defined above

The "hydroxyl C _1-6 alkoxy group, amino C _1-6 alkoxy group, and halogenated C _1-6 alkoxy group" mentioned in the present invention refers to one or more of the "C _1-6 alkoxy group" The hydrogen is replaced by one or more hydroxyl groups, amino groups or halogens.

The "hydroxyl C _1-6 alkylthio group, amino C _1-6 alkylthio group, and halogenated C _1-6 alkylthio group" mentioned in the present invention refers to one or more of the "C _1-6 alkylthio group" The hydrogen is replaced by one or more hydroxyl groups, amino groups or halogens.

The "C _1-6 alkylamino and di(C _1-6 alkyl)amino" mentioned in the present invention refer to C _1-6 alkyl-NH-,

"C _2-6 alkenyl" as used in the present invention refers to a linear, branched or cyclic alkenyl group containing at least one double bond and having 2-6 carbon atoms, including, for example, "C _2-4 alkenyl""wait. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl Alkenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexenyl Dienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, etc.

The "C _2-6 alkynyl group" mentioned in the present invention refers to a linear or branched chain alkynyl group containing at least one triple bond and having 2-6 carbon atoms, including, for example, "C _2-4 alkynyl group" and the like. Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3 -Hexynyl, 5-methyl-2-hexynyl, etc.

The "3-10-membered cycloalkyl group" used in the present invention refers to a saturated or partially saturated monocyclic or polycyclic group containing 3-10 carbon atoms and without aromaticity. The "monocyclic cycloalkyl" is preferably "3-8 membered monocyclic alkyl", and the "polycyclic cycloalkyl" includes "fused cyclic group, bridged cyclic group and spirocyclic group", preferably "7-10 "Member fused ring alkyl", "7-10 membered bridged ring group" and "7-10 membered spirocyclic group".

The "3-8 membered monocyclic alkyl group" mentioned in the present invention refers to a saturated or partially saturated monocyclic cyclic alkyl group containing 3-8 carbon atoms and not aromatic, including "3-8 membered saturated "Monocyclic alkyl" and "3-8 membered partially saturated monocyclic alkyl"; preferably "3-4 membered monocyclic alkyl", "3-5 membered monocyclic alkyl", "3-6 membered monocyclic alkyl" "Basic", "3-7 membered monocyclic alkyl", "4-5 membered monocyclic alkyl", "4-6 membered monocyclic alkyl", "4-7 membered monocyclic alkyl", "4- "8-membered monocyclic alkyl", "5-6-membered monocyclic alkyl", "5-7-membered monocyclic alkyl", "5-8-membered monocyclic alkyl", "6-7-membered monocyclic alkyl" ", "6-8 membered monocyclic alkyl group", "7-8 membered monocyclic alkyl group", "3-6 membered saturated monocyclic alkyl group", "5-8 membered saturated monocyclic alkyl group", "5 -7-membered saturated monocyclic alkyl", "5-6-membered saturated monocyclic alkyl", etc. Optionally, the ring carbon atoms in the cyclic structure can be oxo-substituted. Specific examples of the "3-8 membered saturated monocyclic alkyl" include but are not limited to: cyclopropyl (cyclopropyl), cyclobutyl (cyclobutyl), cyclopentyl (cyclopentyl) , cyclohexyl (cyclohexyl), cycloheptyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.; specific examples of the "3-8 membered partially saturated monocyclic alkyl" include But not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptyl Alkenyl, 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.

The "7-10-membered fused ring group" mentioned in the present invention refers to a saturated or partial cyclic structure containing 7-10 ring atoms formed by two or more cyclic structures sharing two adjacent carbon atoms with each other. Saturated, non-aromatic cyclic groups, one of the rings in the fused ring can be an aromatic ring, but the fused ring as a whole is not aromatic; including "8-9 membered fused ring group", "9-10 "Member fused ring group" etc., the fusion method can be: 5-6 membered cycloalkyl, 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl etc. Optionally, ring atoms in the cyclic structure may be oxo-substituted. Examples include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl , Bicyclo[4.2.0]octyl, octahydropentadienyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthyl, bicyclo[3.1.0]hexan-2- Alkenyl, 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- Tetrahydropentadienyl, 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-decahydrophenanthyl, benzocyclopentyl, benzo Cyclohexyl, benzocyclohexenyl, benzocyclopentenyl, etc.

The "7-10-membered bridged cyclic group" mentioned in the present invention refers to a cyclic ring containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing two non-adjacent carbon atoms with each other. structure. Optionally, carbon atoms in the cyclic structure can be oxo-substituted. Specific examples include but are not limited to: wait.

The "7-10 membered spiroheterocyclyl" in the present invention refers to a cyclic structure containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing one carbon atom with each other. Optionally, carbon atoms in the cyclic structure can be oxo-substituted. Specific examples include but are not limited to: wait.

The "3-10 membered heterocyclic group" mentioned in the present invention refers to a saturated or partially saturated (including 1 or 2 double bonds) composed of 3-10 carbon atoms and heteroatoms selected from nitrogen, oxygen or sulfur. Non-aromatic cyclic group, this cyclic group can be a monocyclic or polycyclic group. In the present invention, the number of heteroatoms in the heterocyclic group is preferably 1, 2, 3 or 4, and the nitrogen in the heterocyclic group is preferably 1, 2, 3 or 4. , carbon or sulfur atoms may optionally be oxidized. The nitrogen atoms may optionally be further substituted with other groups to form tertiary amines or quaternary ammonium salts.

Monocyclic heterocyclyl is preferably "3-8 membered monoheterocyclyl", which refers to one containing at least one heteroatom (for example, containing 1, 2, 3, 4 or 5) and the number of ring atoms is 3 -8 saturated or partially saturated monocyclic cyclic groups without aromaticity, the heteroatoms are nitrogen atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms in the cyclic structure ( For example, a carbon atom, a nitrogen atom or a sulfur atom) can be oxo-substituted. The "3-8 membered monoheterocyclyl group" in the present invention includes "3-8 membered saturated monoheterocyclyl group" and "3-8 membered partially saturated monoheterocyclyl group". Preferably, the "3-8-membered monoheterocyclyl" described in the present invention contains 1-3 heteroatoms; preferably, the "3-8-membered monoheterocyclyl" described in the present invention contains 1-2 heteroatoms. atom, and the heteroatom is selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8-membered monoheterocyclic group" described in the present invention contains 1 nitrogen atom. The "3-8 membered monoheterocyclyl" is preferably "3-7 membered monoheterocyclyl", "3-6 membered monoheterocyclyl", "4-7 membered monoheterocyclyl", "4-6 "Monoheterocyclyl", "6-8-membered monoheterocyclyl", "5-7-membered monoheterocyclyl", "5-6-membered monoheterocyclyl", "3-6-membered saturated monoheterocyclyl" ”, “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” "Cyclic group", "5-6 membered saturated nitrogen-containing monoheterocyclic group", etc. For example, it contains only 1 or 2 nitrogen atoms, or it contains one nitrogen atom and 1 or 2 other heteroatoms (such as oxygen atoms and/or sulfur atoms). Specific examples of "3-8 membered monoheterocyclyl" include, but are not limited to: aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diaaziridinyl, aza cyclobutanyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxanyl, 1,4-dioxanyl Dialkenyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrogen Thienyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidinonyl, tetrahydropyridinonyl, dihydropiperidonyl, piperazine base, morpholinyl, 4,5-dihydroxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, oxazolidinyl, 2H-1,2-oxazolyl Azinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl Azinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyran Key et al.

Polycyclic heterocyclyl includes "fused heterocyclyl", "spiroheterocyclyl" and "bridged heterocyclyl", preferably "7-10 membered fused heterocyclyl", "7-10 membered spiroheterocyclyl" and "7-10-membered bridged heterocyclic group".

The "7-10-membered fused heterocyclic group" mentioned in the present invention refers to a ring structure containing 7-10 ring atoms and at least one ring formed by two or more cyclic structures sharing two adjacent atoms. The atom is a heteroatom, a saturated or partially saturated, non-aromatic cyclic group. One of the rings in the fused ring may be an aromatic ring, but the entire fused ring is not aromatic. The heteroatom is nitrogen. atoms, oxygen atoms and/or sulfur atoms, optionally, ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxygenated, including but not limited to "8-9 membered fused heterocyclic groups" ", "9-10-membered fused heterocyclyl", etc., the fusion method can be 5-6-membered heterocyclyl and 5-6-membered heterocyclyl, 5-6-membered heterocyclyl and 5-6-membered cycloalkane base, benzo 5-6 membered heterocyclyl, benzo 5-6 membered saturated heterocyclyl, 5-6 membered heteroaryl 5-6 membered heterocyclyl, 5-6 membered heteroaryl 5-6 One-membered saturated heterocyclyl; 5-6-membered heteroaryl is as defined above; specific examples of the "8-10-membered fused heterocyclyl" include but are not limited to: pyrrolidinylcyclopropyl, cyclopentylazo Heterocyclopropyl, pyrrolidinolocyclobutyl, pyrrolidinolopyrrolidinyl, pyrrolidinolopiperidinyl, pyrrolidinolopiperazinyl, pyrrolidinolomorpholinyl, piperidinomorpholinyl Phenyl, benzopyrrolidyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuryl, benzopyrrolidyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, Benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidyl, benzomorpholinyl, benzopiperazinyl, chromanyl, pyridocyclopentyl, pyridocyclyl Hexyl, pyridotetrahydrofuranyl, pyridopyrrolidinyl, pyridinoimidazolidinyl, pyridoxazolidinyl, pyridothiazolidinyl, pyridinoisoxazolidinyl, pyridinoisothiazolidinyl, pyridopiperidinyl Aldyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl , pyrimidooxazolidinyl, pyrimidothiazolidinyl, pyrimidinoisoxazolidinyl, pyrimidinoisothiazolidinyl, pyrimidopiperidinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrazine Hydropyranyl; tetrahydroimidazo[4,5-c]pyridyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3 ]Dioxolyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, 4H-1,3-benzene Oxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H-furo[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, octahydrocyclopentene And [c] pyrrolyl, 4H-1,3-benzoxazinyl, etc.

The term "benzocyclopentyl", its structure refers to (Also known as 2,3-dihydro-1H-indenyl); the term "benzopyrrolidine" has a structure including etc.; the term "pyridotetrahydrofuranyl" has a structure including Specific examples of other "other fused heterocyclyl groups as defined above" as defined above have similar cyclic structures.

The "7-10-membered spiroheterocyclyl" mentioned in the present invention refers to a group formed by two or more cyclic structures sharing one ring atom with each other and containing 7-10 ring atoms (at least one of which is The cyclic structure of a heteroatom (such as a nitrogen atom, an oxygen atom or a sulfur atom) includes "7-10 membered saturated spiroheterocyclyl" and "7-10 membered partially saturated spiroheterocyclyl". Optionally, ring atoms (eg carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. Specific examples include but are not limited to:

wait.

The "7-10-membered bridged heterocyclyl" mentioned in the present invention refers to a cyclic structure formed by two or more cyclic structures sharing two non-adjacent ring atoms and containing 7-10 ring atoms (wherein Ring structures in which at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom) include "7-10-membered saturated bridged heterocyclyl" and "7-10-membered partially saturated bridged heterocyclyl". Optionally, ring atoms (eg carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. Specific examples include but are not limited to:

wait.

The "6-10-membered aryl group" mentioned in the present invention includes "6-8-membered monocyclic aryl group" and "8-10-membered fused ring aryl group".

The "6-8 membered monocyclic aryl group" described in the present invention refers to a monocyclic aryl group containing 6-8 ring carbon atoms. Examples thereof include but are not limited to: phenyl, cyclooctatetraenyl, etc.; benzene is preferred base.

The "8-10 membered fused ring aryl group" mentioned in the present invention refers to an aryl group formed by two or more cyclic structures sharing two adjacent atoms and containing 8-10 ring carbon atoms. Saturated, aromatic cyclic groups are preferably "9-10 membered fused ring aryl groups", specific examples include naphthyl, etc.

The "5-10-membered heteroaryl" in the present invention includes "5-8-membered monoheteroaryl" and "8-10-membered fused heteroaryl".

The "5-8 membered monoheteroaryl group" used in the present invention refers to an aromatic monoheteroaryl group containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom). Ring cyclic group. Optionally, ring atoms (eg carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. "5-8-membered monoheteroaryl" includes, for example, "5-7-membered monoheteroaryl", "5-6-membered monoheteroaryl", "5-6-membered nitrogen-containing monoheteroaryl", "6-membered "Nitrogen-containing monoheteroaryl", etc., the heteroatom in the "nitrogen-containing heteroaryl" contains at least one nitrogen atom, for example, only contains 1 or 2 nitrogen atoms, or contains one nitrogen atom and other 1 or 2 heteroatoms (such as oxygen atoms and/or sulfur atoms), or, containing 2 nitrogen atoms and another 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 furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadizoyl Azolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole base, 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, azepantrienyl, 1,3-diazepantrienyl Alkenyl, azacycline tetraenyl, etc. The "5-6 membered monoheteroaryl group" refers to specific examples of 5-8 membered heteroaryl groups containing 5-6 ring atoms.

The "8-10-membered fused heteroaryl" mentioned in the present invention refers to a group formed by two or more cyclic structures sharing two adjacent atoms and containing 8-10 ring atoms (at least one of which is The ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom) and is an unsaturated aromatic ring structure. Optionally, ring atoms (eg carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure can be oxo-substituted. Including "9-10-membered condensed heteroaryl", "8-9-membered condensed heteroaryl", etc., the condensation method can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl 5- 6-membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazothiophene, furanothiophene, pyrazooxazole, benzofuranyl, benzoiso Furyl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinonyl, 4 -Quinolinonyl, 1-isoquinolinonyl, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, Naphthyridinyl etc.

"A carbon atom, a nitrogen atom or a sulfur atom is oxo-substituted" in the present invention refers to the formation of a structure of C=O, N=O, S=O or _SO2 .

"Optionally substituted" as mentioned in the present invention refers to two situations in which one or more hydrogen atoms on the substituent can be "substituted" or "unsubstituted" by one or more substituents.

The "pharmaceutically acceptable salt" mentioned in the present invention refers to the salt formed by the acidic functional group (such as -COOH, -OH, -SO ₃ H, etc.) present in the compound and the appropriate inorganic or organic cation (base), including with Salts formed by alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and salts formed by basic functional groups (such as -NH2, etc.) present in the compound and appropriate inorganic or organic anions (acids), Included are salts formed with inorganic acids or organic acids (such as carboxylic acids, etc.). Examples include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, bismuth, hydrochloride, sulfate, nitrate, phosphate, hydrobromide, hydroiodide, formate , acetate, propionate, oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, methanesulfonic acid Salt, ethanesulfonate, benzenesulfonate, toluenesulfonate, tetrafluoroborate, arginate, aspartate and glutamic acid, etc.

The "isomer" mentioned in the present invention refers to when the compound of the present invention contains one or more asymmetric centers, and thus can be used as a racemate and a racemic mixture, a single enantiomer, and a diastereoisomer. 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 invention includes all possible optical isomers and mixtures thereof. If the compounds described in the present invention contain olefin double bonds, unless otherwise specified, they include cis isomers and trans isomers. The compounds of the present invention may exist as tautomers (a type of functional group isomer) having different points of attachment of hydrogens through the displacement of one or more double bonds, for example, a ketone and its alkene The alcohol form is the keto-enol tautomer. The compound of the present invention contains a spiro ring structure. Affected by the three-dimensional structure of the ring, the substituents on the ring can exist on both sides of the ring to form relative cis (cis) and trans (trans) isomers. Each tautomer and mixtures thereof are included within the scope of the invention. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers and their Mixtures, etc. are included in the scope of the present invention.

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

When the stereochemistry of a disclosed compound is named or depicted by a structure, the named or depicted stereoisomer is at least 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight relative to the other stereoisomers Or 99.9% pure by weight. 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 the enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

The "dosage form" mentioned in the present invention refers to the form of the drug that is suitable for clinical use, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections) , sterile powder for injection and concentrated solution for injection), spray, aerosol, powder mist, lotion, liniment, ointment, plaster, paste, patch, gargle or suppository, more preferably Powder, tablet, granule, capsule, solution, injection, ointment, gargle or suppository.

Beneficial effects of the invention

1. The compounds of the present invention, their pharmaceutically acceptable salts or their stereoisomers have excellent HPK1 activity inhibitory effects, good pharmacokinetic properties in vivo, long-lasting effects, and good liver microsome stability. properties, exposure, and bioavailability to treat and/or prevent HPK1-mediated diseases.

2. The compound of the present invention, its pharmaceutically acceptable salt or its stereoisomer has a good therapeutic effect on HPK1-mediated cancer.

3. The compound of the present invention has a simple preparation process, high pharmaceutical purity, stable quality, and is easy to carry out large-scale industrial production.

Specific implementation plan

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

The abbreviations used in the following experiments have the following meanings:

LiAlH ₄ : lithium aluminum hydride

LDA: lithium diisopropylamide

DCC: dicyclohexylcarbodiimide

Preparation Example 1: 7-amino-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 1)

1. Preparation of 2,2'-(1,2-phenylene)bis(ethane-1-ol)

2,2'-(1,2-phenylene)diacetic acid (10.0 g, 51.5 mmol) was dissolved in tetrahydrofuran (200 mL). Add LiAlH ₄ (5.9g, 0.15mol) in batches at 0°C, complete the addition, and react at 15°C for 18 hours. LCMS detected the end of the reaction. Add 5.9 mL of water at 0°C to quench the reaction. A solid precipitated. Filter through Celite and wash the solid with tetrahydrofuran. The filtrate was dried and concentrated to obtain 7.0 g of the title compound. Yield: 81.8%.

2. Preparation of 1,2-phenylenebis(ethane-2,1-diyl)dimethanesulfonate

Dissolve 2,2'-(1,2-phenylene)bis(ethane-1-ol) (7.0g, 42.2mmol) in dichloromethane (150mL), and add triethylamine (8.5g) at 0°C , 84.4mmol) and methylsulfonyl chloride (9.8g, 84.4mmol) were added, and the reaction was carried out at 0°C for 1 hour. The reaction was quenched with 1M dilute hydrochloric acid, the liquids were separated, and the organic phase was dried and concentrated for direct use in the next step.

3. Preparation of 2,3,4,5-tetrahydro-1H-benzo[d]azepine

Dissolve 1,2-phenylenebis(ethane-2,1-diyl)dimethanesulfonate (N/A, 42.2mmol) in acetonitrile (50mL), add ammonia water (50mL), and keep the tank at 90°C Reaction takes 2 hours. Cool to 15°C, concentrate the solvent, add water to dilute, adjust pH=4 with concentrated hydrochloric acid, extract with ethyl acetate, adjust the aqueous phase to pH=11 with sodium hydroxide aqueous solution, and extract with mixed solvent (dichloromethane:methanol=10:1). The organic phase was dried and concentrated to obtain 3.0 g of the target compound. The two-step yield was 48.4%.

4. Preparation of 2,2,2-trifluoro-1-(1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)ethyl-1-one

Dissolve 2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.0g, 20.4mmol) in dichloromethane (100mL), add pyridine (2.4g, 30.6mmol), 0°C Trifluoroacetic anhydride (5.4g, 25.5mmol) was added dropwise at 15°C for 15 hours. LCMS detected the end of the reaction, added water to quench the reaction, extracted with dichloromethane, and dried and concentrated the organic phase for silica gel column purification (petroleum ether: ethyl acetate = 3:1) to obtain 4.0 g of the target compound, yield: 80.8%.

5. 2,2,2-Trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)ethane-1- Preparation of ketones

2,2,2-Trifluoro-1-(1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)ethyl-1-one (4.0g, 16.5 mmol) was dissolved in concentrated sulfuric acid (30 mL). At 0°C, potassium nitrate (1.7g, 16.5mmol) was added in batches. After the addition was completed, the reaction was carried out at 15°C for 16 hours. LCMS detects the end of the reaction. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was dried and concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain 3.0 g of the target compound, yield: 63.3%.

6. Preparation of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

2,2,2-Trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)ethane-1-one (3.0g, 10.4mmol) was dissolved in methanol (50mL), potassium carbonate (2.9g, 20.8mmol) was added, and the reaction was completed at 15°C for 15 hours. LCMS detects the end of the reaction. Filter through diatomaceous earth, concentrate the solvent, and purify with C18 column (methanol = 0-70%) to obtain 1.9 g of the target compound, yield: 95.5%.

7. Preparation of 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Dissolve 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (65mg, 0.19mmol) in formaldehyde (37%) (10mL), and add formic acid (5mL). React at 15°C for 1 hour, then raise the temperature to 70°C for 1 hour. LCMS detects the end of the reaction. The pH of the saturated sodium bicarbonate solution was adjusted to 9, and the organic phase was extracted with ethyl acetate, dried and concentrated to obtain 1.9 g of the target compound, yield: 93.1%.

8. Preparation of 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

Dissolve 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.9g, 9.2mmol) in methanol (30mL), and add Pd/C (1.0g), after addition, hydrogenation reaction was carried out at 15°C for 1 hour. LCMS detects the end of the reaction. Filter through diatomaceous earth, dry and concentrate the filtrate to obtain 1.6g of the target compound, yield: 98.6%.

9. Preparation of N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (1.6g, 9.1mmol) in acetic acid (5mL), add acetic anhydride (1.5 mL), after addition, react at 15°C for 12 hours. LCMS detects the end of the reaction. Dilute with water, adjust pH=9 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, and concentrate the aqueous phase for C18 column purification (methanol=0-80%) to obtain 1.9g of the target compound, yield: 96.0%.

10. Preparation of N-(3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.9g, 8.7mmol) in concentrated sulfuric acid (16mL ), add fuming nitric acid (799.0 mg, 11.3 mmol) dropwise at 0°C, and react at 0°C for 10 minutes after the addition is completed. LCMS detects the end of the reaction. Pour into ice water, adjust pH=7 with sodium hydroxide aqueous solution, concentrate the solvent, wash the solid with dichloromethane and methanol, and concentrate the organic phase to obtain a crude product which is directly used in the next step.

11. Preparation of 3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

N-(3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide (N/A, 8.7mmol) Dissolve in methanol (20 mL), add potassium carbonate (2.4 g, 17.4 mmol), complete the addition, and react at 55°C for 36 hours. LCMS detects the end of the reaction. Filter through diatomaceous earth, and the filtrate is concentrated and purified by C18 column (methanol = 0-80%) to obtain 1.6 g of the target compound, yield: 83.2%.

12. 2-(7-Methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)ethyl acetate

Dissolve 3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (1.6g, 7.2mmol) in ethanol (30mL), Pd/C (1.0g) was added, and the hydrogenation reaction was carried out at 15°C for 2 hours. LCMS detects the end of the reaction. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (3.4g.17.4mmol), raise the temperature to 50°C and react for 2 hours. LCMS detects the end of the reaction. Filter through diatomaceous earth, and the filtrate is concentrated and purified on a silica gel column (dichloromethane: methanol = 8:1) to obtain 1.2 g of the target compound, yield: 57.7%.

13. 7-hydroxy-4-(4-methoxybenzyl)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4 , Preparation of 5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)1-one

2-(7-Methyl-1,5,6,7,8,9-hexahydroimidazolylbenzo[1,2-d]azepine-2-yl)ethyl acetate (200 mg, 0.7 mmol ), 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (221.5mg, 0.77mmol) dissolved Add LDA (1.4 mL, 2.8 mmol) to tetrahydrofuran (5 mL), and react at 40°C for 2 hours after addition. LCMS detects the end of the reaction. The reaction was quenched with saturated ammonium chloride, extracted with dichloromethane, and the organic phase was dried and concentrated for silica gel column purification (dichloromethane:methanol=4:1) to obtain 60 mg of the target compound, yield: 17.7%.

14. 4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole And[4',5':4,5]benzo[1,2-d]azepine-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b] Preparation of pyridin-7-yl triflate

7-Hydroxy-4-(4-methoxybenzyl)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4, 5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)1-one (60mg, 0.12mmol) was dissolved in dichloromethane (10mL ), add pyridine (189.8 mg, 2.4 mmol) and trifluoromethanesulfonic anhydride (203.1 mg, 0.72 mmol) at 0°C and complete the addition. React at 0°C for 1 hour. LCMS detects the end of the reaction. Add dichloromethane to dilute, wash with sodium bicarbonate aqueous solution, dry and concentrate the organic phase for direct use in the next step.

15. 7-(((2,4-dimethoxybenzyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1 ,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2- b] Preparation of pyridin-5(4H)-1-one

4-(4-Methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine -7-yl triflate (N/A, 0.12mmol) was dissolved in acetonitrile (5mL), 2,4-dimethoxybenzylamine (60.1mg, 0.36mmol) was added, and the temperature was raised to 45°C after addition. Reaction takes 2 hours. LCMS detects the end of the reaction. The solvent was concentrated and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 90.0 mg of the title compound, with a two-step yield of 95.0%.

16. 7-amino-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of azepine-2-yl)thieno[3,2-b]pyridin-5(4H)-one

7-(((2,4-Dimethoxybenzyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1, 5,6,7,8,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b ] Pyridin-5(4H)-1-one (90 mg, 0.12 mmol) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (7 mL). After addition, the temperature was raised to 110°C and the reaction was carried out for 24 hours. LCMS detected the end of the reaction. Saturated hydrogen carbonate The sodium aqueous solution was adjusted to pH=7, the solvent was concentrated, and Pre-HPLC purification (acetonitrile=0-40%) was performed to obtain 10.0 mg of the title compound, with a yield of 23.4%.

Molecular formula: C ₁₉ H ₁₉ N ₅ OS Molecular weight: 365.5 LC-MS (M/e): 366.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 11.83 (s, 1H), 9.67 (m, 1H), 7.96 (d, J = 5.2Hz, 1H), 7.51 (s, 2H), 7.02 (d ,J＝5.6Hz,1H),3.55-3.95(m,4H),2.95-3.28(m,4H),2.88(s,3H).

Preparation Example 2: 4-amino-5-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (compound 2)

2-(7-Methyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine-2- (100 mg, 0.35 mmol), 2-aminothiophene-3-carbonitrile (47.5 mg, 0.38 mmol) were dissolved in tetrahydrofuran (5 mL), heated to 40°C, and LDA (0.53 mL, 1.05 mmol) was added dropwise , react at 40°C for 2 hours after addition. LCMS detects the end of the reaction. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried and concentrated for C18 column purification (acetonitrile = 0-60%) to obtain 6.6 mg of the target compound, yield: 5.2%.

Molecular formula: C ₁₉ H ₁₉ N ₅ OS Molecular weight: 365.5 LC-MS (M/e): 366.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ )δ:9.91(m,1H),7.57(m,2H),7.23(m,2H),4.45(m,2H),3.20-3.34(m,4H) ,3.17(s,3H),2.98-3.14(m,4H).

Preparation Example 3: 4-amino-5-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1 Preparation of ,2-d]azinocin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (compound 4)

1. Preparation of 2,3,5,6-tetrahydrobenzo[d]acinocin-4(1H)-one

Dissolve 5,6,8,9-tetrahydro-7H-benzo[7]annen-7-one (8.0g, 49.9mmol) in trifluoroacetic acid (60mL), and add sodium azide (4.9g, 75.4mol). React at 65°C for 7 hours. Extract with saturated sodium bicarbonate (200 mL) and ethyl acetate (100 mL), dry and concentrate the organic phase, and purify on a silica gel column (dichloromethane:methanol=20:1) to obtain 5.0 g of the target compound, yield: 57.1%.

2. Preparation of 1,2,3,4,5,6-hexahydrobenzo[d]accine

Dissolve 2,3,5,6-tetrahydrobenzo[d]acinocin-4(1H)-one (5.0g, 28.5mmol) in tetrahydrofuran (200mL), and add lithium aluminum tetrahydrhydride (4.3 g, 113.2 mmol), react at 75°C for 1 hour. Add water (4.3 mL) to quench the reaction, add 10% sodium hydroxide (4.3 mL) solution and water (12.9 mL), filter to remove the solid, and extract with water (100 mL) and ethyl acetate (200 mL) to obtain 4.2 g of crude product.

3. Preparation of 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]acinoline

Dissolve 1,2,3,4,5,6-hexahydrobenzo[d]acinoline (2.0g) in formic acid (10mL), add formaldehyde (37%) (20mL), and react at 70°C for 1 hour. Adjust the pH to 9 with saturated sodium bicarbonate (200 mL), and extract with ethyl acetate (200 mL) to obtain 2.0 g of crude product.

4. Preparation of 3-methyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[d]accine

Dissolve 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]acinoline (2.0g) in concentrated sulfuric acid (15mL), cool to 0°C and add potassium nitrate (1.2 g, 11.9mmol), reacted at 15°C for 15 hours. Adjust the pH to 12 with 2N sodium hydroxide, extract with dichloromethane/methanol = 9:1 (100 mL), dry and concentrate the organic phase for silica gel column purification (dichloromethane: methanol = 9:1) to obtain 1.3g of the target compound.

5. Preparation of 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]acetin-8-amine

Dissolve 3-methyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[d]axine (1.2g, 5.4mmol) in methanol (40mL), add Pd/ C (1.0g), complete addition, hydrogenation reaction at 15°C for 1 hour. Filter through diatomaceous earth, dry and concentrate the filtrate to obtain 1.0 g of the target compound, with a yield of 96.46%.

6. Preparation of N-(3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azexin-8-yl)acetamide

Dissolve 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]acinocin-8-amine (1.0g, 5.2mmol) in acetic acid (8mL), add acetic anhydride ( 2mL), after addition, react at 15°C for 12 hours. LCMS detects the end of the reaction. Dilute with water, adjust pH=9 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane/methanol=9:1 (100mL), concentrate and purify with C18 column (methanol=0-60%) to obtain 1.0g of the target compound, yield: 81.9% .

7. Preparation of N-(3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]acinocin-8-yl)acetamide

Dissolve N-(3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azecin-8-yl)acetamide (1.0g, 4.3mmol) in concentrated sulfuric acid ( 15 mL), add fuming nitric acid (339 mg, 5.4 mmol) dropwise at 0°C, complete the addition, and react at 0°C for 10 minutes. LCMS detects the end of the reaction. Pour into ice water, adjust pH=10 with 2N sodium hydroxide aqueous solution, extract with dichloromethane/methanol=9:1 (100mL), and concentrate the organic phase to obtain 1.8g of crude product.

8. Preparation of 3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]acetin-8-amine

Dissolve N-(3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azecin-8-yl)acetamide (1.8g) in methanol (50mL), add potassium carbonate (1.7g, 12.3mmol), complete the addition, and react at 55°C for 48 hours. Concentrate, extract with dichloromethane/methanol = 9:1 (100 mL), and purify with C18 column (methanol = 0-70%) to obtain 800 mg of the target compound, two-step yield: 79.0%.

9. 2-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-d]acridine Preparation of octine-2-yl)ethyl acetate

Dissolve 3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]acetin-8-amine (800mg, 3.4mmol) in ethanol (30mL), Add Pd/C (320 mg), complete the addition, and perform hydrogenation reaction at 15°C for 1 hour. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (1.66g, 8.5mmol), raise the temperature to 50°C and react for 2 hours. Filter through diatomaceous earth, concentrate the filtrate, and purify through silica gel column (dichloromethane: methanol = 6:1) to obtain 500 mg of the target compound, yield: 48.8%.

10. 4-Amino-5-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2 Preparation of -d]acinocin-2-yl)thieno[2,3-b]pyridin-6(7H)-one

2-(7-Methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-d]azexin In-2-yl)ethyl acetate (70 mg, 0.23 mmol) and 2-aminothiophene-3-carbonitrile (32 mg, 0.26 mmol) were dissolved in tetrahydrofuran (10 mL), and LDA (0.3 mL, 0.9 mmol) was added at 40°C. , react at 40°C for 2 hours after addition. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (50 mL), and the organic phase was dried, concentrated, and purified by a preparatory plate (dichloromethane:methanol=6:1) to obtain 40 mg of crude target compound, which was purified again by a preparatory plate (dichloromethane:methanol=6:1). Methyl chloride: methanol = 6:1) to obtain 2.8 mg of the target compound, yield: 3.2%.

Molecular formula: C ₂₀ H ₂₁ N ₅ OS Molecular weight: 379.5 LC-MS(M/e): 380.1(M+H+)

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 7.45 (s, 1H), 7.32 (s, 1H), 7.22-7.17 (m, 2H), 4.20 (s, 2H), 3.15-3.07 (m, 4H),2.95-2.87(m,4H),2.70-2.54(m,3H),1.95-1.79(m,2H).

Preparation Example 4: 7-amino-6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzene Preparation of di[1,2-e][1,4]dioxin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 7)

1. Preparation of 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)ethan-1-ol

Dissolve 2-(2-chloro-4-fluoro-5-nitrophenyl)ethan-1-ol (4.0g, 18.3mmol) in NMP (50mL), and add 2,4-dimethoxybenzyl Add amine (3.7g, 21.9mmol) and N,N-diisopropylethylamine (4.7g, 36.4mmol) and react at 50°C for 0.5 hours. LCMS detected the end of the reaction, added water to quench the reaction, extracted with ethyl acetate, and dried and concentrated the organic phase for silica gel column purification (petroleum ether: ethyl acetate = 3:1) to obtain 4.0 g of the target compound, yield: 68.1%.

2. Preparation of 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)acetaldehyde

Dissolve 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)ethan-1-ol (4.0g, 10.9mmol) in dichloromethane ( 100 mL), add Dess-Martin reagent (5.6 g, 13.1 mmol) at 0°C, complete the addition, and react at 15°C for 1 hour. LCMS detects the end of the reaction. Dichloromethane was added to the reaction solution, then saturated aqueous sodium bicarbonate solution was added to quench the reaction, extracted with dichloromethane, the organic phase was dried and concentrated, and purified on a silica gel column (petroleum ether: ethyl acetate = 5:1) to obtain 3.9g of the target compound. Rate: 98.3%.

3. (2-((2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenylethyl)(methyl)amino)ethyl)(methyl)amino Preparation of tert-butyl formate

Dissolve 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)acetaldehyde (2.5g, 6.9mmol) in dichloromethane (50mL), Add methyl (2-(methylamino)ethyl)carbamic acid tert-butyl ester (1.6g, 8.2mmol), and then react at 15°C for 10 minutes. Add sodium acetate borohydride (3.2g, 15.0mmol) and acetic acid (900mg, 15.0mmol), and react at 15°C for 16 hours. LCMS detects the end of the reaction. Add 1M aqueous sodium hydroxide solution and extract with dichloromethane. Collect the organic phase, dry it, and concentrate the mixture by solvent column chromatography (methanol/dichloromethane = 0-8%) to obtain 3.1 g of the target compound, yield: 83.8%.

4. Preparation of N ¹ -(4-amino-2-chloro-5-nitrophenylethyl)-N ¹ ,N ² -dimethylethane-1,2-diamine

(2-((2-Chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenylethyl)(methyl)amino)ethyl)(methyl)carbamic acid Tert-butyl ester (3.1g, 5.8mmol) was dissolved in dichloromethane (30mL) and trifluoroacetic acid (10mL). After addition, react at 10°C for 1 hour. LCMS detects the end of the reaction. After concentration, go directly to the next step.

5. Preparation of 1,4-dimethyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[e][1,4]dioxin-9-amine

Dissolve crude N1-(4-amino-2-chloro-5-nitrophenylethyl)-N1,N2-dimethylethane-1,2-diamine in N,N-dimethylacetamide ( 50 mL), add potassium carbonate (3.3 g, 23.8 mmol), and react at 110°C for 2 hours after the addition is completed. LCMS detects the end of the reaction. Water was added to quench the reaction, and ethyl acetate was extracted. The organic phase was collected, dried, and concentrated using solvent column chromatography (methanol/dichloromethane = 0-8%) to obtain 0.3 g of the target compound. The two-step yield was 20.6%.

6. Preparation of 1,4-dimethyl-1,2,3,4,5,6-hexahydrobenzo[e][1,4]dioxin-8,9-diamine

1,4-Dimethyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[e][1,4]dioxin-9-amine (300 mg, 1.2 mmol) in ethanol (10 mL), add Pd/C (150 mg), complete the addition, and react at 10°C for 2 hours under nitrogen protection. LCMS detects the end of the reaction. Filter through diatomaceous earth, and concentrate the solvent to obtain the target compound, which is directly put into the next step.

7. 2-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2- Preparation of e][1,4]dioxin-2-yl)ethyl acetate

Dissolve crude 1,4-dimethyl-1,2,3,4,5,6-hexahydrobenzo[e][1,4]dioxin-8,9-diamine in ethanol (10 mL ), add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (704 mg, 3.6 mmol), and react at 50°C for 3 hours after addition. LCMS detects the end of the reaction. Concentrated solvent column chromatography (methanol/dichloromethane=0-15%) gave 300 mg of the target compound, two-step yield: 79.1%.

8. Preparation of 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione

Dissolve 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (5.0g, 29.5mmol) in N,N-dimethylformamide (50mL) , add p-methoxybenzyl chloride (7.9g, 50.2mmol), potassium carbonate (4.9g, 35.5mmol), potassium iodide (2.0g, 12.0mmol), and react at 10°C for 2 hours after addition. LCMS detects the end of the reaction. Water was added to the reaction solution, a solid precipitated, and 3.0 g of the title compound was obtained by filtration, with a yield of 35.1%.

9. 6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2- e][1,4]dioxin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridine-5(4H)-1- Preparation of ketones

2-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e ][1,4]dioxin-2-yl)ethyl acetate (350 mg, 1.1 mmol), 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1 ,3] Oxazine-2,4(1H)-dione (415mg, 1.4mmol) was dissolved in tetrahydrofuran (10mL), heated to 40°C, under nitrogen protection, LDA (1.7mL, 3.3mmol) was added dropwise, and The reaction was carried out at 40°C for 2 hours. The reaction was quenched with saturated ammonium chloride, extracted with dichloromethane, and the organic phase was dried and concentrated by column chromatography (methanol/dichloromethane=0-15%) to obtain the intermediate. Tetrahydrofuran (10 mL) was added and LDA (10 mL) was added dropwise under nitrogen protection. 1.2 mL) reacted for two hours and repeated the above operation to obtain 150 mg of the target compound, yield: 26.5%.

10. 6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2- e][1,4]dioxin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridine-5(4H)-1- Preparation of ketones

6-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e ][1,4]dioxin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-1-one (150 mg, 0.29 mmol) was dissolved in dichloromethane (10 mL), and pyridine (460 mg, 5.8 mmol) and trifluoromethanesulfonic anhydride (490 mg, 1.74 mmol) were added at 0°C until the addition was completed. React at 0°C for 1 hour. LCMS detects the end of the reaction. Add dichloromethane to dilute, wash with sodium bicarbonate aqueous solution, dry and concentrate the organic phase for direct use in the next step.

11. 6-(5,8-dimethyl-3-((trifluoromethyl)sulfonyl)-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5 ':4,5]benzo[1,2-e][1,4]dioxin-2-yl)-7-((3,4-dimethylbenzyl)amino)-4-( Preparation of 4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one

6-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e ][1,4]dioxin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-1-one (N/A, 0.29mmol) was dissolved in acetonitrile (5mL), 2,4-dimethoxybenzylamine (130mg, 0.78mmol) was added, and the mixture was raised to 45°C for 2 hours. LCMS detects the end of the reaction. The solvent was concentrated and purified by silica gel column (dichloromethane:methanol=20:1) to obtain 200 mg of the title compound, with a two-step yield of 90.2%.

12. 7-amino-6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[ Preparation of 1,2-e][1,4]dioxin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

6-(5,8-Dimethyl-3-((trifluoromethyl)sulfonyl)-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5' :4,5]benzo[1,2-e][1,4]dioxin-2-yl)-7-((3,4-dimethylbenzyl)amino)-4-(4 -Methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (200mg, 0.25mmol) was dissolved in concentrated hydrochloric acid (1mL) and trifluoroacetic acid (7mL). After addition, the temperature reached 110 °C for 24 hours. LCMS detects the end of the reaction. Adjust pH=7, concentrate the solvent, and perform Pre-HPLC purification (acetonitrile=0-40%) to obtain 20 mg of the title compound, with a yield of 20.1%.

Molecular formula: C ₂₀ H ₂₂ N ₆ OS Molecular weight: 394.5 LC-MS (M/e): 395.1 (M+H ⁺ )

¹ H-NMR (400MHz, MeOD) δ: 7.83 (d, J = 5.2 Hz, 1H), 7.37-7.52 (m, 2H), 7.08 (d, J = 5.2 Hz, 1H), 3.10-3.12 (m, 2H),2.89-2.90(m,7H),2.48(s,3H),2.21-2.37(m,2H).

Preparation Example 5: 4-amino-5-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzene Preparation of [1,2-e][1,4]dioxin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (compound 8)

2-(5,8-Dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e ][1,4]oxadiazol-2-yl)ethyl acetate (100 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 mL), and 2-aminothiophene-3-carbonitrile (40 mg, 0.32 mmol) was added under nitrogen protection. Add LDA (0.32 mL, 0.64 mmol), and react at 40°C for 2 hours after addition. LCMS detects the end of the reaction. The reaction was quenched with saturated ammonium chloride, extracted with dichloromethane, the organic phase was dried and concentrated with C18 mixture, and purified by reverse column chromatography (methanol/water=0-45%) to obtain 30.0 mg of the title compound, with a yield of 23.7%.

Molecular formula: C ₂₀ H ₂₂ N ₆ OS Molecular weight: 394.5 LC-MS (M/e): 395.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 7.34-7.41 (m, 1H), 7.28 (s, 1H), 6.95 (d, J = 5.6Hz, 1H), 6.84 (d, J = 5.6Hz ,1H),4.10(s,2H),3.03-3.09(m,2H),2.90-2.91(m,2H),2.84-2.88(m,5H),2.41-2.46(m,3H),2.02-2.04 (m,2H).

Preparation Example 6: 4-amino-5-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)thieno[2,3-b]pyridin-6(7H)-one hydrochloride (hydrochloride of compound 9)

1. 1-(7-Amino-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)-2,2,2-trifluoroethan-1-one Preparation

2,2,2-Trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)ethan-1-one ( 3.0g, 10.4mmol) was dissolved in methanol (50mL), Pd/C (1.0g) was added, and the reaction was completed at 15°C for 15 hours. LCMS detects the end of the reaction. Filter through diatomaceous earth, and concentrate the solvent to obtain 2.6 g of the target compound, yield: 96.7%.

2. Preparation of N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

1-(7-Amino-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-yl)-2,2,2-trifluoroethane-1-one ( 2.6g, 10.1mmol) was dissolved in acetic acid (30mL), acetic anhydride (1.5mL) was added, and the reaction was completed at 15°C for 16 hours. LCMS detects the end of the reaction. Add water, continue stirring for 1 hour, solid precipitates, filter, wash the solid with water, and dry to obtain 2.3 g of the target compound, yield: 76.2%.

3. N-(8-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl ) Preparation of acetamide

N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.3g , 7.7mmol) was dissolved in concentrated sulfuric acid (16mL), and fuming nitric acid (700.0mg, 10.0mmol) was added at 0°C. After the addition was completed, the reaction was carried out at 0°C for 2 hours. LCMS detects the end of the reaction. Pour into ice water, extract with dichloromethane, dry and concentrate the organic phase to obtain 2.3g of the target compound, yield: 86.9%.

4. Preparation of 7-amino-8-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylic acid tert-butyl ester

N-(8-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl) Acetamide (2.3g, 6.7mmol) was dissolved in methanol (30mL), the temperature was raised to 55°C, potassium carbonate (2.8g, 20.1mmol) was added, and the reaction was completed at 55°C for 16 hours. Filter through diatomaceous earth, add Boc ₂ O (2.2g, 10.1mmol) to the filtrate, complete the addition, and react at 15°C for 2 hours. Concentration and silica gel column purification (petroleum ether: ethyl acetate = 5:1) gave 1.7 g of the target compound, yield: 82.9%.

5. 2-(2-ethoxy-2-oxyethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of azepine-7(1H)-carboxylic acid tert-butyl ester

Dissolve 7-amino-8-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylic acid tert-butyl ester (1.7g, 5.5mmol) in ethanol ( 100 mL), add Pd/C (800 mg), and complete the hydrogenation reaction at 15°C for 2 hours. LCMS detects the end of the reaction. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (2.6g.13.3mmol), complete the addition, and raise the temperature to 50°C for 2 hours. LCMS detects the end of the reaction. Filter through diatomaceous earth, and the filtrate is concentrated and purified on a silica gel column (ethyl acetate) to obtain 1.6g of the target compound, yield: 60.4%

6. 2-(4-Amino-6-oxo-6,7-dihydrothio[2,3-b]pyridyl-5-yl)-5,6,8,9-tetrahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepine 7(1H)-carboxylic acid tert-butyl ester

2-(2-ethoxy-2-oxyethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Zezo-7(1H)-carboxylic acid tert-butyl ester (300 mg, 0.8 mmol), 2-aminothiophene-3-carbonitrile (109.9 mg, 0.88 mmol) were dissolved in tetrahydrofuran (5 mL), and heated to 40°C under nitrogen protection. , add LDA (1.2mL, 2.4mmol) dropwise, and react at 40°C for 2 hours after the addition is completed. LCMS detects the end of the reaction. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried and concentrated for silica gel column purification (petroleum ether: ethyl acetate = 5:1) to obtain 260 mg of the target compound, yield: 71.7%

7. 4-Amino-5-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 Preparation of -yl)thieno[2,3-b]pyridin-6(7H)-one hydrochloride

2-(4-Amino-6-oxo-6,7-dihydrothieno[2,3-b]pyridyl-5-yl)-5,6,8,9-tetrahydroimidazo[4 ',5': 4,5]benzo[1,2-d]azepine 7(1H)-carboxylic acid tert-butyl ester (45.0mg, 0.1mmol) was dissolved in ethanol (2mL), and HCl/ethanol ( 1.5mL), and react at 15°C for 4 hours after addition. LCMS detects the end of the reaction. Add 0.5 mL of water, filter, and dry the solid to obtain 12.0 mg of the target compound, yield: 31.0%.

Molecular formula: C ₁₈ H ₁₇ N ₅ OS Molecular weight: 351.4 LC-MS (M/e): 352.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 9.39 (m, 2H), 7.67 (s, 2H), 7.23-7.26 (m, 2H), 4.64 (s, 2H), 3.26-3.36 (m, 4H),3.15-3.25(m,4H).

Preparation Example 7: 7-amino-6-(7-ethyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 10)

1. Preparation of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Dissolve 2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.0g, 34.0mmol) in trifluoroacetic acid (20mL), cool to 0°C, and add concentrated sulfuric acid (7.5mL) and potassium nitrate (5.5g, 56.7mmol), react at 0°C for 2 hours. Pour the reaction solution into ice water, adjust the pH to 11 with 2N sodium hydroxide, and extract with dichloromethane/methanol = 9:1 (100 mL) to obtain 5.0 g of crude product.

2. Preparation of 3-ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Dissolve 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.0g, crude product) in tetrahydrofuran (100mL), add acetaldehyde aqueous solution (40%) (15.75 g, 142.9mmol), acetic acid (3.1g, 51.6mmol) and sodium triacetoxyborohydride (9.65g, 45.5mmol), reacted at 15°C for 2 hours. Adjust the pH to about 10 with 1N sodium hydroxide, extract with dichloromethane/methanol=9:1 (200mL), dry and concentrate the organic phase for silica gel column purification (dichloromethane:methanol=10:1) to obtain 2.0g of the target compound. The two-step reaction yield was 26.8%.

3. Preparation of 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

Dissolve 3-ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.0g, 9.1mmol) in methanol (40mL), and add Pd/C (500 mg), ventilated with hydrogen three times, and hydrogenated at 15°C for 2 hours. Filter through diatomaceous earth, and the filtrate is dried and concentrated to obtain 1.9 g of the target compound.

4. Preparation of N-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (1.9g, crude product) in acetic acid (16mL), and add acetic anhydride (4mL) , after addition, react at 15°C for 1 hour. Dilute with water, adjust pH=11 with sodium hydroxide, extract with dichloromethane/methanol=9:1 (100mL), and purify on C18 column (methanol=0-60%) to obtain 1.5g of the target compound, with a two-step yield of 71.4%.

5. Preparation of N-(3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve N-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.5g, 6.5mmol) in concentrated sulfuric acid (30mL ), add fuming nitric acid (470 mg, 7.5 mmol) dropwise at 0°C, and react at 0°C for 10 minutes after the addition is completed. LCMS detects the end of the reaction. Pour into ice water, adjust pH=10 with 2N sodium hydroxide aqueous solution, extract with dichloromethane/methanol=9:1 (100mL), and purify with C18 column (methanol=0-65%) to obtain 1.2g of the target compound, yield: 66.7%.

6. Preparation of 3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

Dissolve N-(3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide (1.2g, 4.33mmol) To methanol (150 mL), add potassium carbonate (2.3 g, 16.6 mmol), complete the addition, and react at 50°C for 2 hours. Concentrate and purify with silica gel column chromatography (dichloromethane: methanol = 8:1) to obtain 1.0 g of the target compound, yield: 98.2%.

7. 2-(7-ethyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)ethyl acetate

Dissolve 3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (1.0g, 4.2mmol) in ethanol (100mL), Pd/C (300 mg) was added, ventilated with hydrogen three times, and hydrogenated at 15°C for 4 hours. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (2.0g.10.2mmol), raise the temperature to 50°C and react for 2 hours. Filter through diatomaceous earth, concentrate the filtrate, extract with saturated sodium bicarbonate (10 mL), water (20 mL) and dichloromethane/methanol = 9:1 (100 mL), and purify with silica gel column (dichloromethane: methanol = 15:1) ) to obtain 800 mg of the target compound, yield: 63.5%.

8. 7-Amino-6-(7-ethyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d] Preparation of azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-ethyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 -ethyl acetate (50 mg, 0.17 mmol), 3-aminothiophene-2-carbonitrile (21 mg, 0.17 mmol) was dissolved in tetrahydrofuran (10 mL), LDA (0.43 mL, 0.86 mmol) was added at 40°C, and the addition was completed React at 40°C for 3 hours. The reaction was quenched with saturated ammonium chloride, extracted with water (15 mL) and ethyl acetate (15 mL), methanol (3 mL) was added, filtered, and dried to obtain 21 mg of the target compound, yield: 32.6%.

Molecular formula: C ₂₀ H ₂₁ N ₅ OS Molecular weight: 379.5 LC-MS (M/e): 380.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.77 (s, 1H), 11.80 (s, 1H), 10.85-10.51 (brs, 1H), 7.94 (s, 1H), 7.98-7.71 (brs, 1H),7.40-7.34(m,2H),7.02(s,1H),2.98-2.86(m,4H),2.72-2.44(m,6H),1.02(t,J＝7.2Hz,3H).

Preparation Example 8: 7-amino-6-(7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2 Preparation of -d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 11)

1. Preparation of 8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

N-(8-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl) Acetamide (1.0g, 2.9mmol) was dissolved in methanol (10.0mL), potassium carbonate (600.0mg, 4.3mmol) was added, and the reaction was carried out at 20°C for 2.0h. After the reaction was completed, it was filtered, washed with water, extracted and concentrated with dichloromethane. , the crude product was directly used in the next reaction.

2. Preparation of 3-cyclobutyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

Dissolve 8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (crude product from the previous step) in 10.0 mL methanol, and add sodium cyanoborohydride ( 550.0 mg, 8.8 mmol), acetic acid (1.7 g, 28.3 mmol), cyclobutanone (410.0 mg, 5.8 mmol) was added dropwise at 0°C, and the reaction was carried out at 20°C for 2.0 h. Water (100 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spun to dryness to obtain 300 mg of the target compound. The two-step yield was 39.6%.

3. Preparation of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine

Dissolve 3-cyclobutyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (250 mg) in ethanol (10 mL), and add Pd /C (50.0mg), the reaction was completed after 1.5h at 25°C under hydrogen, and the reaction solution was directly used in the next reaction.

4. 2-(7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)ethyl acetate

3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (330.0 mg, 1.7 mmol) was added to the reaction solution in the previous step, and the reaction was completed after the system rose to 80°C for 2 hours. After filtration, adjust the pH to 8 with saturated sodium bicarbonate solution. After concentration, column chromatography (dichloromethane:methanol=10:1) was used to obtain 200 mg of the target compound. The two-step yield was 63.9%.

5. 7-amino-6-(7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d Preparation of ]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (30.0 mg, 0.09 mmol) and 3-aminothiophene-2-carbonitrile (13.0 mg, 0.10 mmol) were dissolved in tetrahydrofuran (3.0 mL). Under nitrogen protection, LDA ( 0.3mL, 0.60mmol), continue the reaction for 2.0h. After the reaction is completed, the system is poured into saturated ammonium chloride solution to quench, extracted with ethyl acetate, the organic phase is spun to dryness, the crude product is separated and purified by silica gel column chromatography (DCM:MeOH=10:1), and the product is purified by methanol pulping. 12.0 mg, yield 32.3%.

Molecular formula: C ₂₂ H ₂₃ N ₅ OS Molecular weight: 405.5 LC-MS (M/e): 406.0 (M+H ⁺ )

¹ H-NMR(400MHz, DMSO-d ₆ )δ:12.73(s,1H),11.76(s,1H),10.80-10.55(br s,1H),7.91(s,1H),7.90-7.75(br s,1H),7.40(s,1H),7.31(s,1H),7.00(s,1H),2.95-2.85(m,4H),2.81-2.71(m,1H),2.47-2.35(m, 4H),2.08-1.98(m,2H),1.90-1.85(m,2H),1.65-1.51(m,2H).

Preparation Example 9: 7-amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2 Preparation of -d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 12)

1. Preparation of 3-cyclopropyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.2g, 21.8mmol), sodium cyanoborohydride (8.7g, 139.5mmol), acetic acid ( 13.6g, 230.6mmol) was dissolved in methanol (120mL), (1-ethoxycyclopropoxy)trimethylsilane (8.7g, 50.1mmol) was added dropwise at 0℃, reacted at 60℃ for 4h, and detected by LCMS After the reaction was completed, water (100 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and spun to dryness to obtain 4 g of the target compound with a yield of 78.7%.

2. Preparation of 3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

Dissolve 3-cyclopropyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.8g, 16.3mmol) in methanol (50mL), and add Pd /C (1.9g), react at 25°C for 16 hours under hydrogen conditions, LCMS detects that the reaction is complete, filter with suction, and spin the filtrate to dryness to obtain 3.5g of crude product.

3. Preparation of N-(3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve 3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (3.5g, crude product) in acetic acid (20mL), add acetic anhydride ( 3mL), react at 25°C for 4 hours, LCMS detects that the reaction is complete, spin the reaction liquid to dryness, adjust the pH to 8-9 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, spin the organic phase to dryness, and separate by silica gel column chromatography (dichloromethane :Methanol=20:1) to obtain 2.12g of the target compound, with a yield of 53.1%.

4. Preparation of N-(3-cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve N-(3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.12g, 8.65mmol) in concentrated sulfuric acid ( 22mL), add fuming nitric acid (849mg, 13mmol) at 0°C, react for 0.5h at 25°C, LCMS detects that the reaction is complete, adjust the pH to 8-9 with 5M sodium hydroxide solution, extract with DCM, and use the organic phase with anhydrous sulfuric acid. After drying over sodium, 2 g of the product was obtained by spinning, with a yield of 79.7%.

5. Preparation of 3-cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

N-(3-Cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide (1.96g, 6.76mmol) Dissolve in methanol (35 mL), add potassium carbonate (4.6 g, 33.4 mmol), react at 65°C for 8 hours, LCMS detects that the reaction is complete, filter through diatomaceous earth, and separate by silica gel column chromatography (methanol: dichloromethane = 1:15) 1.1g of the target compound was obtained with a yield of 65.1%.

6. 2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)ethyl acetate

Dissolve 3-cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (1.1g, 4.4mmol) in ethanol (25mL) Medium, react for 2 hours at 25°C under hydrogen, add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (1.7g, 8.8mmol), LCMS detects that the reaction is complete, filter, spin the filtrate to dryness, and put it on a silica gel column Chromatographic separation (dichloromethane:methanol=10:1) yielded 900 mg of the product, with a yield of 65.1%.

7. 7-Amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d Preparation of ]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (200mg, 0.64mmol) and 3-aminothiophene-2-carbonitrile (76mg, 0.61mmol) were dissolved in tetrahydrofuran (5mL), under nitrogen protection, and LDA (1.5Ml, 2.88) was added dropwise at 40°C. mmol), continue the reaction for 6 hours, and LCMS detects that the reaction is complete. Pour into saturated ammonium chloride solution to quench, extract with ethyl acetate, spin the organic phase to dryness, the crude product is separated and purified by silica gel column chromatography (dichloromethane: methanol = 10:1), and the product is purified by methanol pulping to obtain 77 mg, yield 30.7%.

Molecular formula: C ₂₁ H ₂₁ N ₅ OS Molecular weight: 391.5 LC-MS (M/e): 392.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ )δ:12.96(s,1H),11.79(s,1H),10.55-10.80(br s,1H),7.98(s,1H),7.75-7.95(br s,1H),7.40(s,1H),7.38(s,1H),7.02(s,1H),2.85-2.95(m,4H),2.70-2.84(m,4H),1.75-1.85(m, 1H),0.30-0.50(m,4H).

Preparation Example 10: 6-(7-acetyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of zo-2-yl)-7-aminothieno[3,2-b]pyridine-5(4H) (compound 13)

1. 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetic acid Preparation of ethyl ester hydrochloride

2-(2-ethoxy-2-oxyethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Zazo-7(1H)-carboxylic acid tert-butyl ester (373 mg, 1.0 mmol) was dissolved in 4M HCl/dioxane (10 mL), reacted at 15°C for 2 hours, and concentrated to obtain 241 mg, which was used in the next step.

2.(7-Acetyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine-2- Preparation of ethyl acetate

Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate The ester (210 mg, crude product) was dissolved in dichloromethane (10 mL), acetic anhydride (86 mg, 0.85 mmol) was added dropwise at 0°C, and the reaction was carried out at 0°C for 2 hours. Concentrate, dry and concentrate the organic phase and purify on silica gel column (dichloromethane: methanol = 10:1) to obtain 200 mg of the target compound, two-step yield: 63.5%

3. 6-(7-acetyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)-7-aminothieno[3,2-b]pyridine-5(4H)

7-acetyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine-2-yl) Ethyl acetate (170 mg, 0.54 mmol) and 3-aminothiophene-2-carbonitrile (74 mg, 0.59 mmol) were dissolved in tetrahydrofuran (10 mL). Add LDA (1.1 mL, 2.16 mmol) at 40°C. After addition, add LDA at 40°C. Reaction takes 5 hours. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate (15 mL), methanol (1 mL) and ethyl acetate (1 mL) were added, filtered, and dried to obtain 7.5 mg of the target compound, yield: 3.5%.

Molecular formula: C ₂₀ H ₁₉ N ₅ O ₂ S Molecular weight: 393.13 LC-MS(M/e): 394.47(M+H ⁺ )

¹ H-NMR(400MHz, DMSO-d ₆ )δ:12.81(s,1H),11.80(s,1H),10.85-10.51(brs,1H),7.95(s,1H),7.94-7.71(brs, 1H),7.46-7.40(m,2H),7.02(s,1H),3.59-3.57(m,4H),3.05-2.97(m,2H),2.99-2.90(m,2H),2.08(s, 3H).

Preparation Example 11: 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4' ,5': Preparation of 4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 14-1)

1. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)) Sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno Preparation of [3,2-b]pyridin-5(4H)-one

4-(4-Methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine -7-yl triflate (N/A, 0.37mmol) was dissolved in acetonitrile (20mL), (1s, 4s)-4-aminocyclohexan-1-ol (170.5mg, 1.48mmol) was added, and React at 45°C for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified on a silica gel column (dichloromethane: methanol = 10:1) to obtain 216 mg of the target compound. The two-step yield was 81.8%.

2. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5 Preparation of ':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonate) Acyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[ 3,2-b]pyridin-5(4H)-one (216 mg, 0.3 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and trifluoroacetic acid (14 mL). After addition, the mixture was raised to 110°C and reacted for 24 hours. LCMS detects the end of the reaction. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried, concentrated, and purified by Pre-TLC (dichloromethane:methanol=7:1) to obtain 12.7 mg of the title compound, with a yield of 9.1%.

Molecular formula: C ₂₅ H ₂₉ N ₅ O ₂ S Molecular weight: 463.6 LC-MS (M/e): 464.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.08 (s, 1H), 12.24 (d, J = 8.4Hz 1H), 11.87 (s, 1H), 8.03 (d, J = 5.2Hz, 1H) ,7.50(s,1H),7.42(s,1H),7.05(d,J＝5.2Hz,1H),4.65(d,J＝3.2Hz,1H),4.31(m,1H),3.73(m, 1H),3.05-3.17(m,4H),2.56-2.72(m,4H),2.51(s,3H),1.81-1.95(m,4H),1.65-1.80(m,4H).

Preparation Example 12: 7-(isopropylamino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo Preparation of [1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 15)

1. 7-(isopropylamino)-4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7 ,8,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5( Preparation of 4H)-ketone

4-(4-Methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine -7-yl triflate (N/A, 0.23mmol) was dissolved in acetonitrile (10mL), isopropylamine (54.3mg, 0.92mmol) was added, and the reaction was completed at 40°C for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified on a silica gel column (dichloromethane: methanol = 20:1) to obtain 100 mg of the target compound.

2. 7-(isopropylamino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 , Preparation of 2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

7-(isopropylamino)-4-(4-methoxybenzyl)-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7, 8,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H )-ketone (100 mg, 0.15 mmol) was dissolved in concentrated hydrochloric acid (1.5 mL) and trifluoroacetic acid (10.5 mL). After addition, the mixture was raised to 110°C and reacted for 24 hours. LCMS detects the end of the reaction. The solvent was concentrated, dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried, concentrated, and purified by Pre-TLC (dichloromethane:methanol=7:1) to obtain 12.5 mg of the title compound, with a yield of 20.2%.

Molecular formula: C ₂₂ H ₂₅ N ₅ OS Molecular weight: 407.5 LC-MS (M/e): 408.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.05 (s, 1H), 12.14 (d, J = 8.0Hz 1H), 11.87 (s, 1H), 8.04 (d, J = 5.2Hz, 1H) ,7.45(s,1H),7.39(s,1H),7.05(d,J＝5.2Hz,1H),4.45-4.54(m,1H),3.04-3.14(m,4H),2.74-2.83(m ,4H),2.51(s,3H),1.45(d,J＝6.0Hz,6H).

Preparation Example 13: 4-amino-5-(8-methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2- Preparation of d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (compound 19)

1. N-(6-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl ) Preparation of acetamide

N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide (5.5g , 18.3mmol) was dissolved in concentrated sulfuric acid (50mL), fuming nitric acid (1.5g, 22.0mmol) was added dropwise at 0°C, the addition was completed, and the reaction was carried out at 0°C for 1.5 hours. LCMS detects the end of the reaction. Pour into ice water, extract with dichloromethane, dry and concentrate the organic phase, and separate by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 800 mg of the title compound, with a yield of 12.6%.

2. Preparation of 6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

N-(6-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl) Dissolve acetamide (800 mg, 2.3 mmol) in methanol (20 mL), add potassium carbonate (960 mg, 6.9 mmol), complete the addition, and react at 55°C for 24 hours. Filter through diatomaceous earth, concentrate the filtrate, and purify with C18 column (methanol = 0-50%) to obtain 400 mg of the title compound, with a yield of 83.3%.

3. Preparation of 3-methyl-6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

Dissolve 6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (400 mg, 1.9 mmol) in methanol (10 mL), and add formaldehyde (37% ) (791.2mg, 9.7mmol), acetic acid (114.0mg, 1.9mmol), react at 15°C for 1 hour, add sodium cyanoborohydride (601.4mg, 9.7mmol), complete the addition, and react at 15°C for 1 hour. LCMS detects the end of the reaction. Concentrate the solvent, dissolve the solid with dichloromethane, wash with saturated sodium chloride and saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, spin to dryness, and separate by silica gel column chromatography (methanol:dichloromethane) =1:10) to obtain 280 mg of the title compound, with a yield of 65.6%.

4. 2-(8-Methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d]azepine- Preparation of 2-yl)ethyl acetate

Dissolve 3-methyl-6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (280mg, 1.3mmol) in ethanol (10mL), Add Pd/C (100mg), complete the hydrogenation reaction at 15°C for 1 hour, add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (594.8mg, 3.0mmol), complete the addition, and react at 55°C 1 hour. LCMS detects the end of the reaction. Filter through diatomaceous earth, and concentrate the filtrate. Dissolve the obtained solid with methylene chloride, wash with saturated aqueous sodium bicarbonate solution, separate the liquids, extract with methylene chloride, and dry and concentrate the organic phase for silica gel column chromatography separation (methanol:methylene chloride=1:4). ) to obtain 250 mg of the title compound, with a yield of 68.8%.

5. 4-Amino-5-(8-methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d] Preparation of azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one

2-(8-Methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d]azepine-2 -ethyl acetate (100 mg, 0.35 mmol) and 2-amino-3-cyanothiophene (43.4 mg, 0.35 mmol) were dissolved in tetrahydrofuran (10 mL), and LDA (0.7 mL) was added dropwise at 40°C under nitrogen protection. 1.4mmol), after addition, react at 40°C for 2 hours. LCMS detects the end of the reaction. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain a solid. The solid was slurried with methanol to obtain 16.2 mg of the title compound, with a yield of 12.7%.

Molecular formula: C ₁₉ H ₁₉ N ₅ OS Molecular weight: 365.5 LC-MS (M/e): 366.0 (M+H ⁺ )

¹ H-NMR (400MHz, MeOD) δ: 7.28 (d, J = 8.0 Hz, 1H), 7.03-7.06 (m, 3H), 3.31-3.34 (m, 3H), 3.07-3.10 (m, 2H), 2.20-2.35(m,4H),2.47(s,3H),2.47(s,3H).

Preparation Example 14: 6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2 -d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one hydrochloride (hydrochloride of compound 20)

1. 2-(7-(isopropylamino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6- base)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zhuo-7(1H)-carboxylic acid tert-butyl ester

2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]Azepine-7(1H)-tert-butylcarboxylate (500mg, 0.60mmol) was dissolved in acetonitrile (10mL), add isopropylamine (141.8mg, 2.4mmoL), complete the addition, react at 40°C 2 Hour. LCMS detects the end of the reaction. The reaction solution was concentrated and purified through silica gel column (ethyl acetate: petroleum ether = 1:1) to obtain 180 mg of the target compound, with a yield of 40.2%.

2. 6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2-yl)- Preparation of 7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one

2-(7-(isopropylamino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-6-yl )-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine -7(1H)-tert-butylcarboxylate (180 mg, 0.24 mmol) was dissolved in concentrated hydrochloric acid (1.0 mL) and trifluoroacetic acid (7.0 mL), and reacted at 110°C for 48 hours. LCMS detects the end of the reaction. The solvent was concentrated and used directly in the next reaction.

3. 6-(7-(2-(((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7,8,9-hexahydroimidazo[4', 5':4,5]benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one Preparation

6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(Isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (N/A, 0.51mmol) was dissolved in methanol (10mL), and 2-((tert-butyl) was added at 25°C Dimethylsilyl)oxy)acetaldehyde (266.7mg, 1.5mmol) and acetic acid (30.6mg, 0.51mmol)) were added, sodium cyanoborohydride (96.1mg, 1.5mmol)) was added, and the reaction was continued for 4 hours. Water was added to the reaction to quench the reaction, extracted with dichloromethane (50 mL), and the organic phase was concentrated and purified on a silica gel column (methanol/dichloromethane = 1:10) to obtain 170.0 mg of the target compound, with a two-step yield of 60.5%.

4. 6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d Preparation of ]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one hydrochloride

6-(7-(2-(((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5 ':4,5]benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one( 160.0 mg, 0.29 mmol) was dissolved in tetrahydrofuran (4 mL) and concentrated hydrochloric acid (4 mL), and reacted for 1 hour. After the reaction was completed, filter, collect the filter cake, wash with ethyl acetate and dichloromethane, and obtain 19.4 mg of the target compound, which was collected. The rate is 15.3%.

Molecular formula: C ₂₃ H ₂₇ N ₅ O ₂ S Molecular weight: 437.6 LC-MS (M/e): 438.2 (M+H ⁺ )

¹ H-NMR (400MHz, MeOD)8.01(d,J＝5.6Hz,1H),7.63(s,2H),7.09(d,J＝5.6Hz,1H),4.33-4.27(m,1H),3.96 -3.86(m,4H),3.53-3.47(m,2H),3.40-3.36(m,5H),3.29-3.17(m,2H),1.35(s,6H).

Preparation Example 15: 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8, 9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H)- Preparation of ketones (compound 21-1)

6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(((1s,4s)-4-hydroxycyclohexyl)amino)thieno[3,2-b]pyridin-5(4H)-one (80mg, 0.18mmol), dissolved in methanol (10mL), added 3-Oxetanone (38.5mg, 0.54mmol)\acetic acid (10.8mg, 0.18mmol), react at 20℃ for 30 minutes, add sodium cyanoborohydride (33.5mg, 0.54mmol), complete the addition, react at 20℃ 17 hours. LCMS detects the end of the reaction. Concentrate the solvent, dissolve the solid with dichloromethane, wash with saturated sodium chloride and saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, spin to dryness, and separate by silica gel column chromatography (methanol:dichloromethane) =1:15) to obtain 13.6 mg of the target compound, with a yield of 15.1%.

Molecular formula: C ₂₇ H ₃₁ N ₅ O ₃ S Molecular weight: 505.6 LC-MS (M/e): 506.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.97 (s, 1H), 12.24 (d, J = 4.0Hz, 1H), 11.80 (s, 1H), 7.98 (d, J = 5.2Hz, 1H ),7.39(s,1H),7.30(s,1H),7.01(d,J＝5.6Hz,1H),4.60(s,1H),4.45-4.52(m,4H),4.20-4.30(m, 1H),3.65-3.72(m,1H),3.45-3.48(m,1H),3.14-3.29(m,4H),2.90-3.01(m,4H),1.65-1.86(m,8H).

Preparation Example 16: 7-(((1s,3s)-3-hydroxycyclobutyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8 ,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H) Preparation of -1-one (compound 22-1)

1. 2-(7-(((1s,3s)-3-hydroxycyclobutyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno [3,2-b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5] Preparation of benzo[1,2-d]azepine-7(1H)-carboxylic acid tert-butyl ester

2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]Azepine-7(1H)-carboxylic acid tert-butyl ester (500mg, 0.6mmol) was dissolved in acetonitrile (10mL), and cis-3-aminocyclobutanol hydrochloride (295.7mg, 2.4mmol), after addition, react at 40°C for 2 hours. LCMS detects the end of the reaction. The solvent was concentrated and separated by silica gel column chromatography (methanol: dichloromethane = 1:20) to obtain 400 mg of the target compound, with a yield of 86.6%.

2. 6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2-yl)- Preparation of 7-(((1s,3s)-3-hydroxycyclobutyl)amino)thieno[3,2-b]pyridin-5(4H)-one

2-(7-(((1s,3s)-3-hydroxycyclobutyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[ 3,2-b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzene [1,2-d]azepine-7(1H)-carboxylic acid tert-butyl ester (400 mg, 0.52 mmol) was dissolved in concentrated hydrochloric acid (2 mL) and trifluoroacetic acid (14 mL), and reacted at 110°C for 20 hours. Concentrate the solvent, dissolve the solid with dichloromethane, wash with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, spin to dryness, and separate by C18 column chromatography (methanol=0-60%) to obtain the target compound. 150mg, yield 68.8%.

3. 7-(((1s,3s)-3-hydroxycyclobutyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9 -Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H)-1 -Preparation of ketones

6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(((1s,3s)-3-hydroxycyclobutyl)amino)thieno[3,2-b]pyridin-5(4H)-one (150mg, 0.36mmol) was dissolved in methanol (15mL) and added 3-Oxetanone (77.1mg, 1.1mmol), acetic acid (21.6mg, 0.36mmol), react at 20℃ for 30 minutes, add sodium cyanoborohydride (68.2mg, 1.1mmol), complete the addition, react at 20℃ 17 hours. LCMS detects the end of the reaction. Concentrate the solvent, dissolve the solid with dichloromethane, wash with saturated sodium chloride and saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, spin to dryness, and separate by silica gel column chromatography (methanol:dichloromethane) =1:15) to obtain 16.9 mg of the target compound, with a yield of 9.9%.

Molecular formula: C ₂₅ H ₂₇ N ₅ O ₃ S Molecular weight: 477.6 LC-MS (M/e): 478.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.93 (s, 1H), 12.26 (d, J = 6.8Hz, 1H), 11.83 (s, 1H), 8.01 (d, J = 5.2Hz, 1H ),7.39(s,1H),7.35(s,1H),7.01(d,J＝5.6Hz,1H),4.60(s,1H),4.43-4.53(m,4H),4.19-4.21(m, 1H),3.96-4.06(m,1H),3.45-3.48(m,1H),2.91-3.15(m,8H),2.33(m,4H).

Preparation Example 17: 6-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d] Preparation of azepine-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)thieno[3,2-b]pyridin-5(4H)-one (compound 23- 1)

1. 2-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Preparation of heteroacetate-2-yl)ethyl acetate

Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Ester hydrochloride (1.7g, 5.5mmol), triethylamine (3.9g, 38.5mmol) and cyclopropionyl chloride (600mg, 5.7mmol) were dissolved in 40mL of methylene chloride and reacted at 0°C for 1.5 hours. After the reaction was completed, the mixture was concentrated and purified through silica gel column (methanol: dichloromethane = 10%) to obtain 1.5 g of the target compound, yield: 71.8%.

2. (E)-2-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2- d] Preparation of azepine-2-yl)-3-hydroxy-3-(3-((4-methoxybenzyl)amino)thiophen-2-yl)propionic acid ethyl ester

2-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Zo-2-yl)ethyl acetate (850 mg, 2.5 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4 (1H)-Diketone (790 mg, 2.7 mmol) was dissolved in tetrahydrofuran (10 mL), LDA (5.0 mL, 10.0 mmol) was added at 40°C, and reacted for 2 hours. After the reaction is completed, add saturated aqueous ammonium chloride solution to quench, extract with dichloromethane, concentrate the organic phase, and use the crude product directly for the next step.

3. 6-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine Preparation of zo-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one

Dissolve the crude product from the previous step in 15 mL of tetrahydrofuran, add LDA (5.0 mL) dropwise at 40°C, and react for 1.5 h. After completion, add saturated ammonium chloride aqueous solution to quench, extract with dichloromethane, and concentrate the organic phase to obtain the target The crude compound was 650 mg.

4. 6-(7-(cyclopropanecarbonyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole [4',5':4, 5]benzo[1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b ] Preparation of pyridin-7-yl trifluoromethanesulfonate

6-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine -2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (600 mg, 1.1 mmol) was dissolved in dichloromethane ( 15mL), cooled to -15°C, added pyridine (1.8g, 22.8mmol) and trifluoromethanesulfonic anhydride (3.0g, 10.6mmol), and reacted for 1.0 hours. After 1.0 hours, saturated sodium bicarbonate solution was added to quench the reaction. Dichloro Extract with methane, dry and concentrate the organic phase to obtain the crude product of the target compound, which is directly used in the next reaction.

5. 6-(7-(cyclopropanecarbonyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole [4',5':4, 5]benzo[1,2-d]azepine-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl) Preparation of Thieno[3,2-b]pyridin-5(4H)-one

Dissolve the crude product from the previous step in 10 mL acetonitrile, add (1s, 4s)-4-aminocyclohexan-1-ol (160 mg 1.4 mmol), complete the addition, and react at 50°C for 1 hour. Filter through diatomaceous earth, and the filtrate is dried, concentrated, and subjected to column chromatography (methanol: dichloromethane = 10%) to obtain 300 mg of the target compound, with a two-step yield of 35.1%.

6.(1s,4s)-4-((6-(7-(cyclopropanecarbonyl))-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzene And[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-7-yl)amino)cyclohexyl-2, Preparation of 2,2-trifluoroacetate

6-(7-(cyclopropanecarbonyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole [4',5':4,5 ]benzo[1,2-d]azepine-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)thiophene Dissolve [3,2-b]pyridin-5(4H)-one (300 mg, 0.39 mmol) in trifluoroacetic acid (3 mL) and concentrated hydrochloric acid 1 mL. After reacting at 115°C for 22 h, concentrate and proceed directly to the next step. reaction.

7. 6-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine Preparation of zo-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)thieno[3,2-b]pyridin-5(4H)-one

Dissolve the crude product from the previous step in 10 mL of methanol, add 150 mg of potassium carbonate, and react at 25°C for 1 hour. After the reaction was completed, the solvent was concentrated and 16 mg of the target product was obtained through column chromatography. The two-step yield was 7.9%.

Molecular formula: C ₂₈ H ₃₁ N ₅ O ₃ S Molecular weight: 517.6 LC-MS (M/e): 518.0 (M+H ⁺ )

¹ H-NMR (400MHz, CDCl ₃ ) δ: 12.99 (s, 1H), 12.22 (s, 1H), 11.92-11.82 (m, 1H), 8.0 (s, 1H), 7.51-7.41 (m, 2H) ,7.01(s,1H),4.61(s,1H),4.41-4.31(m,1H),3.81(s,2H),3.80(s,1H),3.71-3.61(m,2H),3.08-2.96 (m,2H),2.91-2.86(m,2H),2.01(s,1H),1.91-1.61(m,8H),0.88-0.71(m,4H).

Preparation Example 18: 7-amino-6-(7-(3-hydroxycyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzene Preparation of thieno[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (bromate of compound 24)

1. 2-(7-(3-(Benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)ethyl acetate)

Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Ester hydrochloride (230 mg, 0.74 mmol), 3-(benzyloxy)cyclobutan-1-one (196 mg, 1.11 mmol), acetic acid (44 mg, 0.74 mmol) were dissolved in dichloromethane (10 mL), 0°C Add sodium acetate borohydride (314 mg, 1.48 mmol) at 25°C for 8 hours. LCMS detects that the reaction is complete. The reaction solution was poured into saturated sodium hydroxide aqueous solution (50 mL), extracted with dichloromethane, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol: dichloromethane = 1:10) to obtain the target compound. 260 mg, yield 81.0%.

2. 7-amino-6-(7-(3-(benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5] Preparation of benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-(3-(Benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepin-2-yl)ethyl acetate (150 mg, 0.35 mmol) and 3-aminothiophene-2-nitrile (43 mg, 0.35 mmol) were dissolved in tetrahydrofuran (5 mL), and added dropwise at 40°C. LDA (1.05mL, 2.1mmol), continue the reaction for 4 hours, LCMS detects that the reaction is complete, pour the reaction solution into saturated ammonium chloride aqueous solution to quench, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, spin dry, and put on a silica gel column Chromatographic separation (methanol:dichloromethane=1:10) gave 100 mg of the target compound, with a yield of 55.8%.

3. 7-Amino-6-(7-(3-hydroxycyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one bromide

7-Amino-6-(7-(3-(benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzene And[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (50 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), - Boron tribromide (100 mg, 0.40 mmol) was added dropwise at 40°C, and the reaction was carried out for 1 hour at 25°C. LCMS detected that the reaction was complete. Methanol was added to quench, the solvent was spun to dryness, and the crude product was pulped with methanol to obtain 19 mg of the target compound, with a yield of 37.8%.

Molecular formula: C ₂₂ H ₂₄ BrN ₅ O ₂ S Molecular weight: 502.4 LC-MS (M/e): 422.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 11.81 (s, 1H), 9.71 (s, 1H), 7.95 (d, J = 5.2Hz, 1H), 7.51 (s, 2H), 6.99 (d ,J＝5.2Hz,1H),3.82-3.92(m,1H),3.52-3.62(m,2H),3.18-3.32(m,3H),3.02-3.17(m,2H),2.75-2.90(m ,2H),2.58-2.62(m,2H),2.02-2.18(m,2H).

Preparation Example 19: 7-amino-6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo Preparation of [1,2-d]azepine-pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride (hydrochloride of compound 25)

1. 2-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)ethyl-1,5,6,7,8,9-hexahydroimidazo[4' , Preparation of 5':4,5]benzo[1,2-d]azepin-2-yl)ethyl acetate

Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate The ester (240 mg, 0.88 mmol) was dissolved in methanol (10 mL), and 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (352 mg, 2.0 mmol) and acetic acid (560 mg, 9.3 mmol) were added at 20°C. )), after reacting at 20°C for 5 minutes, add sodium cyanoborohydride (352 mg, 6.4mmol), and react at 20°C for 6 hours. After the reaction is completed, spin the solvent to dryness, add saturated sodium bicarbonate aqueous solution (20 mL) to quench the reaction, extract with ethyl acetate (50 mL), concentrate the organic phase, and purify through silica gel column (methanol/dichloromethane=1:20) to obtain the target product. Compound 250 mg, yield 65.8%.

2. 7-Amino-6-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7,8,9-hexahydroimidazole [4 ',5': Preparation of 4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)ethyl-1,5,6,7,8,9-hexahydroimidazo[4', 5':4,5]benzo[1,2-d]azepin-2-yl)ethyl acetate (250mg, 0.58mmol) and 3-aminothiophene-2-nitrile (71mg, 0.57mmol) were dissolved in Anhydrous tetrahydrofuran (5mL) was added to LDA (1.2ml, 2.3mmol) at 40°C. After the reaction, saturated aqueous ammonium chloride solution was added at 0°C to quench the reaction. The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol=10:1) to obtain 80 mg of the title compound, yield: 27.0%.

3. 7-Amino-6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 , Preparation of 2-d]azepine-pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride

7-Amino-6-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1,5,6,7,8,9-hexahydroimidazo[4 ',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (50mg, 0.1mmol) dissolved React in 1 ml tetrahydrofuran and 1 ml concentrated hydrochloric acid for 0.5 hours. After the reaction was completed, the filter cake was collected by filtration and washed with ethyl acetate and dichloromethane to obtain 12.4 mg of the target compound with a yield of 26.4%.

Molecular formula: C ₂₀ H ₂₂ ClN ₅ O ₂ S Molecular weight: 431.9 LC-MS (M/e): 396.5 (M+H ⁺ )

¹ H-NMR(400MHz,MeOD)δ:7.98-7.96(m,1H),7.65(s,2H),7.09-7.08(m,1H),3.97-3.90(m,4H),3.55-3.48(m ,2H),3.40-3.30(m,4H),3.24-3.18(m,2H).

Preparation Example 20: 7-amino-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazole [4',5':4,5] Preparation of benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 26)

1. 2-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, Preparation of 2-d]azepine-2-yl)-ethyl acetate

Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Dissolve ester hydrochloride (309.1mg, 1.0mmol) in methanol (30mL), add 3-oxetanone (216.3mg, 3.0mmol) and acetic acid (60.0mg, 1.0mmol), and react at 20°C for 30 minutes. Add sodium cyanoborohydride (186.0 mg, 3.0 mmol), complete the addition, and react at 20°C for 17 hours. LCMS detects the end of the reaction. Concentrate the solvent, dissolve the solid with dichloromethane, wash with saturated sodium chloride and saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, spin to dryness, and separate by silica gel column chromatography (methanol:dichloromethane) =1:15) to obtain 200 mg of the title compound, with a yield of 60.8%.

2. 7-Amino-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo Preparation of [1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(((1s,3s)-3-hydroxycyclobutyl)amino)thieno[3,2-b]pyridin-5(4H)-one (150mg, 0.36mmol) was dissolved in methanol (15mL) and added 3-Oxetanone (77.1mg, 1.1mmol), acetic acid (21.6mg, 0.36mmol), react at 20℃ for 30 minutes, add sodium cyanoborohydride (68.2mg, 1.1mmol), complete the addition, react at 20℃ 17 hours. LCMS detects the end of the reaction. Concentrate the solvent, dissolve the solid with dichloromethane, wash with saturated sodium chloride and saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry the organic phase with anhydrous sodium sulfate, spin to dryness, and separate by silica gel column chromatography (methanol:dichloromethane) =1:15) to obtain 16.9 mg of the target compound, with a yield of 9.1%.

Molecular formula: C ₂₁ H ₂₁ N ₅ O ₂ S Molecular weight: 407.5 LC-MS (M/e): 408.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.74 (s, 1H), 11.76 (s, 1H), 10.54-10.62 (m, 1H), 7.91 (d, J = 5.2Hz, 1H), 7.72 -7.91(m,1H),7.38(s,1H),7.33(s,1H),6.98(d,J＝5.2Hz,1H),4.44-4.53(m,4H),3.44-3.50(m,1H ),2.88-2.95(m,4H),2.25-2.40(m,4H).

Preparation Example 21: 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-3-methyl-6-(7-methyl-1-(1,5,6,7,8,9 -Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one Hydrochloride (hydrochloride of compound 27-1)

1. Preparation of 3-amino-4-methylthiophene-2-carboxylic acid

Dissolve 3-amino-4-methylthiophene-2-carboxylic acid methyl ester (1.71g, 10mmol) and potassium hydroxide (1.12g, 20mmol) in water (20mL), and react at 90°C for 1 hour. The reaction solution was used directly in the next step.

2. Preparation of 7-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione

Cool 3-amino-4-methylthiophene-2-carboxylic acid (reaction solution in the previous step) to 0°C, add trichloromethyl chloroformate (2.37g, 12mol), complete the addition, and react at 20°C for 2 hours. After suction filtration, the solid was collected and spin-dried to obtain 1.6 g of the title compound, with a yield of 87.3%.

3. Preparation of 1-(4-methoxybenzyl)-7-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4-(1H)-dione

7-Methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (1.6g, 8.7mmol), 1-(chloromethyl)- 4-Methoxybenzene (1.65g, 10.5mmol), potassium carbonate (1.45g, 10.5mmol) and potassium iodide (282mg, 1.7mmol) were dissolved in N,N-dimethylformamide (23mL) and reacted at 20°C 16 hours. Pour the reaction solution into water (100 mL), filter with suction, collect the solid, spin to dryness, and purify on a silica gel column (dichloromethane) to obtain 1.5 g of the target compound, with a yield of 64.7%.

4. 3-(3-(((4-methoxybenzyl)amino)-4-methylthiophen-2-yl)-2-(7-methyl-1,5,6,7,8, Preparation of ethyl 9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-3-oxopropionate

2-(7-Methyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepine-2 -ethyl)acetate (475 mg, 1.65 mmol) and 1-(4-methoxybenzyl)-7-methyl-2H-thieno[3,2-d][1,3]oxazine-2 , 4(1H)-dione (500mg, 1.65mmol) was dissolved in tetrahydrofuran (20mL). Under nitrogen protection, add LDA (3.3 mL, 6.6 mmol) at 40°C, complete the addition, and react at 40°C for 4 hours. The reaction was quenched by saturated aqueous ammonium chloride solution at 0°C, the organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol=10:1) to obtain 480 mg of the title compound, with a yield of 53.3%.

5. 7-Hydroxy-4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4' ,5': Preparation of 4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

3-(3-(((4-methoxybenzyl)amino)-4-methylthiophen-2-yl)-2-(7-methyl-1,5,6,7,8,9 -Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2-yl)-3-oxopropionic acid ethyl ester (480 mg, 0.88 mmol) was dissolved in Tetrahydrofuran (8mL), under nitrogen protection, add LDA (1.76mL, 3.52mol) at 40°C, complete the addition, and react at 40°C for 2 hours. Quench the reaction with saturated aqueous ammonium chloride solution (8mL), concentrate the organic phase, and remove it from silica gel. Column purification (dichloromethane:methanol=4:1) gave 390 mg of the title compound, with a yield of 88.7%.

6. 4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8, 9-Hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3, Preparation of 2-b]pyridin-7-yl triflate

7-Hydroxy-4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4', 5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (390mg, 0.78mmol) was dissolved in di To methyl chloride (8 mL), add pyridine (1232 mg, 15.6 mmol) and trifluoromethanesulfonic anhydride (1318 mg, 4.68 mmol) at 0°C. After completion, react at 0°C for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried and concentrated for direct use in the next step.

7. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1-(( (Trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)thieno[3,2-b]pyridin-5(4H)-one

4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9 -Hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2 -b] Pyridin-7-yl triflate (N/A, 0.39mmol) was dissolved in acetonitrile (5mL), and (1s,4s)-4-aminocyclohexan-1-ol (179mg, 1.56mmol) was added ), and react at 40°C for 2 hours after addition. The reaction solution was concentrated and purified on a silica gel column (dichloromethane: methanol = 10:1) to obtain 180 mg of the target compound, with a two-step yield of 63.3%.

8. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-3-methyl-6-(7-methyl-1-(1,5,6,7,8,9-hexa Hydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride Preparation of salt

7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-3-methyl-6-(7-methyl-1-((( Trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 -yl)thieno[3,2-b]pyridin-5(4H)-one (180 mg, 0.25 mmol) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (7 mL). After addition, the temperature was raised to 110°C and the reaction was carried out for 24 hours. . Concentrate the solvent, add dichloromethane (20mL) to dissolve, add NaOH (1N, 20mL) solution and stir for 0.2 hours. The organic phase is concentrated and prepared by medium pressure reverse phase (0-50% methanol/water (0.5% concentrated hydrochloric acid)) 70 mg of the title compound was obtained with a yield of 59.4%.

Molecular formula: C ₂₆ H ₃₂ ClN ₅ O ₂ S Molecular weight: 514.1 LC-MS (M/e): 478.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.08 (s, 1H), 12.08 (s, 1H), 11.47 (s, 1H), 10.39 (s, 1H), 7.66 (s, 1H), 7.47 (s,2H),4.28-4.26(m,1H),3.75-3.65(m,2H),3.40-3.25(m,4H),3.10-2.90(m,4H),2.81(s,3H),2.28 (s,3H),1.91-1.75(m,4H),1.75-1.60(m,4H).

Preparation Example 22: 7-(((1S,4S)-4-hydroxycyclohexyl)amino)-2-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydro Imidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 28 -1)

1. 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-2-methyl-6-(7-methyl-1-(( Trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 Preparation of -yl)thieno[3,2-b]pyridin-5(4H)-one

3-Amino-5-methylthiophene-2-carboxylic acid methyl ester was selected as the starting material, and 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4 was prepared by referring to the method of Preparation Example 21. -(4-methoxybenzyl)-2-methyl-6-(7-methyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexa Hydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one.

2.(1s,4s)-4-((2-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazole [4',5':4,5 ]benzo[1,2-d]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-7-yl)amino)cyclohexyl 2 , Preparation of 2,2-trifluoroacetate

7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-2-methyl-6-(7-methyl-1-((tri Fluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2- 1) Thieno[3,2-b]pyridin-5(4H)-one (150 mg, 0.21 mmol) was dissolved in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (4 mL). After addition, the mixture was raised to 115°C and reacted for 5.0 hours. The solvent was concentrated and used directly in the next reaction.

3. 7-(((1S,4S)-4-hydroxycyclohexyl)amino)-2-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo Preparation of [4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

Dissolve the crude product from the previous step in 5 mL of methanol, add potassium carbonate (300 mg, 2.2 mmol), react at 25°C for 1 hour, concentrate the solvent, and obtain 15 mg of the target compound through column chromatography (dichloromethane: methanol = 10:1). The two-step yield is 15.3%.

Molecular formula: C ₂₆ H ₃₁ N ₅ O ₂ S Molecular weight: 477.6 LC-MS (M/e): 478.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.00 (s, 1H), 12.13 (s, 1H), 11.74 (s, 1H), 10.39 (s, 1H), 7.42 (s, 1H), 7.33 (s,1H),6.77(s,1H),4.62-4.4.58(s,1H),4.28-4.21(m,1H)3.75-3.65(m,1H),3.10-3.25(m,8H), 2.48(m,3H),1.91-1.75(m,4H),1.75-1.60(m,4H).

Preparation Example 23: 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-2,3-dimethyl-6-(7-methyl-1-(1,5,6,7, 8,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine-5(4H )-keto hydrochloride (hydrochloride of compound 29-1)

3-Amino-4,5-dimethylthiophene-2-carboxylic acid was selected as the starting material, and 7-(((1s,4s)-4-hydroxycyclohexyl)amino)- was prepared by referring to the method of Preparation Example 21. 2,3-Dimethyl-6-(7-methyl-1-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride.

Molecular formula: C ₂₇ H ₃₄ ClN ₅ O ₂ S Molecular weight: 528.1 LC-MS (M/e): 492.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.08 (s, 1H), 11.98 (s, 1H), 11.33 (s, 1H), 10.64 (s, 1H), 7.47 (s, 2H), 4.25 -4.15(m,1H),3.80-3.70(m,4H),3.40-3.30(m,2H),3.10-2.90(m,4H),2.80(s,3H),2.41(s,3H),2.18 (s,3H),1.80-1.60(m,8H).

Preparation Example 24: 7-((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazole And[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 30- 1)

1. 2-(7-hydroxy-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydro Preparation of imidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid tert-butyl ester

2-(2-ethoxy-2-oxyethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Heterazole-7(1H)-carboxylic acid tert-butyl ester (1.8g, 4.83mmol) and 1-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H )-diketone (972 mg, 5.3 mmol) was dissolved in tetrahydrofuran (50 mL). Under nitrogen protection, add LDA (9.7 mL, 19.3 mmol) at 40°C, complete the addition, and react at 40°C for 4 hours. Add saturated ammonium chloride aqueous solution at 0°C to quench the reaction, extract and separate the liquids with dichloromethane, and concentrate the organic phase to obtain a crude product mixed with the intermediate. Dissolve the crude product from the previous step in tetrahydrofuran (20 mL), add LDA (9.7 mL, 19.3 mmol) at 40°C under nitrogen protection, complete the addition, and react at 40°C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, the organic phase was concentrated, and purified by silica gel column (100% ethyl acetate) to obtain 710 mg of the title compound, with a yield of 31%.

2. 2-(4-methyl-5-oxo-7-((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene[3,2-b]pyridin-6-yl )-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -7(1H)-carboxylic acid tert-butyl ester

2-(7-Hydroxy-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazole [4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid tert-butyl ester (710mg, 1.52mmol) was dissolved in dichloromethane (15mL), Add pyridine (2.4g, 30.4mmol) and trifluoromethanesulfonic anhydride (2.6g, 9.12mmol) at 0°C, complete the addition, and react at 0°C for 1 hour. The reaction solution was concentrated, extracted with dichloromethane, washed with saturated sodium bicarbonate aqueous solution and saturated brine, the organic phase was dried over anhydrous sodium sulfate, and column chromatography (ethyl acetate/n-heptane=0-60%) was performed to obtain 450 mg of the target compound. , yield 41%.

3. 2-(7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine- 6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazole[4',5':4,5]benzo[1,2-d]nitrogen Preparation of heterozo-7(1H)-carboxylic acid tert-butyl ester

2-(4-Methyl-5-oxo-7-((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene[3,2-b]pyridin-6-yl) -1-((Trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 7(1H)-tert-butylcarboxylate (450mg, 0.62mmol) was dissolved in acetonitrile (10mL), (1s,4s)-4-aminocyclohexan-1-ol (284mg, 2.5mmol) was added, and the addition was completed at 40°C Reaction takes 2 hours. The reaction solution was concentrated and purified through silica gel column (dichloromethane:methanol=10:1) to obtain 430 mg of the target compound, with a yield of 99%.

4. 6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2-yl)- Preparation of 7-((1s,4s)-4-hydroxycyclohexyl)amino)-4-methylthiophene[3,2-b]pyridin-5(4H)-one

2-(7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine-6 -yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazole[4',5':4,5]benzo[1,2-d]azepine Zo-7(1H)-carboxylic acid tert-butyl ester (120 mg, 0.17 mmol) was dissolved in trifluoroacetic acid (4 mL), reacted at 25°C for 1 hour, and concentrated. Add tetrahydrofuran/water (5/5mL) mixed solvent to the reaction solution, add NaOH to adjust pH = 10, react at 25°C for 1 hour, concentrate and use directly for the next reaction.

5. 7-((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -((1s,4s)-4-hydroxycyclohexyl)amino)-4-methylthiophene[3,2-b]pyridin-5(4H)-one (crude product from the previous step) was dissolved in 10 mL methanol and added 40% Formaldehyde aqueous solution (0.1 mL) and sodium cyanoborohydride (70 mg, 1.1 mmol) were reacted at 20°C for 3 hours, the solvent was concentrated, and subjected to column chromatography (dichloromethane: methanol = 7:1), (0.3% TFA in MeOH/H ₂ O=0-75%) to obtain 40 mg of the target compound, with a two-step yield of 49%.

Molecular formula: C ₂₆ H ₃₁ N ₅ O ₂ S Molecular weight: 477.6 LC-MS (M/e): 478.2 (M+H ⁺ )

¹ H-NMR(400MHz,MeOD)δ:7.95(m,1H),7.49(s,2H),7.31(m,1H),7.4(m,1H),3.87-3.68(m,6H),3.38- 2.95(m,9H),2.12-1.73(m,8H).

Preparation Example 25: 7-amino-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 33)

1. 2-(7-(((2,4-dimethoxybenzyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[ 3,2-b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzene Preparation of tert-butyl[1,2-d]azepine-7(1H)-carboxylate

2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepine-7(1H)-carboxylic acid tert-butyl ester (N/A, 0.26mmol) was dissolved in acetonitrile (10mL), and 2,4-dimethoxybenzylamine (130.3mg, 0.78 mmoL), react at 40°C for 2 hours after addition. LCMS detects the end of the reaction. The reaction solution was concentrated and purified on a silica gel column (dichloromethane: methanol = 20:1) to obtain 80 mg of the target compound. The two-step yield was 37.4%.

2. 7-Amino-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-2 Preparation of -yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-(((2,4-dimethoxybenzyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3 ,2-b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo [1,2-d]Azepine-7(1H)-carboxylic acid tert-butyl ester (80 mg, 98.3 μmol) was dissolved in concentrated hydrochloric acid (0.5 mL) and trifluoroacetic acid (3.5 mL), and the reaction was carried out at 110°C for 48 hours. LCMS detected the end of the reaction. Concentrate the solvent, adjust pH=8 with saturated aqueous sodium bicarbonate solution, and purify using Pre-TLC plate (dichloromethane:methanol=7:1) to obtain 4.2 mg of the target compound, yield: 12.8%.

Molecular formula: C ₁₈ H ₁₇ N ₅ OS Molecular weight: 351.4 LC-MS (M/e): 352.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.85 (s, 1H), 11.83 (m, 1H), 7.95 (d, J = 5.2Hz, 1H), 7.49 (s, 1H), 7.44 (s ,1H),7.02(d,J＝5.6Hz,1H),4.07-4.11(m,2H),3.18-3.23(m,4H),3.13-3.17(m,4H).

Preparation Example 26: 2-(7-amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid isopropyl ester (compound 37)

1. 2-(2-ethoxy-2-oxyethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of azepine-7(1H)-carboxylic acid isopropyl ester

Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Dissolve ester (330mg, 1.2mmol) and triethylamine (607mg, 6.0mmol) in dichloromethane (10mL), cool to -10°C, add isopropyl chloroformate (111mg, 0.91mmol), and keep at -10°C After reacting for 2 hours, the system was quenched with methanol (1 mL). The system was spun to dryness and separated by silica gel column chromatography (methanol:dichloromethane=1:15) to obtain 110 mg of the target compound, with a yield of 25.5%.

2. 2-(7-Amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4' , Preparation of 5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid isopropyl ester

2-(2-ethoxy-2-oxyethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Zazo-7(1H)-carboxylic acid isopropyl ester (90 mg, 0.25 mmol) and 3-aminothiophene-2-carbonitrile (32 mg, 0.26 mmol) were dissolved in tetrahydrofuran (8 mL), and LDA (2 M) was added dropwise at 40°C. ,0.63mL,1.26mmol), continue the reaction for 2h. After the reaction was completed, saturated ammonium chloride aqueous solution (5 mL) was added to quench, and then ethyl acetate (20 mL) and water (10 mL) were added for extraction and separation. The organic phase was dried over anhydrous sodium sulfate, and spin-dried to obtain 80 mg of crude product. Methanol (5 mL) was ultrasonically beaten to separate the solid, and then filtered under reduced pressure to obtain 40 mg of the target compound, with a yield of 36.6%.

Molecular formula: C ₂₂ H ₂₃ N ₅ O ₃ S Molecular weight: 437.5 LC-MS (M/e): 438.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.77 (s, 1H), 11.76 (s, 1H), 10.70-10.55 (m, 1H), 7.92 (d, J = 2.8Hz, 1H), 7.84 -7.71(m,1H),7.42(s,1H),7.37(s,1H),6.99(d,J＝2.8Hz,1H),4.82-4.75(m,1H),3.52-3.46(m,4H ),2.96-2.89(m,4H),1.22-1.18(m,6H).

Preparation Example 27: 2-(7-amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid methyl ester (compound 40)

1. 2-(2-ethoxy-2-oxyethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d] Preparation of azepine-7(1H)-carboxylic acid methyl ester

Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate Dissolve ester (300mg, 1.1mmol) and triethylamine (445mg, 4.4mmol) in dichloromethane (40mL). After cooling to 0°C, add methyl chloroformate solution (0.3M/L, 3.7mL, 1.1mmol). ), reacted at 0°C for 2 h, and the system was quenched with methanol (2 mL). The system was spun to dryness and separated by silica gel column chromatography (methanol: dichloromethane = 1:20) to obtain 220 mg of the target compound, with a yield of 60.4%.

2. 2-(7-Amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4' , Preparation of 5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid methyl ester

2-(2-ethoxy-2-oxyethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Zazo-7(1H)-carboxylic acid methyl ester (100mg, 0.30mmol) and 3-aminothiophene-2-nitrile (45mg, 0.36mmol) were dissolved in tetrahydrofuran (15mL), and LDA (2M, 2M, 0.75mL, 1.5mmol), continue the reaction for 2h. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (3 mL), and then added ethyl acetate (20 mL) and water (10 mL) for extraction and separation. The organic phase was dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product. Methanol (10 mL) was added. After ultrasonic beating, the solid was precipitated and filtered under reduced pressure to obtain 35 mg of the target compound, with a yield of 28.5%.

Molecular formula: C ₂₀ H ₁₉ N ₅ O ₃ S Molecular weight: 409.5 LC-MS (M/e): 409.9 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ )δ:12.77(s,1H),11.77(s,1H),10.70-10.55(m,1H),7.92-7.85(m,2H),7.45-7.32( m,2H),6.99-6.93(m,1H),3.60(s,3H),3.52–3.46(m,4H),2.96-2.89(m,4H).

Preparation Example 28: 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]nitrogen Preparation of heterozo-2-yl)-7-(oxa-3-cyclobutylamino)thiophene[3,2-b]pyridin-5(4H)-one (compound 42)

1. 7-Chloro-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d Preparation of ]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

7-Chloro-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine-6-carbaldehyde (500 mg, 2.35 mmol), 3-cyclopropyl-2,3,4,5- Tetrahydro-1H-benzo[d]azepine-7,8-diamine (510mg, 2.35mmol), ferric chloride (1.5g, 9.4mmol) were dissolved in 1,4-dioxane (30mL ), raise the temperature to 110°C, and react for 1 hour. LCMS detects the end of the reaction. Lower to 25°C, adjust the pH of the system to 9 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, dry, concentrate and purify the organic phase on a silica gel column (dichloromethane: methanol = 10:1) to obtain 220g of the target compound, yield 22.9%.

2. 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)-7-(oxa-3-cyclobutylamino)thiophene[3,2-b]pyridin-5(4H)-one

7-Chloro-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d] Azepine-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (220mg, 0.54mmol), 3-aminooxetane (59.2mg, 0.81mmol), sodium bicarbonate (136.1 mg, 1.6 mmol) and tetrabutylammonium iodide (19.9 mg, 54.0 μmol) were dissolved in water (3 mL) and chloroform (18 mL), heated to 60°C, and reacted for 16 hours. LCMS detects the end of the reaction. Cool the temperature to 25°C, add dichloromethane to dilute, add water to wash, the organic phase is dried and concentrated to obtain a solid, and the solid is slurried with methanol to obtain 14.5 mg of the target compound, with a yield of 6.0%.

Molecular formula: C ₂₄ H ₂₅ N ₅ O ₂ S Molecular weight: 447.6 LC-MS (M/e): 448.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.91 (s, 1H), 12.74 (d, J = 6.0Hz, 1H), 11.96 (s, 1H), 8.05 (d, J = 5.6Hz, 1H ),7.43(s,1H),7.42(s,1H),7.06(d,J＝5.2Hz,1H),5.70-5.80(m,1H),5.06-5.10(m,2H),4.67-4.70( m,2H),2.90-2.92(m,4H),2.76-2.90(m,4H),1.75-1.85(m,1H),0.48-0.49(m,2H),0.35-0.40(m,2H).

Preparation Example 29: 7-(((1r,4r)-4-hydroxycyclohexyl)amino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazole [4', Preparation of 5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 44)

1. 2-(((1r,4r)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene [3,2- b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-1,5,7,8,9-hexahydro-7λ ⁴ -imidazole [4',5':4,5] Preparation of benzo[1,2-d]azepine-7-carboxylic acid tert-butyl ester

2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene [3,2-b ]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-1,5,7,8,9-hexahydro-7λ ⁴ -imidazole[4',5':4,5]benzene And [1,2-d]azepine-7-carboxylic acid tert-butyl ester (200.0mg, 0.24mmol) was dissolved in acetonitrile (5mL), and (1r,4r)-4-aminocyclohexane-1- was added Alcohol (110.1 mg, 0.96 mmol) was added, and the reaction was carried out at 45°C for 2 hours. The reaction solution was concentrated and purified by silica gel column (dichloromethane: methanol = 10:1) to obtain 200.0 mg of crude product of the target compound.

2. 6-(1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine-2-yl)-7 Preparation of -((1r,4r)-4-hydroxycyclohexyl)amino)thiophene[3,2-b]pyridin-5(4H)-one

2-(((1r,4r)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene [3,2-b ]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-1,5,7,8,9-hexahydro-7λ ⁴ -imidazole[4',5':4,5]benzene [1,2-d]azepine-7-carboxylic acid tert-butyl ester (200.0 mg crude product, N/A) was dissolved in concentrated hydrochloric acid (4 mL) and trifluoroacetic acid (28 mL). After addition, the temperature was raised to 110 °C for 24 hours. The solvent was concentrated, dissolved in dichloromethane (20 mL), stirred with 1N NaOH (20 mL) for 0.2 hours, the organic phase was concentrated, and the target compound 75.0 was obtained through medium pressure reverse phase preparation (0-50% methanol/water (0.5% concentrated hydrochloric acid)). mg, two-step yield 70.8%.

3. 7-(((1r,4r)-4-hydroxycyclohexyl)amino)-6-(7-methyl-1,5,6,7,8,9-hexahydroimidazole [4',5' : Preparation of 4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

6-(1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7- ((1r,4r)-4-hydroxycyclohexyl)amino)thiophene[3,2-b]pyridin-5(4H)-one (75.0mg, 0.17mmol) was dissolved in 10.0mL methanol, and 1.0mL formaldehyde was added. Sodium cyanoborohydride (21.0 mg, 0.33 mmol), stirred at 25°C for 1 hour, concentrated the solvent, and separated through normal phase column (methanol: dichloromethane = 1:99) to obtain 7.6 mg, yield 9.8%.

Molecular formula: C ₂₅ H ₂₉ N ₅ O ₂ S Molecular weight: 463.2 LC-MS (M/e): 464.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.99 (s, 1H), 12.17 (s, 1H), 11.85 (s, 1H), 8.02 (d, 1H), 7.40 (s, 1H), 7.32 (s,1H),7.05(d,1H),4.66-4.65(m,1H),4.21-4.12(m,1H),3.80-3.60(m,1H),3.32(d,4H),2.95(s ,4H),2.27(s,3H),2.17-2.16(m,2H),1.99-1.96(m,2H),1.58-1.56(m,2H),1.45-1.42(m,2H).

Preparation Example 30: 7-(azetidin-1-yl)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazole Preparation of [4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 45)

1. 2-(7-(azetidin-1-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b] Pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2- d] Preparation of azepine-7(1H)-carboxylic acid tert-butyl ester

2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene [3,2-b ]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazole[4',5':4,5]benzo[1,2- d] Azepine-7-carboxylic acid tert-butyl ester (200 mg, 0.24 mmol) was dissolved in acetonitrile (5 mL), azetidine (55 mg, 0.96 mmol) was added, and the reaction was completed at 40°C for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by silica gel column (dichloromethane:methanol=10:1) to obtain the crude target compound.

2. 7-(Azetidin-1-yl)-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 , Preparation of 2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-(azetidin-1-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine -6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d ]Azepine-7(1H)-carboxylic acid tert-butyl ester (crude product) was dissolved in concentrated hydrochloric acid (1mL) and trifluoroacetic acid (7mL). After the addition was completed, the temperature was raised to 110°C and the reaction was carried out for 24 hours. LCMS detects the end of the reaction. The solvent was concentrated, dissolved in dichloromethane, washed with saturated sodium bicarbonate aqueous solution, and the organic phase was dried, concentrated, and purified by Pre-TLC (dichloromethane:methanol=7:1) to obtain 40 mg of the target compound. The two-step reaction yield was 43%.

3. 7-(azetidin-1-yl)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[ Preparation of 4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

7-(Azetidin-1-yl)-6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, 2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (40 mg, 0.1 mmol) was dissolved in methanol (6 mL), and 3-oxetane was added Ketone (22 mg, 0.3 mmol) and glacial acetic acid (6 mg, 0.1 mmol) were reacted at 20°C for 30 min. Sodium cyanoborohydride (19 mg, 0.3 mmol) was added and the reaction was carried out at 20°C for 4 h. After the reaction is completed, add dichloromethane and saturated sodium bicarbonate solution for liquid extraction three times, spin the organic phase to dryness, and obtain 5 mg of the target compound through forward preparative separation (dichloromethane:methanol=5:1).

Molecular formula: C ₂₄ H ₂₅ N ₅ O ₂ S Molecular weight: 447.5 LC-MS (M/e): 448.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.10 (s, 1H), 11.50 (s, 1H), 7.90-7.91 (d, J = 4Hz, 1H), 7.32 (s, 1H), 7.19 ( s,1H),6.97-6.98(d,J＝4Hz,1H),4.46-4.55(m,4H),3.94(s,4H),3.48-3.51(t,1H),2.96(s,4H), 2.36(s,4H),2.09-2.11(m,2H).

Preparation Example 31: 7-amino-6-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4, Preparation of 5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (compound 46)

1. Preparation of 3-(6-chloropyrazin-3-yl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Mix 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (961mg, 5mmol), triethylamine (1012mg, 10mmol) and 3,6-dichloropyrazine (894 mg, 6 mmol) was dissolved in dimethyl sulfoxide (50 mL) and reacted at 110°C for 1 hour. After the reaction, the reaction was quenched with water (50 mL), extracted with dichloromethane (50 mL), and the organic phase was concentrated and purified by a silica gel column (ethyl acetate/dichloromethane = 1:9) to obtain 500 mg of the target compound, with a yield of 32.8%.

2. Preparation of 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

3-(6-chloropyrazin-3-yl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.64 mmol), chlorinated Ammonium (351 mg, 6.56 mmol) and iron powder (275 mg, 4.92 mmol) were dissolved in ethanol (15 mL) and water (15 mL), and reacted at 95°C for 3 hours. Extract with dichloromethane (50 mL), and the organic phase is concentrated and used directly in the next step.

3. Preparation of N-(3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (crude product from the previous step) in acetic anhydride ( 2 mL) and acetic acid (5 mL), and reacted at 25°C for 1 hour. Water (50 mL) was added to quench the reaction, and dichloromethane (50 mL) was extracted. The organic phase was concentrated to obtain 400 mg of the target compound. The two-step reaction yield was 76.9%.

4. N-(3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl) Preparation of acetamide

N-(3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide (400 mg, 1.26 mmol) was dissolved in concentrated sulfuric acid (4 mL). Add fuming nitric acid (95 mg, 1.52 mmol) dropwise at 0°C, complete the dripping, and react at 0°C for 1 hour. After the reaction, it was diluted with dichloromethane (50 mL), washed with water (50 mL), and the organic phase was concentrated and purified on a silica gel column (ethyl acetate/dichloromethane = 1:4) to obtain 230 mg of the target compound, with a yield of 50.3%.

5. Preparation of 3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

N-(3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)ethane Amide (230 mg, 0.64 mol) and potassium carbonate (263 mg, 1.91 mol) were dissolved in methanol (6 mL) and reacted at 50°C for 2 hours. Quench with water (30 mL), filter with suction, collect the solid and spin dry to obtain 200 mg of the target compound, with a yield of 98.4%.

6. Preparation of 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine

3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (200 mg, 0.63 mmol ), ammonium chloride (167 mg, 3.13 mmol) and iron powder (105 mg, 1.88 mmol) were dissolved in ethanol (10 mL) and water (10 mL), and reacted at 95°C for 2 hours. Extract with dichloromethane (50 mL), wash with water (20 mL), dry the organic phase with anhydrous sodium sulfate, filter and concentrate to obtain 180 mg of the target compound, with a yield of 99.3%.

7. 2-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 , Preparation of 2-d]azepin-2-yl)ethyl acetate

3-(6-Chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine (180 mg, 0.62 mmol) and 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (292 mg, 1.49 mmol) was dissolved in ethanol (10 mL). React at 55°C for 1 hour. Spin to dryness, dilute with dichloromethane (50 mL), wash with ammonia (10 mL), dry the organic phase, concentrate, and purify on a silica gel column (dichloromethane:methanol=19:1) to obtain 160 mg of the target compound, with a yield of 66.8%.

8. 7-Amino-6-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5] Preparation of benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

2-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, 2-d]Azepine-2-yl)ethyl acetate (60 mg, 0.16 mmol) and 3-aminothiophene-2-carbonitrile (20 mg, 0.16 mmol) were dissolved in tetrahydrofuran (4 mL), under nitrogen protection, 40°C Add LDA (0.32 mL, 0.64 mol) at 40°C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (8 mL), the organic phase was concentrated, and purified by reversed-phase column (acetonitrile: water (0.5% hydrochloric acid) = 30%) to obtain 7 mg of the target compound, with a yield of 9.7%.

Molecular formula: C ₂₂ H ₁₈ ClN ₇ OS Molecular weight: 463.9 LC-MS (M/e): 464.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 11.92 (s, 2H), 8.25-8.09 (m, 1H), 8.02 (d, J = 5.2, 1H), 7.60-7.50 (m, 4H), 7.03(d,J＝5.2,1H),3.95-3.85(m,4H),3.15-3.05(m,4H)

Preparation Example 32: 7-amino-6-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (compound 47)

1. 2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)ethyl acetate

Add 3-ethoxy-3-imino to the ethanol solution of 3-methyl-8-amino-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-phenol Ethyl propionate hydrochloride (3.75g.19.3mmol), raised to 50°C and reacted for 16 hours. After the reaction, filter with diatomaceous earth, add sodium bicarbonate solution to the filtrate to adjust the pH to about 8, extract with dichloromethane (100 mL), dry and concentrate the organic phase, and purify through silica gel column (dichloromethane: methanol = 10:1 ), 820 mg of the target compound was obtained, and the reaction yield was 59.0%.

2. 2-(7-Methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)acetic acid

2-(7-Methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepine-2 -ethyl acetate (750 mg, 2.6 mmol) was dissolved in methanol (10 mL) and water (10 mL), sodium hydroxide (312.0 mg, 7.8 mmol) was added, and the reaction was carried out at 25°C for 3 hours. After the reaction, 2M dilute hydrochloric acid solution was added to the system to adjust the pH to neutral. The system was concentrated and spin-dried to obtain a crude target compound, which was directly used in the next reaction.

3. N-(2-cyanothiophen-3-yl)-2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5 Preparation of benzo[1,2-d]azepin-2-yl)acetamide

2-(7-Methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepine-2 -ethyl)acetic acid (N/A, 2.6mmol) was dissolved in dichloromethane (50mL), and 2-aminothiophene-3-carbonitrile (387.5mg, 3.1mmol), 2-(7-azobenzo) were added in sequence. Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.5g, 3.9mmol) and triethylamine (526.2mg, 5.2mmol), the system was reacted at 25°C for 8 hours . After the reaction, water was added to the system to quench the reaction, extracted with dichloromethane (100 mL), the organic phase was dried and concentrated, and purified on a silica gel column (dichloromethane: methanol = 9:1) to obtain 700 mg of crude target compound, which was directly used in the next step of the reaction. .

4. 7-Amino-6-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d] Preparation of azepine-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

N-(2-cyanothiophen-3-yl)-2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5] Benzo[1,2-d]azepin-2-yl)acetamide (600mg, 1.6mmol) was dissolved in methanol (50mL), sodium methoxide (5.2g, 28.9mmol) was added and the system was placed at 70°C React for 2 hours. After the reaction, add 2M dilute hydrochloric acid solution to adjust the pH of the system to neutral, concentrate and spin to dryness, purify through silica gel column (dichloromethane:methanol=7:3), spin to dry the solvent, beat with methanol, filter, wash and dry to obtain The target compound was 19.0 mg, and the three-step reaction yield was 2.3%.

Molecular formula: C ₁₉ H ₁₈ N ₄ O ₂ S Molecular weight: 366.4 LC-MS(M/e): 367.4.1(M+H ⁺ )

¹ H-NMR (400MHz, CDCl ₃ ) δ: 11.51 (s, 1H), 9.30-8.40 (m, 2H), 7.95 (d, J = 5.2HZ, 1H), 7.47 (s, 2H), 6.94 (d ,J=5.2HZ,1H),3.30-3.20(m,4H),3.10-2.90(m,4H),2.28(s,3H).

Preparation Example 33: 6-(7-(2,2-difluoroethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (compound 48)

1. 2-(7-(isopropylamino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridine-6- base)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of Zhuo-7(1H)-carboxylic acid tert-butyl ester

2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]azepine-7(1H)-tert-butylcarboxylate (500mg, 0.60mmol) was dissolved in acetonitrile (10mL), added isopropylamine (106mg, 1.80mmoL), and the temperature was raised to 40°C for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by silica gel column (dichloromethane: methanol = 20:1) to obtain 300 mg of the target compound, yield: 67.1%.

2. 7-(isopropylamino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9 -Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one Preparation

2-(7-(isopropylamino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-6-yl )-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine -7(1H)-tert-butylcarboxylate (300 mg, 0.4 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 ml) was added to react for 1 hour. LCMS detects the end of the reaction. Dilute with methylene chloride, wash with saturated aqueous sodium bicarbonate solution, dry and concentrate the organic phase for direct use in the next step.

3. 6-(7-(2,2-difluoroethyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4' ,5':4,5]benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)-4-(4-methoxybenzyl)thieno[3 , Preparation of 2-b]pyridin-5(4H)-one

7-(isopropylamino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9- Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one( N/A, 0.4mmoL) was dissolved in acetonitrile (5mL), and N,N diisopropylethylamine (155mg, 1.2mmoL) and 2,2-difluoroethyl triflate (256mg, 1.2mmoL) were added. ), the addition was completed and the reaction took 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified by silica gel column (ethyl acetate: petroleum ether = 1:1) to obtain 150 mg of the target compound. The two-step yield was 52.9%.

4. 6-(7-(2,2-difluoroethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, Preparation of 2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one

6-(7-(2,2-Difluoroethyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4', 5':4,5]benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)-4-(4-methoxybenzyl)thieno[3, 2-b]pyridin-5(4H)-one (180 mg, 0.25 mmol) was dissolved in concentrated hydrochloric acid (0.5 mL), trifluoroacetic acid (3.5 mL) was added, and the reaction was carried out at 110°C for 48 hours. LCMS detects the end of the reaction. The solvent was concentrated, and the system pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The target compound was purified through Pre-TLC plate (dichloromethane:methanol=7:1) to obtain 17 mg of the target compound, yield: 14.9%.

Molecular formula: C ₂₃ H ₂₅ F ₂ N ₅ OS Molecular weight: 457.5 LC-MS (M/e): 458.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.00 (s, 1H), 11.14 (d, J = 8.4Hz, 1H), 11.84 (s, 1H), 8.03 (d, J = 5.6Hz, 1H ),7.40(s,1H),7.33(s,1H),7.05(d,J＝5.6Hz,1H),6.18-6.14(m,1H),4.50-4.48(m,1H),2.95-2.90( m,6H),2.87-2.78(m,4H),1.45-1.44(m,6H).

Preparation Example 34: 6-(7-(2,2-difluoroethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (compound 49)

1. 7-amino-6-(7-(2,2-difluoroethyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole And[4',5':4,5]benzo[1,2-d]azepine-2-yl)-4-(4-methoxybenzyl)thieno[3,2-b] Preparation of pyridin-5(4H)-one

7-((3,4-dimethylbenzyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-1,5, 6,7,8,9-Hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridine -5(4H)-one (400mg, 0.53mmoL) was dissolved in acetonitrile (5mL), and N,N diisopropylethylamine (206mg, 1.6mmoL) and 2,2-difluoroethyltrifluoromethanesulfonic acid were added Ester (342mg, 1.6mmoL) was added and the reaction was completed for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified on a silica gel column (ethyl acetate: petroleum ether = 1:1) to obtain 250 mg of the target compound, yield: 70.7%.

2. 6-(7-(2,2-difluoroethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, Preparation of 2-d]azepin-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one

7-Amino-6-(7-(2,2-difluoroethyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo [4',5':4,5]benzo[1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)thieno[3,2-b]pyridine -5(4H)-one (180 mg, 0.27 mmol) was dissolved in concentrated hydrochloric acid (0.5 mL), trifluoroacetic acid (3.5 mL) was added, and the reaction was carried out at 110°C for 48 hours. LCMS detects the end of the reaction. The solvent was concentrated, and the system pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The target compound was purified through Pre-TLC plate (dichloromethane:methanol=7:1) to obtain 20 mg of the target compound, yield: 17.8%.

Molecular formula: C ₂₀ H ₁₉ F ₂ N ₅ OS Molecular weight: 415.5 LC-MS(M/e): 416.0(M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.99 (s, 1H), 7.92 (d, J = 5.6Hz, 1H), 7.39-7.34 (m, 2H), 7.01 (d, J = 5.2Hz ,1H),6.19-6.23(m,1H),2.95-2.90(m,6H),2.87-2.78(m,4H).

Preparation Example 35: 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine Preparation of zo-2-yl)-7-((2,2-difluoroethyl)amino)thiophene[3,2-b]pyridin-5(4H)-one (compound 50)

1. 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5:4,5]benzene And[1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine- Preparation of 7-yl triflate

6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)-7-hydroxy-4-(4-methoxybenzyl)thiophene[3,2-b]pyridin-5(4H)-one (600 mg, 1.2 mmol) was dissolved in dichloromethane (12 mL) , add pyridine (1.90g, 24mmol) and trifluoromethanesulfonic anhydride (2.03g, 7.2mmol) at 0°C, complete the addition, and react at 0°C for 30 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried and concentrated for direct use in the next step.

2. 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5:4,5]benzene And[1,2-d]azepine-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thiophene[3,2- b] Preparation of pyridin-5(4H)-one

6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5:4,5]benzo [1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine-7 -Trifluoromethanesulfonate ester (crude product from the previous step) was dissolved in acetonitrile (10 mL), and 2,2-difluoroethylamine (389 mg, 4.8 mmol) was added. After the addition was completed, the reaction was carried out at 40°C for 1 hour. The reaction solution was concentrated and purified through silica gel column (dichloromethane: methanol = 13:1) to obtain 300 mg of the target compound, with a two-step yield of 36.2%.

3. 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)-7-((2,2-difluoroethyl)amino)thiophene[3,2-b]pyridin-5(4H)-one

6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5:4,5]benzo [1,2-d]Azapyridin-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thiophene[3,2-b ] Pyridin-5(4H)-one (150 mg, 0.21 mmol) was dissolved in concentrated hydrochloric acid (1 mL), and trifluoroacetic acid (7 mL) was added. After the addition was completed, the temperature was raised to 110°C and the reaction was carried out for 24 hours. The solvent was concentrated, dissolved in dichloromethane, washed with saturated sodium bicarbonate aqueous solution, the organic phase was dried, and then subjected to medium pressure reverse phase purification (40% methanol/water (0.5% concentrated hydrochloric acid)) to obtain 40 mg of the target compound, with a yield of 41.4%.

Molecular formula: C ₂₃ H ₂₃ F ₂ N ₅ OS Molecular weight: 455.5 LC-MS(M/e): 456.1(M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.21 (s, 1H), 12.05 (s, 1H), 10.38 (s, 1H), 8.08 (d, J = 5.6Hz, 1H), 7.50 (s ,2H),7.09(d,J＝5.6Hz,1H),6.46(t,J＝14.8Hz,1H),4.40-4.30(m,2H),3.80-3.70(m,2H),3.60-3.50( m,2H),3.30-3.05(m,4H),2.95-2.85(m,1H),1.25-1.20(m,2H),0.90-0.80(m,2H).

Preparation Example 36: 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine Preparation of zo-2-yl)-7-(isopropylamino)thiophene[3,2-b]pyridin-5(4H)-one hydrochloride (hydrochloride of compound 52)

1. 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5:4,5]benzene And[1,2-d]azepin-2-yl)-7-isopropylamino-4-(4-methoxybenzyl)-thieno[3,2-b]pyridine-5(4H )Preparation of ketones

6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5:4,5]benzo [1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridine-7 -Triflate was dissolved in acetonitrile (30 mL), isopropylamine (141.6 mg, 2.4 mmol) was added, and the addition was completed, and the reaction was carried out at 45°C for 1 hour. The reaction solution was concentrated and purified through silica gel column (dichloromethane:methanol=20:1) to obtain 200 mg of the target compound.

2. 6-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepine- Preparation of 2-yl)-7-(isopropylamino)thiophene[3,2-b]pyridin-5(4H)-one hydrochloride

6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5:4,5]benzo [1,2-d]azepin-2-yl)-7-isopropylamino-4-(4-methoxybenzyl)-thieno[3,2-b]pyridine-5(4H) Dissolve the ketone (200 mg, 0.29 mmol) in concentrated hydrochloric acid (2 mL), add trifluoroacetic acid (14 mL), complete the addition, and raise the temperature to 110°C for 16 hours. The solvent was concentrated and purified through C ₁₈ column (acetonitrile = 0-30%) to obtain 11.5 mg of the target compound, with a yield of 8.4%.

Molecular formula: C ₂₄ H ₂₈ N ₅ OSCl Molecular weight: 469.2 LC-MS (M/e): 434.0 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.11 (m, 1H), 12.09 (m, 1H), 11.87 (s, 1H), 9.03 (m, 1H), 8.04 (d, J = 5.2Hz ,1H),7.51(s,2H),7.05(d,J＝5.2Hz,1H),4.47-4.52(m,1H),3.70-3.85(m,2H),3.14-3.24(m,4H), 2.96-3.05(m,2H),1.45(d,J＝6.4Hz,6H),1.20-1.30(m,1H),1.02-1.10(m,2H),0.89-0.91(m,2H).

Preparation Example 37: 7-amino-6-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo Preparation of [1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (compound 53)

1. Preparation of 1,5-dihydrobenzo[d]oxazepine-2,4-dione

Dissolve 2,2'-(1,2-phenylene)diacetic acid (12g, 61.9mmol) in dichloromethane (200mL), add DCC (12.8g, 61.9mmol) at 25°C, and react at 25°C After 4 hours, LCMS detected that the reaction was completed, filtered, and dried the filter cake to obtain 12 g of crude target compound.

2. Preparation of 2-(2-(2-(ethylamino)-2-oxyethyl)phenyl)acetic acid

Dissolve 1,5-dihydrobenzo[d]oxazepine-2,4-dione (12g, crude product) in dichloromethane (200mL), and add ethylamine hydrochloride (2.7g) at 0°C. 33mmol) and triethylamine (13.7g, 136mmol), react for 4 hours at 25°C. LCMS detects that the reaction is complete. Water is added to the system to quench the reaction. The organic phase is extracted with dichloromethane. The organic phase is concentrated and purified by a silica gel column (methanol/dichloromethane). Methane = 1:10) to obtain 7 g of the target compound, with a two-step yield of 50.9%.

3. Preparation of N-ethyl-2-(2-(2-hydroxyethyl)phenyl)acetamide

Dissolve 2-(2-(2-(ethylamino)-2-oxyethyl)phenyl)acetic acid (7g, 31.5mmol) in tetrahydrofuran (10mL), and add borane (37.8mL, 37.8 mL) dropwise at 0°C. mmol), the dropwise addition was completed, and the system reacted for 3 hours at 25°C. LCMS detected that the reaction was complete. Methanol was added to the system to quench the reaction. After water washing, ethyl acetate extraction, organic phase concentration, and silica gel column purification (methanol/dichloromethane=1 :10) 5g of the target compound was obtained with a yield of 76.3%.

4. Preparation of 2-(2-(ethylamino)-2-oxyethyl)phenylethyl methanesulfonate

Dissolve N-ethyl-2-(2-(2-hydroxyethyl)phenyl)acetamide (5g, 24mmol) in tetrahydrofuran (10mL), and add methanesulfonyl chloride (5.6g, 48mmol) dropwise at 0°C. and triethylamine (7.3g, 72mmol). After the dropwise addition, the system reacted for 3 hours at 0°C. LCMS detected that the reaction was complete. Water was added to the system to quench the reaction. It was extracted with ethyl acetate, the organic phase was concentrated, and purified on a silica gel column (methanol / dichloromethane = 1:10) to obtain 4.9 g of the target compound, with a yield of 71.4%.

5. Preparation of 3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine-2-one

Dissolve 2-(2-(ethylamino)-2-oxyethyl)phenylethylmethanesulfonate (4.5g, 15.7mmol) in N,N-dimethylformamide (10mL), 0°C Sodium hydride (1.2g, 31.4mmol) was added dropwise. After the dropwise addition, the system reacted at 0°C for 2 hours. LCMS detected that the reaction was complete. Water was added to the system to quench the reaction, extracted with ethyl acetate, and the organic phase was concentrated and purified on a silica gel column. (Ethyl acetate/petroleum ether=1:1) 2.35g of crude product was obtained.

6. Preparation of 3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepine-2-one

Dissolve 3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine-2-one (2.35g, crude product) in concentrated sulfuric acid (10mL), and add it at 0°C After the dropwise addition of potassium nitrate (1.4g, 13.8mmol), the system reacted at 0°C for 2 hours, and LCMS detected that the reaction was complete. The reaction solution was added dropwise to ice water to quench the reaction. After extraction with ethyl acetate, concentration of the organic phase, and purification on a silica gel column (ethyl acetate/petroleum ether = 1:3), 1 g of the target compound was obtained. The two-step yield was 27.1%.

7. Preparation of 8-amino-3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine-2-one

Dissolve 3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (1g, 4.3mmol) in methanol (20mL), Add Pd/C (500 mg), react at 25°C for 2 hours, and detect the completion of the reaction by LCMS. Filter and spin the filtrate to obtain 860 mg of the target compound, with a yield of 90.4%.

8. Preparation of N-(3-ethyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve 8-amino-3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepine-2-one (860 mg, 4.20 mmol) in acetic acid (10 mL). Acetic anhydride (2 mL) was added and the reaction was carried out at 25°C for 2 hours. LCMS detected that the reaction was complete. The reaction solution was spun to dryness, diluted with dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was spun to dryness, and separated and purified by silica gel column chromatography (methanol/dichloromethane=1:1) to obtain 650 mg of the target compound, with a yield of 62.7%.

9. Preparation of N-(3-ethyl-8-nitro-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide

Dissolve N-(3-ethyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide (580 mg, 2.35 mmol) in In concentrated sulfuric acid (10 mL), fuming nitric acid (181 mg, 2.82 mmol) was added dropwise at 0°C and reacted at 25°C for 2 hours. LCMS detected that the reaction was complete. The reaction solution was added dropwise to ice and water to quench the reaction. The organic phase was extracted with dichloromethane. Phase concentration and silica gel column purification (methanol/dichloromethane=1:10) yielded 230 mg of the target compound, with a yield of 33.5%.

10. Preparation of 7-amino-3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepine-2-one

N-(3-ethyl-8-nitro-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-yl)acetamide (230 mg, 0.79mmol) was dissolved in methanol (10mL), potassium carbonate (327mg, 2.37mmol) was added, and the reaction was carried out at 25°C for 4h. LCMS detected that the reaction was complete, the reaction liquid was spin-dried, and the crude product was purified by a silica gel column (methanol/dichloromethane=1: 10) Obtain 190 mg of the target compound, with a yield of 96.54%

11. 2-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d] Preparation of azepine-2-yl)ethyl acetate

Dissolve 7-amino-3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepine-2-one (190 mg, 0.76 mmol) in ethanol (10mL), add Pd/C (120mg), react at 25°C for 2h, LCMS detects that the reaction is complete, add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (297mg, 1.52mmol), 50 The reaction was carried out for 2 hours at ℃, and LCMS detected that the reaction was completed. Filter, spin the filtrate to dryness, dilute with dichloromethane, wash with saturated aqueous sodium bicarbonate solution, spin the organic phase to dryness, and separate by silica gel column chromatography (methanol/dichloromethane = 1:10) to obtain 150 mg of the target compound, with a yield of 62.4%. .

12. 7-amino-6-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 , Preparation of 2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

2-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]nitrogen Azo-2-yl)ethyl acetate (100 mg, 0.32 mmol) and 3-aminothiophene-2-carbonitrile (40 mg, 0.32 mmol) were dissolved in tetrahydrofuran (10 mL), and LDA (1 mL, 1.92 mmol) was added at 40°C. ), react at 40°C for 2 hours, and LCMS detects that the reaction is complete. The reaction solution was poured into a saturated aqueous ammonium chloride solution to quench, extracted with ethyl acetate, the organic phase was spin-dried, and slurried with methanol to obtain 18.5 mg of the target compound, with a yield of 14.7%.

Molecular formula: C ₂₀ H ₁₉ N ₅ O ₂ S Molecular weight: 393.5 LC-MS(M/e): 394.0(M+H+)

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.80 (d, J = 6.0 Hz, 1H), 11.79 (d, J = 6.8 Hz, 1H), 10.50-10.70 (br s, 1H), 7.94 ( d,J＝4.2Hz,1H),7.80-7.94(br s,1H),7.30-7.45(m,2H),7.03(d,J＝4.2Hz,1H),3.88(d,J＝9.2Hz, 2H),3.71(t,J＝5.2Hz,1H),3.35-3.40(m,2H),3.21(s,2H),1.03(t,J＝7.2Hz,3H).

Preparation Example 38: 7-amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydro-5,9-bridgemethyleneimidazole [4',5':4, Preparation of 5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (compound 54)

1. Preparation of 7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methanol benzo[d]azepine

1-(7,8-dinitro-1,2,4,5-tetrahydro-3H-1,5-methoxybenzo[d]azepine-3-yl)-2,2, 2-Trifluoroethane-1-one (200.0 mg, 0.58 mol) was dissolved in methanol (8 mL) and water (3 mL), sodium carbonate (127.2 mg, 1.2 mmol) was added, and the reaction was continued for 16 hours. Water was added to the system to quench the reaction, and the mixture was extracted with dichloromethane (100 mL). The organic phase was dried and concentrated to obtain 170 mg of crude target compound, which was directly used in the next reaction.

2. Preparation of 3-cyclopropyl-7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine

Dissolve 7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methanolbenzo[d]azepine (crude product) (170.0 mg, 0.68 mmol) in methanol (10.0 mL), add acetic acid (432.0mg, 7.2mmol), sodium cyanoborohydride (276.3mg, 4.4mmol) and (1-ethoxycyclopropoxy)trimethylsilane (278.9mg, 1.6mmol), The system reacted at 65°C for 3 hours. Water was added to the system to quench the reaction, and the organic phase was extracted with dichloromethane. The organic phase was concentrated and purified by a silica gel column (ethyl acetate/petroleum ether = 2:3) to obtain 127.0 mg of the target compound. The two-step yield was 75.7%.

3. Preparation of 3-cyclopropyl-7,8-diamino-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine

Dissolve 3-cyclopropyl-7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine (320.0 mg, 1.1 mmol) To ethanol (10 mL), Pd/C (200.0 mg) was added, and the system was placed in a hydrogen atmosphere at 25°C for a hydrogenation reaction for 40 minutes. The reaction solution was directly used in the next reaction.

4. 2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine Preparation of -2-yl)ethyl acetate

Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (508.6 mg.2.6 mmol) to the reaction solution in the previous step, and raise the temperature to 50°C for 2 hours. Filter through diatomaceous earth, concentrate and spin the filtrate to dryness, add water to dilute, adjust the pH to alkaline with sodium bicarbonate solution, extract with dichloromethane (100 mL), dry and concentrate the organic phase, and purify on a silica gel column (dichloromethane: methanol = 10 :1), 250.0 mg of the target compound was obtained, yield (two steps): 69.4%.

5. 7-Amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydro-5,9-oxomethyleneimidazole [4',5':4,5] Preparation of benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (250 mg, 0.66 mmol) was dissolved in tetrahydrofuran (15 mL), 2-aminothiophene-3-carbonitrile (113.1 mg, 0.91 mmol) was added, and the mixture was placed at 40°C under a nitrogen atmosphere. Lithium diisopropylamide (1.5 mL, 3.0 mmol) was added and stirring was continued for 1 hour. Ammonium chloride aqueous solution was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried, concentrated, and purified on a silica gel column (ethyl acetate = 100%) to obtain 19.0 mg of the target compound, yield: 7.1%.

Molecular formula: C ₂₂ H ₂₁ N ₅ OS Molecular weight: 403.5 LC-MS (M/e): 404.0 (M+H ⁺ )

¹ H-NMR (400MHz, CDCl ₃ ) δ: 12.75 (s, 1H), 11.75 (s, 1H), 10.72-10.52 (m, 1H), 7.94 (d, J = 8.8HZ, 1H), 7.91-7.67 (m,1H),7.36(s,1H),7.28(s,1H),7.01(d,J＝5.2HZ,1H),3.20-3.10(m,2H),2.92-2.82(m,2H), 2.64-2.50(m,2H),2.25-2.15(m,1H),1.85-1.75(m,1H),1.70-1.60(m,1H),0.30-0.20(m,2H),-0.1--0.2 (m,2H).

Preparation Example 39: 7-amino-6-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazole[4',5]:4,5]benzo Preparation of [1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 55)

1. 2-(7-Cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2- d] Preparation of azepine-2-yl)ethyl acetate

Using 1,5-dihydrobenzo[d]oxazepine-2,4-dione and cyclopropylamine as starting materials, and referring to the preparation method of Preparation Example 37, 2-(7-cyclopropyl-6 -Oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)ethyl acetate ester.

2. 7-amino-6-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazole[4',5]:4,5]benzo[1 , Preparation of 2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

2-(7-Cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d ]Azepine-2-yl)ethyl acetate (32.7 mg, 0.1 mmol) and 2-cyano-3-aminothiophene (12.4 mg, 0.1 mmol) were dissolved in tetrahydrofuran (5 mL), and the temperature was raised to Add 2M lithium diisopropylamide solution (0.25 mL, 0.5 mmol) dropwise at 40°C, complete the addition, and react at 40°C for 3 hours. LCMS detects the end of the reaction. The temperature was lowered to 25°C, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried and concentrated. The obtained solid was slurried with methanol, filtered to obtain a solid, and the solid was dried to obtain 14.5 mg of the title compound. Yield: 35.8%.

Molecular formula: C ₂₁ H ₁₉ N ₅ O ₂ S Molecular weight: 405.5 LC-MS (M/e): 406.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.80 (s, 1H), 11.81 (m, 1H), 7.94 (d, J = 5.2Hz, 1H), 7.89 (m, 1H), 7.41 (s ,1H),7.36(s,1H),7.01(d,J＝5.2Hz,1H),3.87(s,2H),3.72-3.70(m,2H),3.15-3.20(m,2H),2.65- 2.75(m,1H),0.69-0.71(m,2H),0.60-0.62(m,2H).

Preparation Example 40: 7-((2,2-difluoroethyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexane Hydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one trifluoro Preparation of acetate salt (trifluoroacetate salt of compound 58)

1. 2-(7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 , Preparation of 2-d]azepine-7(1H)-carboxylic acid tert-butyl ester

2-(4-(4-Methoxybenzyl)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothieno[3,2 -b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1 ,2-d]Azepine-7(1H)-carboxylic acid tert-butyl ester (500mg, 0.60mmol), was dissolved in acetonitrile (5mL), and 2,2-difluoroethyl-1-amine (388mg, 4.78mmol), react at 40℃ for 2h. LCMS detects that the reaction is complete, spins the solvent dry, and separates through silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain 300 mg of the target compound, with a yield of 65.4%.

2. 7-((2,2-difluoroethyl)amino)-6-(1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[ Preparation of 1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2- b]pyridin-6-yl)-1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1, 2-d]Azepine-7(1H)-carboxylic acid tert-butyl ester (300 mg, 0.39 mmol) was dissolved in trifluoroacetic acid (3.5 ml) and hydrochloric acid (0.5 mL), heated to 110°C, reacted for 24 hours, and detected by LCMS The reaction is complete. Spin the reaction liquid to dryness, adjust the system pH=8 with saturated aqueous sodium bicarbonate solution, extract with dichloromethane, dry and concentrate to obtain 200 mg of crude target compound.

3. 7-((2,2-difluoroethyl)amino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazole And[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one trifluoroacetic acid Preparation of salt

7-((2,2-Difluoroethyl)amino)-6-(1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1 ,2-d]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (200mg, N/A) was dissolved in methanol (5mL), and oxetane was added Alkane-3-one (30 mg, 0.40 mmol) and acetic acid (144 mg, 2.4 mmol) were reacted at 25°C for 1 hour. Then sodium cyanoborohydride (150 mg, 2.4 mmol) was added and the reaction was continued for 8 hours. LCMS detected that the reaction was complete. . Add sodium bicarbonate aqueous solution to the system, extract with dichloromethane, collect the organic phase solvent and spin dry, and perform reverse-phase column chromatography (methanol/water = 0-40%, each of the two phases contains 0.3% trifluoroacetic acid) to obtain The target compound was 19 mg, and the yield was 37.8%.

Molecular formula: C ₂₅ H ₂₄ F ₅ N ₅ O ₃ S Molecular weight: 569.15 LC-MS(M/e): 472.5(M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.06 (s, 1H), 12.35-12.33 (m, 1H), 12.04 (s, 1H), 11.07 (s, 1H), 8.09-8.07 (d, J＝5.6Hz,1H),7.54-7.47(m,2H),7.10-7.08(d,J＝5.6Hz,1H),6.46-6.33(m,1H),4.91-4.89(m,2H),4.75 -4.72(m,2H),4.47-4.41(m,3H),3.54-3.48(m,4H),3.12-3.10(m,2H),2.88-2.86(m,2H).

Preparation Example 41: 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2 Preparation of -d]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)thieno[3,2-b]pyridin-5(4H)-one (compound 59)

1. 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d Preparation of ]imidazol-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d] Imidazol-2-yl)ethyl acetate (130 mg, 0.4 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4 (1H)-Diketone (173 mg, 0.6 mmol) was dissolved in tetrahydrofuran (20 mL), and the temperature was raised to 40°C. LDA (2 mL, 4 mmol) was added under nitrogen protection. After the addition was completed, the reaction was carried out for 2 hours. LCMS detects the end of the reaction. Add saturated ammonium chloride solution to quench, extract with a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol=10:1 (100mL×4)), dry and concentrate the organic phase, and purify on a silica gel column (dichloromethane:methanol) =10:1) to obtain 190 mg of the title compound, with a yield of 90%.

2. 6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptanyl [4,5]benzo[1,2-d]imidazol-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2 Preparation of -b]pyridin-7-yl trifluoromethanesulfonate

At 0°C, 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1, 2-d]imidazol-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (190 mg, 0.36 mmol) dissolved To dichloromethane (100 mL), pyridine (285 mg, 3.3 mmol) and trifluoromethanesulfonic anhydride (620 mg, 2 mmol) were added, and the reaction was carried out for 1 hour. LCMS detects the end of the reaction. The solvent was concentrated, saturated sodium bicarbonate was added to quench the reaction, and dichloromethane (100 mL × 4 times) was extracted. The organic phase was dried and concentrated to obtain 390 mg of crude title compound, which was put into the next step without further treatment.

3. 6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptanyl [4,5]benzo[1,2-d]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thieno Preparation of [3,2-b]pyridin-5(4H)-one

6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl[ 4,5]benzo[1,2-d]imidazol-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothieno[3,2- b] Pyridin-7-yl trifluoromethanesulfonate (390 mg) was dissolved in acetonitrile (100 mL), difluoroethylamine (291 mg, 3.6 mmol) was added, and the temperature was raised to 40°C and reacted for 4 hours. LCMS detects the end of the reaction. The organic phase was dried and concentrated, and purified by silica gel column (dichloromethane:methanol=10:1) to obtain 140 mg of the title compound, with a two-step yield of 66%.

4. 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d Preparation of ]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl[ 4,5]benzo[1,2-d]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thieno[ 3,2-b]pyridin-5(4H)-one (140 mg, 0.24 mmol) was placed in a 100 mL single-mouth bottle, trifluoroacetic acid (6 mL) and concentrated hydrochloric acid (1 mL) were added, and the temperature was raised to 110°C for 24 hours. LCMS detects the end of the reaction. The organic phase was concentrated and purified by reverse-phase column chromatography (water:methanol=10:3) to obtain 52 mg of the title compound, with a yield of 57%.

Molecular formula: C ₂₄ H ₂₅ F ₂ N ₅ OS Molecular weight: 469.6 LC-MS (M/e): 470.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.22 (s, 1H), 7.99 (d, J = 5.6Hz 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.07 (d, J＝5.6Hz 1H),6.57-6.29(t,J＝15.2Hz,1H),4.37-4.28(m,2H),3.12-3.08(m,4H),2.95-2.90(m,2H),2.71- 2.65(m,2H),2.34(s,1H),2.26-2.23(m,1H),2.00-1.90(m,1H),1.89-1.75(m,4H),1.15-1.08(m,2H).

Preparation Example 42: 7-amino-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazole- Preparation of 2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 60)

1. Preparation of 7-amino-1,2,4,5-tetrahydrobenzo[d]oxazepine

Dissolve 7-nitro-1,2,4,5-tetrahydrobenzo[d]oxazepine (140mg, 0.73mmol) in methanol (5mL), add palladium on carbon (100mg, N/A), and mix under hydrogen React in the atmosphere for 2 hours. LCMS detects the end of the reaction. Filter, collect the filtrate and concentrate to obtain the crude target compound, which is directly used in the next step.

2. Preparation of N-(1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide

Dissolve 7-amino-1,2,4,5-tetrahydrobenzo[d]oxazepine (crude product from the previous step) in acetic acid (2mL), add acetic anhydride (2mL), and react at 15°C for 1 hour. . LCMS detects the end of the reaction. Dilute with water, adjust pH=9 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, concentrate the aqueous phase, and purify through C18 column (methanol=0-80%) to obtain 100 mg of the target compound, with a two-step yield of 66.8%.

3. Preparation of N-(8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazepin-7-yl)acetamide

Dissolve N-(1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide (100mg, 0.49mmol) in concentrated sulfuric acid (2mL), add it dropwise at 0°C to produce fuming Nitric acid (38 mg, 0.61 mmol) was added, and the reaction was carried out at 0°C for 10 minutes. LCMS detects the end of the reaction. Pour into ice water, adjust pH=7 with sodium hydroxide aqueous solution, concentrate the solvent, wash the solid with dichloromethane and methanol, and concentrate the organic phase to obtain a crude target compound, which is directly used in the next step.

4. Preparation of 8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazepine-7-amine

Dissolve N-(8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazol-7-yl)acetamide (N/A, 0.49mmol) in methanol (5mL), and add Potassium carbonate (166 mg, 1.2 mmol) was added and reacted at 55°C for 8 hours. LCMS detects the end of the reaction. Filter through diatomaceous earth, concentrate the filtrate, and purify through C18 column (methanol = 0-80%) to obtain 80 mg of the target compound, with a yield of 78.1%.

5. Ethyl 2-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)acetate Preparation of esters

Dissolve 8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazepine-7-amine (80mg, 0.38mmol) in ethanol (3mL), add Pd/C (100mg), and add Afterwards, the hydrogenation reaction was carried out at 15°C for 2 hours. LCMS detects the end of the reaction. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (149 mg, 0.76 mmol), raise the temperature to 50°C and react for 2 hours. LCMS detects the end of the reaction. Filter through diatomaceous earth, concentrate the filtrate, and purify through silica gel column (dichloromethane: methanol = 15:1) to obtain 100 mg of the target compound, with a yield of 94.9%.

6. 7-Amino-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazole-2- Preparation of thieno[3,2-b]pyridin-5(4H)-one

2-(5,6,8,9-Tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)acetate (50 mg, 0.18 mmol) and 3-aminothiophene-2-carbonitrile (27 mg, 0.22 mmol) were dissolved in tetrahydrofuran (2 mL), LDA (0.41 mL, 0.81 mmol) was added, and the reaction was completed at 40°C for 2 hours. LCMS detects the end of the reaction. Saturated ammonium chloride was added to quench the reaction, and dichloromethane was extracted. The organic phase was dried, concentrated, and slurried with methanol to obtain 5 mg of the target compound, with a yield of 7.98%.

Molecular formula: C ₁₈ H ₁₆ N ₄ O ₂ S Molecular weight: 352.1 LC-MS(M/e): 353.1(M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.78 (s, 1H), 11.81 (s, 1H), 10.60 (s, 1H), 7.98-7.93 (m, 2H), 742 (d, J＝ 5.2Hz,2H),7.02-7.00(m,1H),3.92-3.88(m,4H),3.17-3.00(m,4H).

Preparation Example 43: 7-((2,2-difluoroethyl)amino)-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5 Preparation of ]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 61)

1. 7-hydroxy-4-(4-methoxybenzyl)-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzene Preparation of [1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(5,6,8,9-Tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)acetate (500mg, 1.8mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (686mg, 2.4 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, add LDA (4.5 mL, 5 mol) at 40°C, complete the addition, and react at 40°C for 1 hour. LCMS detects the end of the reaction, cools down to 15°C, quenches the reaction with saturated aqueous ammonium chloride solution, extracts with dichloromethane, dries the organic phase, and concentrates to obtain the crude target compound. Add the crude target compound to tetrahydrofuran (10 mL) again, add LDA (4.5 mL, 5 mol) under nitrogen protection, complete the addition, and react at 40°C for 1 hour. Cool the temperature to 15°C, add saturated aqueous ammonium chloride solution to quench the reaction, extract with dichloromethane, and dry, concentrate, and purify the organic phase on a silica gel column (dichloromethane:methanol=20:1) to obtain 320 mg of the target compound, with a yield of 37.1%. .

2. 4-(4-methoxybenzyl)-5-oxo-6-(1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydro-1H-oxa Zozo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)-4,5-dihydrothieno[3,2-b]pyridin-7-yltri Preparation of fluoromethanesulfonate

7-Hydroxy-4-(4-methoxybenzyl)-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo [1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (320 mg, 0.68 mmol) was dissolved in dichloromethane (10 mL) and added at 0°C After adding pyridine (1.1g, 13.6mmol) and trifluoromethanesulfonic anhydride (1.2g, 4.1mmol), react at 0°C for 30 minutes. LCMS detects the end of the reaction. Add saturated sodium bicarbonate aqueous solution to quench the reaction, extract with dichloromethane, dry and concentrate the organic phase, and use it directly in the next step.

3. 7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-5,6, 8,9-Tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridine- Preparation of 5(4H)-ketone

4-(4-Methoxybenzyl)-5-oxo-6-(1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydro-1H-oxazole And[4',5':4,5]benzo[1,2-d]imidazol-2-yl)-4,5-dihydrothieno[3,2-b]pyridin-7-yltrifluoro Methanesulfonate (N/A, 0.68mmol) was dissolved in acetonitrile (10mL), 2,2-difluoroethyl-1-amine (440mg, 5.4mmol) was added, and the reaction was completed at 40°C for 2 hours. LCMS detects the end of the reaction. The reaction solution was concentrated and purified on a silica gel column (dichloromethane: methanol = 20:1) to obtain 130 mg of the target compound, with a two-step yield of 28.6%.

4. 7-((2,2-difluoroethyl)amino)-6-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzene Preparation of [1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one

7-((2,2-Difluoroethyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-5,6,8 ,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridine-5 (4H)-ketone (130 mg, 0.19 mmol) was dissolved in concentrated hydrochloric acid (1.5 mL), trifluoroacetic acid (10.5 mL) was added, and the mixture was raised to 110°C to react for 24 hours. LCMS detects the end of the reaction. The solvent was concentrated, dichloromethane was dissolved, saturated sodium bicarbonate aqueous solution was added, filtered, and the filter cake was slurried with methanol to obtain 40 mg of the target compound, with a yield of 50.5%.

Molecular formula: C ₂₀ H ₁₈ F ₂ N ₄ O ₂ S Molecular weight: 416.4 LC-MS(M/e): 417.1(M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.96 (s, 1H), 12.38 (s, 1H), 12.03 (s, 1H), 8.04 (d, J = 5.2Hz, 1H), 7.44 (s ,1H),7.32(s,1H),7.07(d,J＝4.8Hz,1H),6.75-6.38(m,1H),4.38-4.31(m,2H),3.88-3.74(m,4H), 3.02-2.98(m,4H).

Preparation Example 44: 7-amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2 Preparation of -d]azepin-2-yl)-1-methyl-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (compound 62)

2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (50 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), and 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (20 mg, 0.16 mmol) was added under nitrogen protection. Add lithium diisopropylamide (0.40 mL, 0.80 mmol) at 40°C, complete the addition, and react at 40°C for 2 hours. LCMS detects the end of the reaction. Saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried, concentrated, and slurried with methanol to obtain 33 mg of the title compound, with a yield of 53.0%.

Molecular formula: C ₂₁ H ₂₃ N ₇ O Molecular weight: 389.5 LC-MS (M/e): 390.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.90 (s, 1H), 11.23 (s, 1H), 7.40-7.35 (m, 3H), 4.27 (s, 3H), 2.90-2.85 (m, 4H),2.75-2.65(m,4H),1.78-1.76(m,1H),0.49-0.43(m,4H).

Preparation Example 45: 7-amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[ Preparation of 1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (compound 63)

1. Preparation of 2-nitro-5,6,8,9-tetrahydro-7H-benzo[7]annen-7-one

Dissolve 5,6,8,9-tetrahydro-7H-benzo[7]annen-7-one (2.0g, 12.4mmol) in concentrated sulfuric acid (20mL). After stirring for 1 hour, slowly add nitric acid in batches. Potassium (1.5g, 14.9mmol), after addition, react at 0°C for 2 hours. LCMS detects the end of the reaction. Pour into ice water (200 mL), extract with ethyl acetate (100 mL × 4 times), dry and concentrate the organic phase, and purify on a silica gel column (n-heptane: ethyl acetate = 5:1) to obtain 2.0 g of the title compound, yield 79 %.

2. Preparation of 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annen-7-yl)azetidine

Dissolve 2-nitro-5,6,8,9-tetrahydro-7H-benzo[7]annen-7-one (2.0g, 9.7mmol) in methanol (100mL), add cyanohydroboration Sodium (1.6g, 23.5mmol) and azetidine (673mg, 11.8mmol) were added and reacted at 35°C for 12 hours. LCMS detects the end of the reaction. The solvent was concentrated, saturated sodium bicarbonate was added to quench the reaction, extracted with ethyl acetate (100 mL × 4 times), the organic phase was dried and concentrated, and purified on a silica gel column (dichloromethane: methanol = 10:1) to obtain 2.3 g of the title compound, yield 96%.

3. Preparation of 7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annen-2-amine

Dissolve 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annen-7-yl)azetidine (2.3g, 9.3mmol) in methanol ( 100 mL), add Raney nickel (790 mg, 9.3 mmol), and react at 30°C for 4 hours. LCMS detects the end of the reaction. Filter through diatomaceous earth and concentrate to obtain 1.6 g of the title compound, with a crude product yield of 80%.

4. Preparation of N-(7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annen-2-yl)acetamide

Place 7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annen-2-amine (1.6g, 7.5mmol) in a single port of 100 mL In the bottle, add acetic acid (5mL) and acetic anhydride (5mL), and react at 25°C for 1 hour. LCMS detects the end of the reaction. Concentrate to semi-dryness, quench with saturated sodium bicarbonate, extract with a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol=5:1) (100mL×4 times), dry and concentrate the organic phase, and purify on a silica gel column (dichloro Methane: methanol = 10:1) to obtain 1.5 g of the title compound, with a yield of 78%.

5. N-(7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annen-2-yl)ethyl Preparation of amides

N-(7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annen-2-yl)acetamide (1.5g, 5.9 mmol) in concentrated sulfuric acid (15 mL), stir at 0°C for 1 hour, add potassium nitrate (656 mg, 6.5 mmol) in batches, complete the addition, and react at 0°C for 1 hour. LCMS detects the end of the reaction. Pour into ice water, quench the reaction with saturated sodium carbonate, extract with a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol=10:1) (200mL×4 times), dry and concentrate the organic phase, and purify on a silica gel column (two times). Methyl chloride: methanol = 10:1) to obtain 1.6 g of the title compound, with a yield of 89%.

6. Preparation of 7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annen-2-amine

N-(7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annen-2-yl)acetamide (1.6g, 5.3mmol) was dissolved in methanol (100mL), and potassium carbonate (2.2g, 15.8mmol) was added. After the addition was completed, the reaction was continued at 50°C for 4 hours. LCMS detects the end of the reaction. Suction filtration through diatomaceous earth, drying and concentrating the organic phase for silica gel column purification (dichloromethane: methanol ester = 10:1) gave 854 mg of the title compound, with a yield of 62%.

7. 2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d] Preparation of imidazol-2-yl)ethyl acetate

7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]cycloen-2-amine (854 mg, 3.3 mmol) Dissolve in ethanol (50 mL), add Pd/C (489 mg, 1.7 mmol), complete the addition, and hydrogenate at 25°C for 8 hours. LCMS detects the end of the reaction. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (1.5g, 7.9mmol), raise the temperature to 50°C, stir and reflux for 3 hours, and detect the end of the reaction by LCMS. Celite was added to filter, and the organic phase was dried and concentrated for silica gel column purification (dichloromethane: methanol ester = 10:1) to obtain 755 mg of the title compound, with a two-step yield of 70.6%.

8. 7-Amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1, Preparation of 2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one

2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazole -2-yl)ethyl acetate (755 mg, 2.3 mmol) and 2-cyano-3-aminothiophene (682 mg, 5.5 mmol) were dissolved in tetrahydrofuran (15 mL). The temperature was raised to 40°C under nitrogen protection, and LDA was slowly added. (1.2mmol, 0.6mL), after addition, react at 40°C for 2 hours. LCMS detects the end of the reaction. Add saturated ammonium chloride aqueous solution to quench the reaction, extract with ethyl acetate, dry and concentrate the organic phase, extract with a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol=10:1) (200mL×4 times), and dry the organic phase Concentrate and purify on silica gel column (dichloromethane:methanol=10:1) to obtain 401 mg of the title compound, yield: 43%.

Molecular formula: C ₂₂ H ₂₃ N ₅ OS Molecular weight: 405.5 LC-MS (M/e): 406.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.73 (s, 1H), 11.79 (s, 1H), 7.94-7.93 (d, J = 5.2Hz, 1H), 7.38 (s, 1H), 7.33 (s,1H),7.01-7.00(d,J＝5.2Hz,1H),3.12-3.09(m,4H),2.93-2.92(m,2H),2.70-2.63(m,2H),2.49-2.51 (m,1H),1.90-1.80(m,4H),1.30-1.23(m,2H).

Preparation Example 46: 7-(isopropylamino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4', 5: Preparation of 4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (compound 64)

6-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7 -(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (120 mg, 0.30 mmol) was dissolved in methanol (10 mL), and 3-oxetanone (90 mg, 0.54 mmol) and acetic acid (186 mg, 0.18 mmol), react at 25°C for 30 minutes, add sodium cyanoborohydride (96 mg, 0.54mmol), complete the addition, and react at 35°C for 16 hours. LCMS detects the end of the reaction. Add saturated sodium bicarbonate to adjust pH=8, extract with dichloromethane (40 mL), and separate with silica gel column chromatography (methanol:dichloromethane=1:15) to obtain 60 mg of the target compound, with a yield of 43.8%.

Molecular formula: C ₂₄ H ₂₇ N ₅ O ₂ S Molecular weight: 449.6 LC-MS (M/e): 450.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.00 (s, 1H), 12.15 (d, J = 8.2, 1H), 11.86 (s, 1H), 8.03 (d, J = 5.2, 1H), 7.40(s,1H),7.34(s,1H),7.04(s,1H),4.54-4.45(m,5H),3.49-3.47(m,1H),3.01-2.85(m,4H),2.49- 2.25(m,4H),1.50-1.40(m,6H).

Preparation Example 47: 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2- d]imidazol-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one (compound 65)

1. 6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl[ 4,5]benzo[1,2-d]imidazol-2-yl)-7-(isopropylamino)-4-(4-methoxybenzyl)thieno[3,2-b]pyridine Preparation of -5(4H)-ketone

6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptane[4, 5]benzo[1,2-d]imidazol-2-yl)-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrothieno[3, 2-b] Pyridin-7-yl trifluoromethanesulfonate (315 mg, 0.4 mmol) and isopropylamine (235 mg, 4 mmol) were dissolved in acetonitrile (50 mL), heated to 40°C and reacted for 3 hours. LCMS detects the end of the reaction. Separate by column chromatography and purify on silica gel column (dichloromethane:methanol=10:1) to obtain 157 mg of the title compound, with a yield of 56.5%.

2. 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d] Preparation of imidazol-2-yl)-7-(isopropylamino)thieno[3,2-b]pyridin-5(4H)-one

6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocycloheptyl[4 ,5]benzo[1,2-d]imidazol-2-yl)-7-(isopropylamino)-4-(4-methoxybenzyl)thieno[3,2-b]pyridine- 5(4H)-one (157 mg, 0.22 mmol) was placed in a 100 mL single-neck bottle, trifluoroacetic acid (6 mL) and concentrated hydrochloric acid (1 mL) were added, and the temperature was raised to 110°C and the reaction was carried out for 24 hours. LCMS detects the end of the reaction. The organic phase was concentrated and purified by reverse-phase column chromatography (water: methanol = 10:3) to obtain 38 mg of the target compound, with a yield of 39%.

Molecular formula: C ₂₅ H ₂₉ N ₅ OS Molecular weight: 447.6 LC-MS (M/e): 480.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 13.08-13.03 (d, J＝5.2Hz, 1H), 12.15-12.13 (d, J＝5.2Hz, 1H), 8.02-8.00 (d, J＝ 5.2Hz,1H),7.43-7.37(d,J＝5.2Hz,1H),7.30(s,1H),7.06(s,1H),7.04(s,1H),4.43-4.48(m,1H), 3.08-3.30(m,4H),2.6-2.7(m,2H),2.49-2.51(m,2H),2.32-2.30(m,1H),2.24-2.23(m,4H),2.22-2.00(m ,6H),1.89-1.97(m,2H).

Preparation Example 48: 2-(7-amino-1-methyl-5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-6-yl)-7-cyclo Propyl-5,7,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-6(1H)-one (compound 66)

2-(7-Cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d ]Azepine-2-yl)ethyl acetate (200mg, 0.61mmol) was dissolved in tetrahydrofuran (10mL), and 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (89mg, 0.73mmol) was added ), add LDA (2.44mL, 4.88mmol) dropwise at 40°C, continue the reaction for 6 hours, and LCMS detects that the reaction is complete. Pour into saturated ammonium chloride aqueous solution to quench, extract with ethyl acetate, spin the organic phase to dryness, and slurry with methanol to obtain 40 mg of crude target compound, which is purified by reverse-phase chromatography (methanol: water = 0-50%) to obtain 2.4 mg of the target compound. Yield 1.0%.

Molecular formula: C ₂₁ H ₂₁ N ₇ O ₂ Molecular weight: 403.4 LC-MS (M/e): 404.1 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.93 (d, J = 10.4Hz, 1H), 11.23 (d, J = 7.9Hz, 1H), 7.35-7.45 (m, 3H), 4.46 (s ,3H),4.26(s,3H),3.88(d,J＝11.6Hz,2H),3.71(t,J＝5.4Hz,2H),3.15-3.19(m,2H),2.68-2.72(m, 1H),0.68-0.73(m,2H),0.50-0.60(m,2H).

Preparation Example 49: 7-amino-1-methyl-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4', 5':4,5]benzo[1,2-d]azepin-2-yl)-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one Preparation (Compound 67)

1. Preparation of 8-nitro-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine

Dissolve 8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (500mg, 5.42mmol) and oxetanone (523mg, 7.26mmol) To methanol (20 mL), add acetic acid (1.5 g, 24.2 mmol) and sodium cyanoborohydride (900 mg, 14.5 mmol), and react at 25°C for 16 hours. LCMS detects that the reaction is complete. Adjust pH=7-8 with saturated sodium bicarbonate aqueous solution, extract with dichloromethane, spin the organic phase to dryness, and purify on a silica gel column (dichloromethane:methanol=15:1) to obtain 420 mg of the target compound, with a yield of 66.0%.

2. 2-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1 , Preparation of 2-d]azepin-2-yl)ethyl acetate

8-Nitro-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (420 mg, 1.6 mmol ) was dissolved in ethanol (10 mL), Pd/C (200 mg) was added, and hydrogenation was performed at 25°C for 2 hours. Add 3-ethoxy-3-iminopropionic acid ethyl ester hydrochloride (657 mg, 3.36 mmol), raise the temperature to 50°C and continue the reaction for 4 hours. LCMS detects that the reaction is complete. Filter through diatomaceous earth, spin the filtrate to dryness, dilute with dichloromethane, wash with saturated sodium bicarbonate, spin the organic phase to dryness, and purify through silica gel column (dichloromethane:methanol=10:1) to obtain 370 mg of the target compound, with a yield of 70.1%.

3. 7-amino-1-methyl-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5' : Preparation of 4,5]benzo[1,2-d]azepin-2-yl)-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one

2-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1, 2-d]Azepine-2-yl)ethyl acetate (80 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL), and 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (29 mg ,0.24mmol), add LDA (0.96mL, 1.92mmol) dropwise at 45℃, continue the reaction for 5h, and LCMS detects that the reaction is complete. Pour into saturated ammonium chloride aqueous solution to quench, extract with ethyl acetate, spin the organic phase to dryness, and beat with methanol to obtain 17.5 mg of the target compound, with a yield of 17.8%.

Molecular formula: C ₂₁ H ₂₃ N ₇ O ₂ Molecular weight: 405.5 LC-MS (M/e): 406.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.90 (s, 1H), 11.23 (s, 1H), 7.30-7.45 (m, 3H), 4.40-4.58 (m, 4H), 4.26 (s, 3H),3.40-3.50(m,1H),2.85-2.95(m,4H),2.35-2.45(m,4H).

Preparation Example 50: 7-amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocyclohepta[4,5]benzo Preparation of [1,2-d]imidazol-2-yl)-1-methyl-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (Compound 68)

2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazole -2-yl)ethyl acetate (200mg, 0.61mmol) and 3-amino-1,5-dimethyl-1hydro-pyrrole-2-cyano (112mg, 0.92mmol) were dissolved in tetrahydrofuran (50mL), Raise the temperature to 40°C under nitrogen protection, slowly add LDA (3.1mL, 6.1mmoL), complete the addition, and react at 40°C for 2 hours. LCMS detects the end of the reaction. Add saturated aqueous ammonium chloride solution to quench the reaction, extract with ethyl acetate, dry and concentrate the organic phase, extract with a mixed solvent of ethyl acetate/methanol (ethyl acetate:methanol=10:1, 200mL×4 times), dry and concentrate the organic phase. Purification by reverse-phase column chromatography (water:methanol=10:4) gave 100 mg of the target compound, with a yield of 40.6%.

Molecular formula: C ₂₂ H ₂₅ N ₇ O Molecular weight: 403.5 LC-MS (M/e): 404.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.87 (s, 1H), 11.21 (s, 1H), 7.39-7.33 (m, 3H), 4.27 (s, 3H), 7.33 (s, 1H) ,3.17-3.08(m,4H),2.98-2.94(m,2H),2.67-2.56(m,2H),2.33-2.26(m,1H),1.99-1.85(m,4H),1.23-1.4( m,2H).

Preparation Example 51: 4-amino-5-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2- Preparation of d]azepin-2-yl)-1-methyl-1,7-dihydro-6H-pyrazole[3,4-b]pyridin-6-one (compound 69)

2-(7-Cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine- 2-yl)ethyl acetate (100 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 mL), and 6-methyl-1-methyl-1H-pyrazole-4-carbonitrile (39 mg, 0.32 mmol) was added under nitrogen protection. Add LDA (2M, 1.3 mL, 2.6 mmol) at 40°C, complete the addition, and react at 40°C for 3 hours. LCMS detects the end of the reaction. Pour into saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate, dry and concentrate the organic phase, and then slurry with methanol and dichloromethane to obtain 10 mg of the target compound, with a yield of 8.1%.

Molecular formula: C ₂₁ H ₂₃ N ₇ O ₂ Molecular weight: 389.5 LC-MS (M/e): 390.2 (M+H ⁺ )

¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 12.17 (s, 1H), 10.71 (s, 1H), 10.55 (s, 1H), 7.60 (s, 1H), 7.33 (s, 1H), 7.25 (s,1H),7.10(s,1H),2.92(s,3H),2.91(s,4H),4.40-2.72(s,4H),1.75(s,1H),0.37-0.46(d,4H ).

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

Experimental program

The following provides exemplary experimental schemes for some compounds of the present invention to demonstrate the beneficial activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental solutions are only examples of the content of the present invention and do not limit the scope of the present invention.

Experimental Example 1 Inhibition experiment of in vitro kinase activity by compounds of the present invention

Test substances: some compounds of the present invention, their structural formulas and preparation methods are shown in the preparation examples of the present invention.

The abbreviations used in the following experiments have the following meanings:

DMSO: dimethyl sulfoxide;

HEPES: Hydroxyethylpiperazineethanesulfonic acid

Experimental method: Compounds were evaluated on 6 kinases in vitro using the Lantha screen Assay method.

Experimental steps:

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

2. Compound dilution:

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

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

2) Transfer 40 μl 100% DMSO into two empty wells as a positive control without compound and a negative control without enzyme;

3) Use Echo 550 to transfer 100nl of the compound into the 384-well test plate. The starting concentration of the compound for detection is 1 μM.

3. Prepare 2× kinase solution with 1× kinase buffer, transfer 5 μl of 2× kinase solution to the reaction well of the 384-well plate, add 1× kinase buffer to the negative control well, mix well by shaking at 450 rpm, and let stand at room temperature. Incubate for 10 minutes.

4. Use 1× kinase buffer to prepare 2× substrate solution, transfer 5 μl of 2× substrate solution to the reaction well of the 384-well plate, and shake at 450 rpm to mix.

5. Carry out the reaction at room temperature for 90 minutes.

6. Prepare 2× stop reaction solution containing antibody, transfer 10 μl of 2× stop reaction solution into the reaction well of the 384-well plate, centrifuge at 1000 rpm for 1 minute, and leave it at room temperature for 60 minutes before detection.

7. Data reading: Read the values excited at 340nm, emission at 520nm and 495nm on the Envision2104 Multilable Reader.

8.Data calculation

1) Convert the numerical ratio of fluorescence readings (Lantha signal (520nm/495nm)) into inhibition percentage through the formula:

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

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.

2) Import the data into MS Excel, and use XLFit excel add-in version 5.4.0.8 for curve fitting of the IC ₅₀ results.

Experimental results

Table 1 In vitro enzymatic inhibitory activity of the compounds of the present invention

Experimental results

The compound of the present invention has good inhibitory activity against MAP4K1/HPK1, and the compound of the present invention has excellent selectivity for HPK1.

Experimental Example 2 Inhibition experiment of the compounds of the present invention on in vitro cytological activity

Test substances: some compounds of the present invention, their structural formulas and preparation methods are shown in the preparation examples of the present invention.

The abbreviations used in the following experiments have the following meanings:

ELISA: enzyme-linked immunosorbent assay;

Jurkat: human acute T-cell leukemia cells;

SLP76: 76kDa leukocyte protein containing SH2 domain;

CD3: cluster of differentiation 3 (leukocyte differentiation antigen);

PBS buffer: phosphate balanced saline;

TMB: 3,3',5,5'-Tetramethylbenzidine.

Experimental method: ELISA method was used to detect the inhibitory level of the compound on the phosphorylation of serine 376 of SLP76 on Jurkat cells in vitro.

Experimental steps:

1. Cell preparation: Harvest Jurkat cells in the logarithmic growth phase and adjust to an appropriate cell concentration; add 81 μL of cell suspension per well to a 96-well plate.

2. Drug dilution and dosing:

1) Prepare a 10-fold drug solution with a maximum concentration of 3 μM, 3-fold dilution, and 6 concentrations;

2) Add 9 μL of drug solution to each well of a 96-well plate seeded with cells, and set two duplicate wells for each drug concentration. The cells in the 96-well plate were cultured at 37°C and 5% _CO2 for 1 h.

3. Cell stimulation: Add 10 μL of 50 μg/mL CD3 antibody to each well and treat for 30 min, then lyse the cells for pSLP76 detection.

4. Cell collection and lysis

1) Transfer the cells to a centrifuge tube by blowing up the air, and centrifuge at 3000 rpm and 4°C for 3 minutes;

2) Discard the supernatant, add 100 μL/well pre-cooled PBS buffer to resuspend, and centrifuge at 3000 rpm and 4°C for 3 min;

3) Discard the supernatant and add 100 μL/tube of cell lysis solution;

4) Ultrasonic lysis for 5 minutes and centrifugation at 14,000 rpm for 5 minutes.

5. pSLP76 detection

1) Transfer 50 μL/well sample supernatant to a 96-well plate;

2) Add 50 μL/well mixed antibody;

3) Shake at room temperature for 1 hour;

4) Discard the supernatant and wash 3 times with cleaning solution, 200 μL/well;

5) Add 100 μL/well TMB substrate and shake at room temperature for 15 minutes;

6) Add 100 μL/well stop solution and detect at 450nm within 30 minutes.

6. Data processing

Data were analyzed using GraphPad Prism 5.0 software, and nonlinear S-curve regression was used to fit the data to obtain a dose-response curve, from which the IC ₅₀ value was calculated.

pSLP76 inhibition (%) = (reading of test article wells - mean reading of cells without CD3 wells)/(mean reading of wells with cells plus CD3 - mean reading of wells with cells without CD3) × 100%

Experimental results

Experimental results prove that the compounds of the present invention have good inhibitory activity on the phosphorylation of serine 376 of the MAP4K1/HPK1 downstream protein SLP76, such as compound 1, compound 10, compound 11, compound 12, compound 14-1, compound 15, and compound 23 -1. The IC ₅₀ values of compound 26, compound 49, compound 50, compound 53, compound 55, compound 58, compound 63, compound 64, etc. are all less than 100 nM, that is, the compounds of the present invention have good inhibitory activity against HPK1.

Claims (14)

The compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer, in, X ¹ and Y ¹ are each independently selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-; X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )- or -S-; Y ² and Y ⁴ are independently selected from -C(R ² ) or -N-; Y ³ is selected from -C(R ⁵ ) or -N-; Y ⁵ is selected from -C(R ⁶ ); Y ⁶ is selected from -C(R ⁷ ) or -N-; Each R ² , R ³ , and each R ⁴ are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, C _{1- 6} alkoxy or halo C _1-6 alkoxy; One of R ⁵ and R ⁷ together with R ⁶ and the ring atoms connected to each of them form a 3-10-membered cycloalkyl group optionally substituted by 1-5 Q1, a 3-10-membered heterocyclyl group, a 6-10 Aryl or 5-10-membered heteroaryl; uncyclic R ⁵ or R ⁷ is selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, halogenated C _{1- 6} alkyl, C _1-6 alkoxy or halo C _1-6 alkoxy; R ¹ 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 , -C(O)OR ^a or any Select the following groups substituted by substituents: -(CH ₂ ) _p -3-10-membered cycloalkyl, -(CH ₂ ) _p -3-10-membered heterocyclyl, -(CH ₂ ) _p -5-10 Heteroaryl, -(CH ₂ ) _p -6-10 aryl; the substituent _is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 Alkoxy or halo C _1-6 alkyl; Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR ^a R ^b , -OR ^a , -SR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-3 Q2: C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, -(CH ₂ ) _m -3-10-membered cycloalkyl, -(CH ₂ ) _m -3-10-membered heterocyclyl, -(CH ₂ ) _m -5-10-membered heteroaryl or -( CH ₂ ) _m -6-10 yuan aryl _; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen Substituted C _1-6 alkyl group, halogenated C _1-6 alkoxy group, hydroxyl C _1-6 alkyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclyl group, 5-10 membered heteroaryl group or 6-10 yuan aryl group; Each R ^a and 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, halo C _1-6 alkyl, hydroxyl C 1-6 _{alkyl, amino C 1-6 alkyl, C 1-6 alkylthio ,} halo C _{1- 6} alkoxy group, halogenated C _1-6 alkylthio group, hydroxyl C _1-6 alkoxy group, hydroxyl C _1-6 alkylthio group, amino C _1-6 alkoxy group, amino C _1-6 alkylthio group Or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-10-membered cycloalkyl, -(CH ₂ ) _m -3-10-membered heterocyclyl, -(CH ₂ ) _m -5 -10-membered heteroaryl, -(CH ₂ ) _m -6-10-membered aryl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _{1 -6} alkoxy or halo C _1-6 alkyl; Each m and each p are independently selected from 0, 1, 2, 3, 4 or 5. The compound of claim 1, its pharmaceutically acceptable salt or its stereoisomer, which has a structure represented by general formula (II-1) or general formula (II-2): in, Each R ² , each R ³ , each R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-6 alkyl, halogenated C _{1- 6} alkyl, C _1-6 alkoxy or halo C _1-6 alkoxy; R ¹ 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 , -C(O)OR ^a or any Select the following groups substituted by substituents: -(CH ₂ ) _p -3-10-membered cycloalkyl, -(CH ₂ ) _p -3-10-membered heterocyclyl, -(CH ₂ ) _p -5-10 Heteroaryl, -(CH ₂ ) _p -6-10 aryl; the substituent _is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 Alkoxy or halo C _1-6 alkyl; Ring A is selected from 3-10-membered cycloalkyl, 3-10-membered heterocyclyl, 6-10-membered aryl or 5-10-membered heteroaryl; Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR ^a R ^b , -OR ^a , -SR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-3 Q2: C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkoxy-C _1-6 Alkyl, -(CH ₂ ) _m -3-10-membered cycloalkyl, -(CH ₂ ) _m -3-10-membered heterocyclyl, -(CH ₂ ) _m -5-10-membered heteroaryl or -( CH ₂ ) _m -6-10 yuan aryl _; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, halogen Substituted C _1-6 alkyl group, halogenated C _1-6 alkoxy group, hydroxyl C _1-6 alkyl group, 3-10 membered cycloalkyl group, 3-10 membered heterocyclyl group, 5-10 membered heteroaryl group or 6-10 yuan aryl group; Each R ^a and 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, halo C _1-6 alkyl, hydroxyl C 1-6 _{alkyl, amino C 1-6 alkyl, C 1-6 alkylthio ,} halo C _{1- 6} alkoxy group, halogenated C _1-6 alkylthio group, hydroxyl C _1-6 alkoxy group, hydroxyl C _1-6 alkylthio group, amino C _1-6 alkoxy group, amino C _1-6 alkylthio group Or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-10-membered cycloalkyl, -(CH ₂ ) _m -3-10-membered heterocyclyl, -(CH ₂ ) _m -5 -10-membered heteroaryl, -(CH ₂ ) _m -6-10-membered aryl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _{1 -6} alkoxy or halo C _1-6 alkyl; Each m, each n, and each p are independently selected from 0, 1, 2, 3, 4 or 5; X ¹ , X ² , X ³ , X ⁴ , Y ^{1 , Y 2 ,} Y ³ , Y ⁴ , Y ⁵ , Y ⁶ are as defined in claim 1 . The compound of claim 2, its pharmaceutically acceptable salt or its stereoisomer, wherein, Each R ² , R ³ , each R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C _1-4 alkyl, and halogenated C _1-4 Alkyl, C _1-4 alkoxy or halogenated C _1-4 alkoxy; R ¹ is selected from hydrogen, halogen, hydroxyl, nitro, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, hydroxy C _1-4 alkyl, amino C _1-4 alkyl, -NR ^a R ^b , -OR ^a , -SR ^a , -NR ^a -C(O)-R ^b -, -C(O)R ^a , -C(O)NR ^a , -C(O)OR ^a or any Select the following groups substituted by substituents: -(CH ₂ ) _p -3-6-membered cycloalkyl, -(CH ₂ ) _p -3-6-membered heterocyclyl, -(CH ₂ ) _p -5-8 Metaheteroaryl, -(CH ₂ ) _p -phenyl; 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; Ring A is selected from 5-10-membered cycloalkyl, 5-10-membered heterocyclyl, 6-10-membered aryl or 5-10-membered heteroaryl; Each Q1 is independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, -NR ^a R ^b , -OR ^a , -SR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-3 Q2: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 Alkyl, -(CH ₂ ) _m -3-8-membered cycloalkyl, -(CH ₂ ) _m -3-8-membered heterocyclyl, -(CH ₂ ) _m -5-8-membered heteroaryl or -( CH ₂ ) _m -phenyl; the Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _{1- 4-} alkyl, halogenated C _1-4 alkoxy, hydroxyl C _1-4 alkyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclyl, 5-8-membered heteroaryl or phenyl; Each R ^a and 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, halo C _1-4 alkyl _{, hydroxyl C 1-4 alkyl, amino C 1-4 alkyl, C 1-4 alkylthio ,} halo C _{1- 4} alkoxy group, halogenated C _1-4 alkylthio group, hydroxyl C _1-4 alkoxy group, hydroxyl C _1-4 alkylthio group, amino C _1-4 alkoxy group, amino C _1-4 alkylthio group Or the following groups optionally substituted by substituents: -(CH ₂ ) _m -3-8-membered cycloalkyl, -(CH ₂ ) _m -3-8-membered heterocyclyl, -(CH ₂ ) _m -5 -8-membered heteroaryl, -(CH ₂ ) _m -phenyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-6 alkyl, C _1-6 alkoxy base or halo C _1-6 alkyl; Each m, each n and each p are independently selected from 0, 1, 2 or 3. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or its stereoisomer, which has a structure represented by general formula (III-1) or general formula (III-2): Among them, Y ¹ is selected from -C(R ² )(R ³ )-, -O-, -N(R ⁴ )- or -S-; Y ⁴ is selected from -C(R ² ) or -N-; Y ³ is selected from -C(R ⁵ ) or -N-; Y ⁶ is selected from -C(R ⁷ ) or -N-; X ² , X ³ , and X ⁴ are each independently selected from -C(R ² )-, -O-, -N-, -N(R ⁴ )- or -S-; Each R ² , R ³ , R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, halogen, C _1-4 alkyl or halogenated C _1-4 alkyl; R ¹ is selected from hydrogen, halogen, nitro, cyano, C _1-4 alkyl, halogenated C _1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, -NR ^a - C(O)-R ^b -, -NR ^a R ^b , -OR ^a or the following groups optionally substituted by substituents: -(CH ₂ ) _p -3-6-membered cycloalkyl, -(CH ₂ ) _p -3-6 membered heterocyclyl; 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; Ring A is selected from Wherein, each ring atom in ring A is optionally oxo-substituted, Each Q1 is independently selected from halogen, nitro, amino, cyano, carboxyl, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or optionally 1-2 The following groups substituted by Q2: C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkoxy-C _1-4 alkyl, -(CH ₂ ) _m -3-6-membered cycloalkyl base, -(CH ₂ ) _m -3-6-membered heterocyclyl, -(CH ₂ ) _m -5-6-membered heteroaryl or -(CH ₂ ) _m -phenyl; the Q2 are independently selected from Halogen, hydroxyl, nitro, amino, cyano, carboxyl, C _1-4 alkyl, C _1-4 alkoxy or hydroxy C _1-4 alkyl; Each R ^a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl base, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiryl , oxetanyl, aziridyl, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from Halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl; Each R ^b is independently selected from hydrogen or C _1-4 alkyl; Each m, each n and each p are independently selected from 0, 1, 2 or 3. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or its stereoisomer, wherein: Each R ² , R ³ , each R ⁴ , R ⁵ , and R ⁷ are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl; R ¹ is selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, aziridyl, oxetanyl, aziridyl, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, Imidazolidinyl, tetrahydrofuranyl, -NR ^a -C(O)-R ^b -, -NR ^a R ^b or -OR ^a , preferably selected from -NR ^a R ^b ; Ring A is selected from Preferably selected from Preferably selected from Preferably selected from Wherein, each ring atom in ring A is optionally oxo-substituted; Each Q1 is independently selected from halogen, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-2 Q2: methyl, Ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxy Propyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH ₂ ) _m -cyclopropyl, -(CH ₂ ) _m -cyclobutyl, -(CH ₂ ) _m -cyclopentyl, -(CH ₂ ) _m -cyclohexyl, -(CH ₂ ) _m -oxanyl, -(CH ₂ ) _m -oxy Heterocyclylbutyl, -(CH ₂ ) _m -azetidinyl, -(CH ₂ ) _m -azetidinyl, -(CH ₂ ) _m -tetrahydrofuranyl, -(CH ₂ ) _m -oxa Cyclohexyl, -(CH ₂ ) _m -tetrahydropyranyl, -(CH ₂ ) _m -pyrrolidinyl, -(CH ₂ ) _m -piperidinyl, -(CH ₂ ) _m -piperazinyl, - (CH ₂ ) _m -pyridyl, -(CH ₂ ) _m -pyrimidinyl, -(CH ₂ ) _m -pyridazinyl, -(CH _{2 )} m -pyrazinyl; the Q2 are independently selected from fluorine , chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoro Methyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl; Each R ^a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl base, trifluoroethyl, trifluoroethoxy, trifluoromethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl , oxetanyl, piperidyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl ethyl, propyl, isopropyl or trifluoromethyl; Each R ^b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; Each m and each n are independently selected from 0, 1, 2 or 3. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt or its stereoisomer, wherein, One of X ² , X ³ and X ⁴ is selected from S, O, N or -N(R ⁴ )-, and the other two are independently -C(R ² )-. The compound according to any one of claims 1 to 5, its pharmaceutically acceptable salt or its stereoisomer, which has a structure represented by general formula (IV-1) or general formula (IV-2): ^{Among them , X 2 ,} X ^{3 ,} narrate. The compound according to any one of claims 1 to 3, its pharmaceutically acceptable salt or its stereoisomer, which has general formula (VII-1), general formula (VII-2), general formula (VII -3), the structure represented by general formula (VII-4), general formula (VII-5) or general formula (VII-6): Among them, ring A, R ¹ , R ⁴ , R ^a , R ^b , Q1, Q2, m, n, and p are as defined in any one of claims 1 to 3. The compound of claim 8, its pharmaceutically acceptable salt or its stereoisomer, wherein, R ¹ is selected from -NR ^a R ^b , -OR ^a , -SR ^a , -NH-C(O)-R ^b -, or the following groups optionally substituted by substituents: -(CH ₂ ) _p -3 -6-membered cycloalkyl, -(CH ₂ ) _p -3-6-membered heterocyclyl; the substituent is selected from halogen, C _1-4 alkyl or halogenated C _1-4 alkyl; Each R ⁴ is independently selected from hydrogen, halogen, C _1-4 alkyl or halogenated C _1-4 alkyl; Ring A is selected from Wherein, each ring atom in ring A is optionally oxo-substituted; Each Q1 is independently selected from -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a or the following groups optionally substituted by 1-2 Q2: C _1-4 alkane base, C _1-4 alkoxy group, C _1-4 alkoxy-C _1-4 alkyl group, 3-6 membered cycloalkyl group, 3-6 membered heterocyclyl group, 5-6 membered heteroaryl group or benzene base; the Q2 are independently selected from halogen, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, halogenated C _1-4 alkyl or hydroxyl C _1-4 alkyl; Each R ^a is independently selected from hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy, halo C _1-4 alkyl, halo C _1-4 alkoxy, or optionally The following groups substituted by substituents: 3-6-membered cycloalkyl, 3-6-membered heterocyclyl; the substituents are selected from halogen, hydroxyl, C _1-6 alkyl or halogenated C _1-6 alkyl; Each R ^b is independently selected from hydrogen or C _1-4 alkyl; Each n and each p are independently selected from 0, 1 or 2. The compound of claim 9, its pharmaceutically acceptable salt or its stereoisomer, wherein, R ¹ is selected from azetidinyl, oxetanyl, -NR ^a -C(O)-R ^b -, -NR ^a R ^b or -OR ^a ; Each R ⁴ is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl; Ring A is selected from Wherein, each ring atom in ring A is optionally oxo-substituted; Each Q1 is independently selected from -C(O)R ^a , -C(O)OR ^a or the following groups optionally substituted by 1-2 Q2: methyl, ethyl, propyl, isopropyl, Methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropyl, propoxymethyl, cyclopropyl, cyclobutyl, oxanyl, oxetanyl, Tetrahydrofuryl, oxanyl, tetrahydropyranyl, azetidinyl, azetidinyl, pyrrolidinyl, pyridinyl or pyridazinyl; the Q2 are independently selected from fluorine, chlorine, bromine , hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl; Each R ^a is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoroethyl, Fluoromethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidyl, piperazinyl , tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituent is selected from halogen, hydroxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl; Each R ^b is independently selected from hydrogen, methyl, ethyl, propyl or isopropyl. The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, is selected from the following compounds: A pharmaceutical preparation containing the compound of any one of claims 1 to 11, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that it contains one or more pharmaceutically acceptable excipients, The pharmaceutical preparation is in any pharmaceutically acceptable dosage form. A pharmaceutical composition containing the compound according to any one of claims 1 to 11, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, characterized in that it contains one or more second therapeutically active agents, The second active therapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, anti-tumor antibiotics, growth factor inhibitors, signaling inhibitors, cell cycle inhibitors, enzyme inhibitors, Vitamin A 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 inhibitor. The compound of any one of claims 1-11, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the pharmaceutical preparation of claim 12, or the pharmaceutical composition of claim 13 is used in the preparation of Use in medicines to treat and/or prevent diseases and related disorders mediated by HPK1, the diseases and related disorders mediated by HPK1 are selected from cancer or benign tumors, and the cancer is selected from lung cancer, squamous epithelium Cell cancer, 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, hypertrophy Cellular tumors, multiple myeloma, melanoma, leukemia, glioma or sarcoma.