Tricyclic HPK1 inhibitors and uses thereof

Abstract

The present invention belongs to the field of pharmaceutical technology and specifically relates to a class of tricyclic HPK1 inhibitor compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof, pharmaceutical compositions and preparations containing the compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof, methods for preparing the compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof, and uses of the compounds, pharmaceutically acceptable salts thereof, or stereoisomers thereof. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a tricyclic HPK1 compound represented by general formula (I), a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, a pharmaceutical composition and preparation containing the compound, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, a method for preparing the compound, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, and uses of the compound, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof. Background Art

[0002] T cell receptor (TCR)-mediated T cell activation plays a crucial role in thymic T cell development, T cell subset differentiation, and effector T cell function. The TCR recognizes MHC (major histocompatibility complex) on the surface of antigen-presenting cells, which in turn transmits signals to the cell interior. Signal transmission triggers 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. Activation of these signals ultimately activates T cell-specific gene expression, leading to cell proliferation and differentiation into effector T cells. Endogenous or adoptively transferred effector T cells are important mediators of anti-tumor immunity. Continuous antigen exposure leads to the gradual differentiation of T cells into an exhausted state, characterized by a gradual loss of effector function and proliferative capacity, as well as significant transcriptional, epigenetic, and metabolic changes. Preventing T cell exhaustion and expanding effector T cell function is one of the most pressing issues in tumor immunology.

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

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

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

[0006] The technical problem addressed by the present invention is to provide a novel HPK1 inhibitor compound with excellent inhibitory activity against HPK1. Furthermore, this compound can be used to inhibit HPK1 kinase activity, thereby enhancing the body's immune response to tumors. Furthermore, this compound can also be used to treat or prevent HPK1-mediated diseases, particularly cancer. This compound exhibits excellent inhibitory effects against a variety of cancer cells and possesses good drugability.

[0007] The technical solutions of the present invention are as follows:

[0008] 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:

[0009]

[0010] in,

[0011] X 1 、Y 1 are independently selected from -C(R 2 )(R 3 )-、-O-、-N(R 4 )-or-S-;

[0012] X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-O-、-N-、-N(R 4 )-or-S-;

[0013] Y 2 、Y 4 are independently selected from -C(R 2 ) or -N-;

[0014] Y 3 Selected from -C(R 5 ) or -N-;

[0015] Y 5 Selected from -C(R 6 );

[0016] Y 6 Selected from -C(R 7 ) or -N-;

[0017] Each R 2 、R 3 , each R 4 are independently selected from hydrogen, halogen, hydroxyl, thiol, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy;

[0018] R 5 and R 7 There is one with R 6 and the ring atoms to which they are attached together form a 3-10 membered cycloalkyl, a 3-10 membered heterocyclyl, a 6-10 membered aryl or a 5-10 membered heteroaryl group optionally substituted with 1-5 Q1; the uncyclic R 5 or R 7 Selected from hydrogen, halogen, hydroxyl, mercapto, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy;

[0019] R 1 Selected from hydrogen, halogen, hydroxy, 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 、-ORa 、-SR a 、-NR a -C(O)-R b -、-C(O)R a 、-C(O)NR a 、-C(O)OR a or the following groups optionally substituted by substituents: -(CH2) p -3-10 membered cycloalkyl, -(CH2) p -3-10 membered heterocyclic group, -(CH2) p -5-10 membered heteroaryl, -(CH2) p -6-10 membered aryl; 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;

[0020] 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 group optionally substituted by 1-3 Q2: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, -(CH2) m -3-10 membered cycloalkyl, -(CH2) m -3-10 membered heterocyclic group, -(CH2) m -5-10 membered heteroaryl or -(CH2) m -6-10 membered aryl; said Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl;

[0021] Each R a , each R b are independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 Alkylthio or the following groups optionally substituted by substituents: -(CH2) m -3-10 membered cycloalkyl, -(CH2) m -3-10 membered heterocyclic group, -(CH2) m -5-10 membered heteroaryl, -(CH2) 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 halogenated C 1-6 alkyl;

[0022] Each m and each p are independently selected from 0, 1, 2, 3, 4 or 5.

[0023] In certain embodiments, the compound represented by the aforementioned general formula (I), its pharmaceutically acceptable salt or its stereoisomer has the structure represented by the following general formula (II-1) or general formula (II-2):

[0024]

[0025] in,

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

[0027] X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-O-、-N-、-N(R 4 )-or-S-;

[0028] Y 2 、Y 4 are independently selected from -C(R 2 ) or -N-;

[0029] Y 3 Selected from -C(R 5 ) or -N-;

[0030] Y 6 Selected from -C(R 7 ) or -N-;

[0031] Each R 2 , each R 3 , each R 4 、R 5 、R 7 are independently selected from hydrogen, halogen, hydroxyl, thiol, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy;

[0032] R 1 Selected from hydrogen, halogen, hydroxy, 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 the following groups optionally substituted by substituents: -(CH2) p -3-10 membered cycloalkyl, -(CH2) p -3-10 membered heterocyclic group, -(CH2) p -5-10 membered heteroaryl, -(CH2) p -6-10 membered aryl; 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;

[0033] Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0034] 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 group optionally substituted by 1-3 Q2: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, -(CH2) m -3-10 membered cycloalkyl, -(CH2) m -3-10 membered heterocyclic group, -(CH2) m -5-10 membered heteroaryl or -(CH2) m -6-10 membered aryl; said Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl or 6-10 membered aryl;

[0035] Each R a , each R b are independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, C 1-6 Alkylthio, halo C 1-6 Alkoxy, halogenated C 1-6 Alkylthio, hydroxy C 1-6 Alkoxy, hydroxy C 1-6 Alkylthio, amino C 1-6 Alkoxy, amino C 1-6 Alkylthio or the following groups optionally substituted by substituents: -(CH2) m -3-10 membered cycloalkyl, -(CH2) m -3-10 membered heterocyclic group, -(CH2) m -5-10 membered heteroaryl, -(CH2) 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 halogenated C 1-6alkyl;

[0036] Each m, each n, and each p are independently selected from 0, 1, 2, 3, 4, or 5.

[0037] 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,

[0038] X 1 、Y 1 are independently selected from -C(R 2 )(R 3 )-、-O-、-N(R 4 )-or-S-;

[0039] X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-O-、-N-、-N(R 4 )-or-S-;

[0040] Y 2 、Y 4 are independently selected from -C(R 2 ) or -N-;

[0041] Y 3 Selected from -C(R 5 ) or -N-;Y 6 Selected from -C(R 7 ) or -N-;

[0042] Each R 2 、R 3 , each R 4 、R 5 、R 7 are independently selected from hydrogen, halogen, hydroxyl, thiol, amino, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkoxy;

[0043] R 1 Selected from hydrogen, halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, -NR a R b 、-OR a 、-SR a 、-NR a-C(O)-R b -、-C(O)R a 、-C(O)NR a 、-C(O)OR a or the following groups optionally substituted by substituents: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group, -(CH2) p -5-8 membered heteroaryl, -(CH2) p -phenyl; the substituent is selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0044] Ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0045] 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 group optionally substituted by 1-3 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -(CH2) m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocyclic group, -(CH2) m -5-8 membered heteroaryl or -(CH2) m -phenyl; said 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, hydroxy C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl;

[0046] Each R a , each R b are independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Alkylamino, di(C 1-4 Alkyl)amino, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, C 1-4 Alkylthio, halo C 1-4 Alkoxy, halogenated C 1-4 Alkylthio, hydroxy C 1-4 Alkoxy, hydroxy C 1-4 Alkylthio, amino C 1-4 Alkoxy, amino C 1-4 Alkylthio or the following groups optionally substituted by substituents: -(CH2) m -3-8 membered cycloalkyl, -(CH2) m - 3-8 membered heterocyclic group, -(CH2) m -5-8 membered heteroaryl, -(CH2) m -phenyl; the substituent is selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0047] Each m, each n, and each p are independently selected from 0, 1, 2, or 3.

[0048] In certain embodiments, the compound represented by general formula (II-1) or general formula (II-2), its pharmaceutically acceptable salt or stereoisomer thereof, wherein,

[0049] X 1 、Y 1 are independently selected from -C(R 2 )(R 3 )-、-O-、-N(R 4 )-or-S-;

[0050] X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-O-、-N-、-N(R 4 )-or-S-;

[0051] Y 2 、Y 4 are independently selected from -C(R 2 )-or-N-;

[0052] Y 3 Selected from -C(R 5 ) or -N-;

[0053] Y6 Selected from -C(R 7 ) or -N-;

[0054] Each R 2 、R 3 , each R 4 、R 5 、R 7 are independently selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0055] R 1 Selected from hydrogen, halogen, hydroxy, 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: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl;

[0056] Ring A is selected from a 5-10 membered cycloalkyl group or a 5-10 membered heterocyclyl group;

[0057] 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 group optionally substituted by 1-3 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group, -(CH2) m -5-6 membered heteroaryl or -(CH2) m -phenyl; said Q2 are independently selected from halogen, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C1-4 Alkoxy, hydroxy C 1-4 Alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl or phenyl;

[0058] Each R a , each R b are independently selected from hydrogen, halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy or optionally substituted by the following groups: -(CH2) m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocyclic 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;

[0059] Each m, each n, and each p are independently selected from 0, 1, 2, or 3.

[0060] In certain embodiments, X 1 、Y 1 are independently selected from -C(R 2 )(R 3 )-、-O-、-N(R 4 )-or-S-; each R 2 , each R 3 , each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0061] In certain embodiments, X 1 、Y 1 are independently selected from -C(R 2 )(R 3 )-, -O- or -N(R 4 )-; each R 2 , each R 3 , each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0062] In certain embodiments, X 1 、Y 1 are independently selected from CH2, O or NH.

[0063] In certain embodiments, Y 2 、Y 4are independently selected from -C(R 2 ) or -N-; each R 2 are independently selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0064] In certain embodiments, Y 2 、Y 4 are independently selected from -C(R 2 ) or -N-; each R 2 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0065] In certain embodiments, R 7 Selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0066] In certain embodiments, R 7 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0067] In certain embodiments, R 5 For hydrogen.

[0068] In certain embodiments, Y 2 is N.

[0069] In certain embodiments, Y 3 、Y 4 are independently selected from CH or N.

[0070] In certain embodiments, X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-O-、-N-、-N(R 4 )-or-S-; each R 2 , each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0071] In certain embodiments, X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-O-、-N-、-N(R 4 )-or-S-; each R 2 , each R 4are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0072] In certain embodiments, X 2 、X 3 、X 4 One of the following is selected from S, O, N or -N(R 4 )-, and the other two are independently -C(R 2 )-; each R 2 , each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0073] In certain embodiments, X 2 、X 3 、X 4 One of the following is selected from S, O, N or -N(R 4 )-, and the other two are independently -C(R 2 )-; each R 2 , each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0074] In certain embodiments, X 2 、X 3 、X 4 One of -C(R 2 )-, the other two are independently S, O, N or -N(R 4 )-; each R 2 , each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0075] In certain embodiments, X 2 、X 3 、X 4 One of -C(R 2 )-, the other two are independently S, O, N or -N(R 4 )-; each R 2 , each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0076] In certain embodiments, X 2 、X 3 、X 4 One of them is selected from S or O, and the other two are independently -C(R 2 )-; each R2 are independently selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0077] In certain embodiments, X 2 、X 3 、X 4 One of them is selected from S or O, and the other two are independently -C(R 2 )-; each R 2 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl.

[0078] In certain embodiments, X 3 Selected from -C(R 2 )-, where R 2 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl. 2 、X 3 、X 4 One of -C(R 2 )-, the other two are independently N or -N(R 4 )-; each R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0079] In certain embodiments, X 3 N, X 2 and X 4 One of them is -N(R 4 )-, the other is -C(R 2 )-;R 2 and R 4 are independently selected from hydrogen, halogen, C 1-6 Alkyl or halogenated C 1-6 alkyl.

[0080] In certain embodiments, R 1 Selected from hydrogen, halogen, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group, -NR a -C(O)-R b -、-NR a R b OR a ; Each p is independently selected from 0, 1, 2 or 3.

[0081] In certain embodiments, R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, -NR a -C(O)-R b -、-NR a R b 、-OR a , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxirane, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl or tetrahydrothiophenyl.

[0082] In certain embodiments, Ring A is selected from 5-8 membered cycloalkyl or 5-8 membered heterocyclyl.

[0083] In certain embodiments, Ring A is selected from a 5-8 membered cycloalkyl or a 5-8 membered nitrogen-containing heterocyclyl.

[0084] In certain embodiments, Ring A is selected from a 5-8 membered monocycloalkyl, a 5-8 membered monoheterocyclyl, a 6-8 membered fused heterocyclyl, a 6-8 membered bridged heterocyclyl, or a 6-8 membered spiroheterocyclyl.

[0085] In certain embodiments, Ring A is selected from a 7-8 membered monocycloalkyl, a 7-8 membered monoheterocyclyl, or an 8 membered nitrogen-containing bridged heterocyclyl.

[0086] In certain embodiments, Ring A is selected from a 7-8 membered nitrogen-containing monoheterocyclic group or a 7-8 membered oxygen-containing monoheterocyclic group.

[0087] 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 group optionally substituted by 1-3 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group, -(CH2) m -5-8 membered heteroaryl or -(CH2) m -phenyl; said 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.

[0088] In certain embodiments, each Q1 is independently selected from -C(O)R a 、-C(O)OR a 、-C(O)NR a or the following group optionally substituted by 1-3 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group, -(CH2) m -5-6 membered heteroaryl or -(CH2) m -phenyl; said 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 hydroxy C 1-4 alkyl.

[0089] In certain embodiments, each Q1 is independently selected from fluoro, chloro, bromo, 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, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -oxetanyl, -(CH2) m -tetrahydrofuranyl, -(CH2) m -Oxyheterocyclohexyl, -(CH2) m -tetrahydropyranyl, -(CH2) m -aziridine, -(CH2) m -azetidinyl, -(CH2) m -pyrrolidinyl, -(CH2) m -piperidinyl, -(CH2) m -piperazinyl, -(CH2)m -tetrahydropyrrolyl, -(CH2) m -pyrazolidinyl, -(CH2) m -imidazolidinyl, -(CH2) m -piperazinyl, -(CH2) m -piperidinyl, -(CH2) m -pyrazolyl, -(CH2) m -pyrrolyl, -(CH2) m -imidazolyl, -(CH2) m -pyridyl, -(CH2) m -pyrimidinyl, -(CH2) m -pyridazinyl, -(CH2) m -pyrazinyl or -(CH2) m -phenyl; said Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0090] 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: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -oxetanyl, -(CH2) m -tetrahydrofuranyl, -(CH2) m -Oxyheterocyclohexyl, -(CH2) m -tetrahydropyranyl, -(CH2) m -aziridine, -(CH2) m -azetidinyl, -(CH2) m -pyrrolidinyl, -(CH2) m -piperidinyl, -(CH2) m -piperazinyl, -(CH2) m -pyridyl, -(CH2) m -pyrimidinyl, -(CH2)m -pyridazinyl, -(CH2) m -pyrazinyl; said Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl or trifluoromethyl.

[0091] In certain embodiments, each R a , 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, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, halogenated C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, amino C 1-4 Alkoxy or optionally substituted by the following groups: -(CH2) m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocyclic group, -(CH2) m -5-8 membered heteroaryl or -(CH2) m -phenyl; the substituent is selected from halogen, hydroxy, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl.

[0092] In certain embodiments, each R a are independently selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy or optionally substituted by the following groups: -(CH2) m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 Alkyl; each R b are independently selected from hydrogen or C 1-4 alkyl.

[0093] In certain embodiments, each R aR is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy or the following groups optionally substituted by substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, tetrahydrofuranyl, azetidinyl, aziridine, tetrahydropyrrolyl, pyrazolidinyl, imidazolidinyl, piperazinyl or piperidinyl; the substituents are selected from fluorine, chlorine, bromine, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, isopropyl, methoxy, ethoxy or trifluoromethyl; each R b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0094] In certain embodiments, each R a are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy or the following groups optionally 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 are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0095] In certain embodiments, the compound of formula (I), formula (II-1), or formula (II-2), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, has the structure shown in formula (III-1) or formula (III-2):

[0096]

[0097] Among them, Y 1 Selected from -C(R 2 )(R 3 )-、-O-、-N(R 4 )-or-S-;

[0098] Y 4 Selected from -C(R 2 ) or -N-;

[0099] Y 3 Selected from -C(R 5 ) or -N-;

[0100] Y 6 Selected from -C(R 7 ) or -N-;

[0101] X 2 、X 3 、X 4are independently selected from -C(R 2 )-、-O-、-N-、-N(R 4 )-or-S-;

[0102] Each R 2 、R 3 、R 4 、R 5 、R 7 are independently selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0103] R 1 Selected from hydrogen, halogen, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, -NR a -C(O)-R b -、-NR a R b 、-OR a or the following groups optionally substituted by substituents: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; 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;

[0104] Ring A is selected from wherein each ring atom in ring A is optionally oxidized;

[0105] Each Q1 is independently selected from halogen, nitro, amino, cyano, carboxyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a or the following group optionally substituted by 1-2 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group, -(CH2) m -5-6 membered heteroaryl or -(CH2) m -phenyl; said Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or hydroxy C 1-4 alkyl;

[0106] Each R a are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, aziridine, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

[0107] Each R b are independently selected from hydrogen or C 1-4 alkyl;

[0108] Each m, each n, and each p are independently selected from 0, 1, 2, or 3.

[0109] 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), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein,

[0110] Y 1 Selected from -C(R 2 )(R 3 )-、-O-、-N(R 4 )-or-S-;

[0111] Y 4 Selected from -C(R 2 ) or -N-;

[0112] Y 3 Selected from -C(R 5 ) or -N-;

[0113] Y 6 Selected from -C(R 7 ) or -N-;

[0114] X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-O-、-N-、-N(R 4 )-or-S-;

[0115] Each R 2 、R3 , each R 4 、R 5 、R 7 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

[0116] R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxirane, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, -NR a -C(O)-R b -、-NR a R b OR a , preferably selected from -NR a R b ;

[0117] Ring A is selected from wherein each ring atom in ring A is optionally oxidized;

[0118] 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, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -oxetanyl, -(CH2) m -aziridine, -(CH2) m -azetidinyl, -(CH2) m -tetrahydrofuranyl, -(CH2) m -Oxyheterocyclohexyl, -(CH2) m -tetrahydropyranyl, -(CH2) m -pyrrolidinyl, -(CH2)m -piperidinyl, -(CH2) m -piperazinyl, -(CH2) m -pyridyl, -(CH2) m -pyrimidinyl, -(CH2) m -pyridazinyl, -(CH2) m -pyrazinyl; said Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl; each R a are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

[0119] Each R b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl;

[0120] Each m and each n are independently selected from 0, 1, 2 or 3.

[0121] In certain embodiments, Ring A is selected from wherein each ring atom in ring A is optionally oxidized;

[0122] 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, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -oxetanyl, -(CH2) m -tetrahydrofuranyl, -(CH2) m-Oxyheterocyclohexyl, -(CH2) m -tetrahydropyranyl, -(CH2) m -aziridine, -(CH2) m -azetidinyl, -(CH2) m -pyrrolidinyl, -(CH2) m -piperidinyl, -(CH2) m -piperazinyl, -(CH2) m -pyridyl, -(CH2) m -pyrimidinyl, -(CH2) m -pyridazinyl, -(CH2) m -pyrazinyl; said Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;

[0123] Each m and each n are independently selected from 0, 1, 2 or 3.

[0124] In certain embodiments, Ring A is selected from Preferably selected from Preferably selected from wherein each ring atom in ring A is optionally oxidized;

[0125] 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, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -oxetanyl, -(CH2) m -tetrahydrofuranyl, -(CH2) m -Oxyheterocyclohexyl, -(CH2) m -tetrahydropyranyl, -(CH2) m-aziridine, -(CH2) m -azetidinyl, -(CH2) m -pyrrolidinyl, -(CH2) m -piperidinyl, -(CH2) m -piperazinyl, -(CH2) m -pyridyl, -(CH2) m -pyrimidinyl, -(CH2) m -pyridazinyl, -(CH2) m -pyrazinyl; said Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;

[0126] Each m and each n are independently selected from 0, 1, 2 or 3.

[0127] 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, oxacyclopropyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, tetrahydropyranyl, aziridine, azetidinyl, pyridyl or pyridazinyl; wherein Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl.

[0128] In certain embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1) or Formula (III-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, has the structure shown in the following Formula (IV-1) or Formula (IV-2):

[0129]

[0130] Among them, X 2 、X 3 、X 4 , Ring A, R 1 、R 2 、R 4 、R a 、R b , Q1, Q2, m, n, and p are defined as described in any of the previous schemes.

[0131] In certain embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (IV-1) or Formula (IV-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, has the structure shown in Formula (V-1) or Formula (V-2):

[0132]

[0133] Among them, X 3 、X 4 are independently selected from -C(R 2 )-; Ring A, R 1 、R 2 , Q1, Q2, R a 、R b The definitions of , m, n, and p are as described in any of the previous schemes.

[0134] In certain embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), Formula (IV-1), or Formula (IV-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, has a structure represented by Formula (V-3) or Formula (V-4):

[0135]

[0136] Among them, X 2 、X 4 are independently selected from -C(R 2 )-; Ring A, R 1 、R 2 、R 4 , Q1, Q2, R a 、R b The definitions of , m, n, and p are as described in any of the previous schemes.

[0137] In certain embodiments, the compound of Formula (I), Formula (II-1), Formula (II-2), Formula (III-1) or Formula (III-2), Formula (IV-1) or Formula (IV-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has the structure shown in Formula (VI-1) or Formula (VI-2):

[0138]

[0139] Among them, X 2 、X 3 are independently selected from -C(R 2 )-; Ring A, R 1 、R2 , Q1, Q2, R a 、R b The definitions of , m, n, and p are as described in any of the previous schemes.

[0140] In certain embodiments, the compound represented by Formula (V-1), Formula (V-2), Formula (V-3), Formula (V-4), Formula (VI-1) or Formula (VI-2), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:

[0141] X 2 、X 3 、X 4 are independently selected from -C(R 2 )-;

[0142] Each R 2 , each R 4 are independently selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0143] R 1 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: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; the substituent is selected from halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0144] Ring A is selected from Preferably selected from Preferably selected from wherein each ring atom in ring A is optionally oxidized;

[0145] Each Q1 is independently selected from halogen, -C(O)R a 、-C(O)OR a 、-C(O)NR a or the following group optionally substituted by 1-2 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C1-4 Alkyl, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group, -(CH2) m -5-6 membered heteroaryl or -(CH2) m -phenyl; said Q2 are independently selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or hydroxy C 1-4 alkyl;

[0146] Each R a are independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, or the following groups optionally substituted by substituents: -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0147] Each R b are independently selected from hydrogen or C 1-4 alkyl;

[0148] Each m, each n, and each p are independently selected from 0, 1, or 2.

[0149] In certain embodiments, the compound, its pharmaceutically acceptable salt or stereoisomer thereof has a structure represented by the following general formula (VII-1) or general formula (VII-2):

[0150]

[0151] Among them, ring A, R 1 , Q1, Q2, R a 、R b The definitions of , m, n, and p are as described in any of the previous schemes.

[0152] In certain embodiments, the compound, its pharmaceutically acceptable salt or stereoisomer thereof has a structure represented by the following general formula (VII-3) or general formula (VII-4):

[0153]

[0154] Among them, ring A, R 1 , Q1, Q2, R a 、Rb The definitions of , m, n, and p are as described in any of the previous schemes.

[0155] In certain embodiments, the compound, its pharmaceutically acceptable salt or stereoisomer thereof has a structure represented by the following general formula (VII-5) or general formula (VII-6):

[0156]

[0157] Among them, ring A, R 1 、R 4 , Q1, Q2, R a 、R b The definitions of , m, n, and p are as described in any of the previous schemes.

[0158] In certain embodiments, the compound, its pharmaceutically acceptable salt or stereoisomer thereof has a structure represented by the following formula (VII-7) or formula (VII-8):

[0159]

[0160] Among them, ring A, R 1 、R 4 , Q1, Q2, R a 、R b The definitions of , m, n, and p are as described in any of the previous schemes.

[0161] In certain embodiments, the compound represented by Formula (VII-1), Formula (VII-2), Formula (VII-3), Formula (VII-4), Formula (VII-5), Formula (VII-6), Formula (VII-7) or Formula (VII-8), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,

[0162] R 1 Selected from-NR a R b 、-OR a 、-SR a 、-NH-C(O)-R b -, or the following groups optionally substituted by substituents: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; the substituent is selected from halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0163] Each R 4 are independently selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0164] Ring A is selected from wherein each ring atom in ring A is optionally oxidized;

[0165] Each Q1 is independently selected from -C(O)R a 、-C(O)OR a 、-C(O)NR a or the following group optionally substituted by 1-2 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl; said Q2 are independently selected from halogen, hydroxyl, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0166] Each R a are independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, or the following groups optionally substituted by substituents: 3-6 membered cycloalkyl, 3-6 membered heterocyclic group; the substituents are selected from halogen, hydroxyl, C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0167] Each R b are independently selected from hydrogen or C 1-4 alkyl;

[0168] Each n and each p are independently selected from 0, 1 or 2.

[0169] In certain embodiments, R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, azetidinyl, oxetanyl, -NR a -C(O)-R b -、-NR a R b OR a , preferably selected from -NR a R b .

[0170] In certain embodiments, the compound represented by Formula (VII-1), Formula (VII-2), Formula (VII-3), Formula (VII-4), Formula (VII-5), Formula (VII-6), Formula (VII-7) or Formula (VII-8), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein,

[0171] R 1 Selected from azetidinyl, oxetanyl, -NR a -C(O)-R b -、-NR a R b OR a , each R a Each R is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, 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 are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0172] Each R 4 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl;

[0173] Ring A is selected from wherein each ring atom in ring A is optionally oxidized;

[0174] 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, oxapropyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, tetrahydropyranyl, aziridine, azetidinyl, pyrrolidinyl, pyridyl or pyridazinyl; said Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or trifluoromethyl;

[0175] Each R aare independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituents are selected from halogen, hydroxy, methyl, ethyl, propyl, isopropyl or trifluoromethyl;

[0176] Each R b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

[0177] In certain embodiments, R 1 Selected from -NH2,

[0178] In the technical solution of the present invention, the hydrogen on the ring nitrogen atom in Ring A can be optionally replaced by Q1. In certain embodiments, Q1 replaces one or more hydrogen on the ring nitrogen atom in Ring A.

[0179] In certain embodiments, each Q1 is independently selected from methyl, ethyl, cyclopropyl, cyclobutyl,

[0180] The various technical solutions in the present invention can be combined with each other to form new technical solutions, and the formed new technical solutions are also included in the scope of the present invention.

[0181] In certain embodiments, the compound of the aforementioned general formula (I), its pharmaceutically acceptable salt or stereoisomer thereof is selected from the following compounds:

[0182]

[0183]

[0184]

[0185]

[0186]

[0187] The present invention also provides a pharmaceutical composition comprising 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 pharmaceutical composition can be prepared into any clinically or pharmaceutically acceptable dosage form, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays, etc.

[0188] In certain embodiments of the present invention, the pharmaceutical preparations described above can be administered to patients or subjects requiring such treatment orally, parenterally, rectally, or transpulmonaryly. For oral administration, the pharmaceutical composition can be formulated into oral preparations, such as conventional oral solid preparations such as tablets, capsules, pills, granules, or oral liquid preparations such as oral solutions, oral suspensions, and syrups. Suitable fillers, binders, disintegrants, lubricants, and the like can be added to these oral preparations. For parenteral administration, the pharmaceutical preparations described above can also be formulated into injectables, including injections, sterile powders for injection, and concentrated solutions for injection. Injectables can be produced using conventional methods in the pharmaceutical field. Additives may be omitted or added depending on the properties of the drug. For rectal administration, the pharmaceutical composition can be formulated into suppositories. For transpulmonary administration, the pharmaceutical composition can be formulated into inhalers or sprays.

[0189] The pharmaceutically acceptable carriers and / or diluents useful in the pharmaceutical compositions or pharmaceutical formulations of the present invention may be any conventional carriers and / or diluents in the pharmaceutical formulation art. The selection of a particular carrier and / or diluent will depend on the mode of administration or the type and condition of disease to be treated in a particular patient. The preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical arts.

[0190] In another aspect, the present invention also relates to the use of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a medicament for preventing and / or treating diseases mediated by HPK1 and related diseases, wherein the medicament 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 cancers or benign tumors, including carcinoma in situ and metastatic cancers. Furthermore, 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.

[0191] Furthermore, the present invention also relates to the use of a pharmaceutical preparation containing the compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof in the preparation of a drug, which can be used in combination with one or more drugs to treat and / or prevent diseases mediated by HPK1 and related conditions.

[0192] In another aspect, the present invention relates to pharmaceutical compositions containing a compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which can be administered alone or in combination with one or more second therapeutic agents, which are used in combination with the HPK1 inhibitor compounds of the present application to treat and / or prevent diseases and related conditions mediated by HPK1. Therefore, in certain embodiments, the pharmaceutical compositions further contain one or more second therapeutic agents. In certain embodiments, the second therapeutic agent is selected from anticancer agents, including mitotic inhibitors, alkylating agents, antimetabolites, antisense DNA or RNA, antitumor antibiotics, growth factor inhibitors, signal transduction inhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators, proteasome inhibitors, topoisomerase inhibitors, biological response modifiers, hormones, angiogenesis inhibitors, cell growth inhibitors, targeted antibodies, HMG-CoA reductase inhibitors, and prenyl protein transferase inhibitors.

[0193] In certain embodiments, the components to be combined (e.g., a compound of the present invention, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a second therapeutically active agent) can be administered simultaneously or separately in sequence. For example, the second therapeutically active agent can be administered before, simultaneously with, or after the administration of the compound of the present invention, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. In addition, the components to be combined can also be administered in combination in the form of the same formulation or in separate, different formulations.

[0194] In another aspect, the present invention also provides a method for treating diseases and related conditions mediated by HPK1, comprising administering to a patient in need thereof an effective amount of a compound of the aforementioned general formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, the aforementioned preparation or pharmaceutical composition; the diseases and related conditions mediated by HPK1 are as defined above.

[0195] The term "effective amount" refers to a dose of a drug that can alleviate, delay, inhibit, or cure a subject's condition. The dose is determined by the route of administration, the pharmacokinetics of the drug, the severity of the disease, and the subject's individual characteristics (gender, weight, height, age). [Detailed description of the invention]

[0197] In the present invention, unless otherwise specified, 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, the following definitions of some terms are provided. In the event that the definitions and explanations of terms provided herein are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of terms provided herein shall prevail.

[0198] The "halogen" mentioned in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0199] The "C 1-6 "Alkyl" means a straight or branched chain alkyl group containing 1 to 6 carbon atoms, including, for example, "C 1-4 Alkyl", "C 1-3 Alkyl", "C 1-2 Alkyl", "C 2-6 Alkyl", "C 2-5 Alkyl", "C 2-4 Alkyl", "C 2-3 Alkyl", "C 3-6 Alkyl", "C 3-5 Alkyl", "C 3-4 Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc. The “C 1-4 "Alkyl" refers to C 1-6 Specific examples of alkyl groups contain 1 to 4 carbon atoms.

[0200] The "C 1-6 "Alkoxy" refers to "C 1-6 Alkyl-O-", the "C 1-6 "C alkyl" is as defined above. 1-4 "Alkoxy" refers to "C 1-4 Alkyl-O-", the "C 1-4 "Alkyl" is as defined above.

[0201] The "C 1-6 "Alkylthio" refers to "C 1-6 Alkyl-S-", the "C 1-6 "C alkyl" is as defined above. 1-4 "Alkylthio" refers to "C 1-4 Alkyl-S-", the "C 1-4 "Alkyl" is as defined above.

[0202] The "hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halogenated C 1-6 "Alkyl" refers to C 1-6One or more hydrogen atoms in the alkyl group are replaced by one or more hydroxyl groups, amino groups or halogen groups. 1-6 Alkyl is as defined above

[0203] The "hydroxy C 1-6 Alkoxy, amino C 1-6 Alkoxy, halogenated C 1-6 "Alkoxy" refers to "C 1-6 One or more hydrogen atoms in the "alkoxy" group are replaced by one or more hydroxyl groups, amino groups or halogen groups.

[0204] The "hydroxy C 1-6 Alkylthio, amino C 1-6 Alkylthio, halo C 1-6 "Alkylthio" refers to "C 1-6 One or more hydrogen atoms in the "alkylthio" group are replaced by one or more hydroxyl groups, amino groups or halogen groups.

[0205] The "C 1-6 Alkylamino, di(C 1-6 "alkyl)amino" refers to C 1-6 Alkyl-NH-,

[0206] The "C 2-6 "Alkenyl" refers to a linear, branched or cyclic alkenyl group containing at least one double bond and having 2 to 6 carbon atoms, including, for example, "C 2-4 Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,4-hexadienyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, and the like.

[0207] The "C 2-6 "Alkynyl" refers to a straight or branched chain alkynyl group containing at least one triple bond and having 2 to 6 carbon atoms, including, for example, "C 2-4 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, and the like.

[0208] The "3-10 membered cycloalkyl" herein refers to a saturated or partially saturated, non-aromatic monocyclic or polycyclic group containing 3-10 carbon atoms. The "monocyclic cycloalkyl" is preferably a "3-8 membered monocyclic cycloalkyl," and the "polycyclic cycloalkyl" includes "fused ring groups, bridged ring groups, and spiro ring groups," with "7-10 membered fused ring alkyl," "7-10 membered bridged ring groups," and "7-10 membered spiro ring groups" being preferred.

[0209] The “3-8 membered monocycloalkyl” described in the present invention refers to a saturated or partially saturated monocyclic alkyl group containing 3-8 carbon atoms and not aromatic, including “3-8 membered saturated monocycloalkyl” and “3-8 membered partially saturated monocycloalkyl”; preferably “3-4 membered monocycloalkyl”, “3-5 membered monocycloalkyl”, “3-6 membered monocycloalkyl”, “3-7 membered monocycloalkyl”, “4-5 membered monocycloalkyl”, “4-6 membered monocycloalkyl”, “4-7 membered monocycloalkyl”, “4-8 membered monocycloalkyl”, “5-6 membered monocycloalkyl”, “5-7 membered monocycloalkyl”, “5-8 membered monocycloalkyl”, “6-7 membered monocycloalkyl”, “6-8 membered monocycloalkyl”, “7-8 membered monocycloalkyl”, “3-6 membered saturated monocycloalkyl”, “5-8 membered saturated monocycloalkyl”, “5-7 membered saturated monocycloalkyl”, “5-6 membered saturated monocycloalkyl”, etc. Optionally, the ring carbon atoms in the cyclic structure may be oxo-substituted. Specific examples of the “3-8 membered saturated monocyclic alkyl” include, but are not limited to, cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl), cyclooctane (cyclooctyl), etc.; specific examples of the “3-8 membered partially saturated monocyclic alkyl” include, but are not limited to, cyclopropane, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexa-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl, cyclooctenyl, cyclooct-1,3-dienyl, cyclooct-1,4-dienyl, cyclooct-1,5-dienyl, cyclooct-1,3,5-trienyl, cyclooctatetraenyl, etc.

[0210] The "7-10 membered fused ring group" described in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-10 ring atoms formed by two or more cyclic structures sharing two adjacent carbon atoms. One ring in the fused ring can be an aromatic ring, but the fused ring as a whole does not have aromaticity; it includes "8-9 membered fused ring group", "9-10 membered fused ring group", etc., and its fusion mode can be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl, etc. Optionally, the ring atoms in the cyclic structure can be oxo-substituted. Examples include, but are not limited to, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrenyl, bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydropentalenyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,8a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9,10-decahydrophenanthryl, benzocyclopentyl, benzocyclohexyl, benzocyclohexenyl, benzocyclopentenyl and the like.

[0211] The "7-10 membered bridged ring group" of the present invention refers to a ring structure containing 7-10 ring carbon atoms formed by two or more ring structures sharing two non-adjacent carbon atoms. Optionally, the carbon atoms in the ring structure may be oxo-substituted. Specific examples include, but are not limited to: wait.

[0212] The "7-10 membered spiro heterocyclic group" of the present invention refers to a cyclic structure containing 7-10 ring carbon atoms formed by two or more cyclic structures sharing a carbon atom. Optionally, the carbon atoms in the cyclic structure may be oxo-substituted. Specific examples include, but are not limited to: wait.

[0213] The "3-10 membered heterocyclic group" of the present invention refers to a saturated or partially saturated (containing one or two double bonds) non-aromatic cyclic group consisting of 3-10 carbon atoms and heteroatoms selected from nitrogen, oxygen, or sulfur. This cyclic group may 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. The nitrogen, carbon, or sulfur atoms in the heterocyclic group may be optionally oxidized. The nitrogen atom may be further substituted with other groups to form a tertiary amine or a quaternary ammonium salt.

[0214] The monocyclic heterocyclic group is preferably a "3-8 membered monoheterocyclic group", which refers to a saturated or partially saturated monocyclic group that does not have aromaticity and contains at least one heteroatom (for example, 1, 2, 3, 4 or 5) and 3-8 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom. Optionally, the ring atoms (for example, carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure may be oxo-substituted. The "3-8 membered monoheterocyclic group" of the present invention includes a "3-8 membered saturated monoheterocyclic group" and a "3-8 membered partially saturated monoheterocyclic group". Preferably, the "3-8 membered monoheterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered monoheterocyclic group" of the present invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and / or oxygen atoms; preferably, the "3-8 membered monoheterocyclic group" of the present invention contains 1 nitrogen atom. The “3-8 membered monoheterocyclic group” is preferably a “3-7 membered monoheterocyclic group”, “3-6 membered monoheterocyclic group”, “4-7 membered monoheterocyclic group”, “4-6 membered monoheterocyclic group”, “6-8 membered monoheterocyclic group”, “5-7 membered monoheterocyclic group”, “5-6 membered monoheterocyclic group”, “3-6 membered saturated monoheterocyclic group”, “5-6 membered saturated monoheterocyclic group”, “3-6 membered nitrogen-containing monoheterocyclic group”, “3-6 membered saturated nitrogen-containing monoheterocyclic group”, “5-6 membered nitrogen-containing monoheterocyclic group”, “5-6 membered saturated nitrogen-containing monoheterocyclic group”, etc. For example, it contains only 1 or 2 nitrogen atoms, or contains one nitrogen atom and other 1 or 2 heteroatoms (for example, oxygen atoms and / or sulfur atoms). Specific examples of "3-8 membered monoheterocyclic group" include, but are not limited to, aziridinyl, 2H-aziridinyl, diaziridinyl, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolane, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, thiazolidinyl, piperidinyl, piperidinyl, oxazolyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl, etc.

[0215] The polycyclic heterocyclic group includes a "fused heterocyclic group", a "spiro heterocyclic group" and a "bridged heterocyclic group", and preferably a "7-10 membered fused heterocyclic group", a "7-10 membered spiro heterocyclic group" and a "7-10 membered bridged heterocyclic group".

[0216] The "7-10 membered fused heterocyclic group" of the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-10 ring atoms formed by two or more cyclic structures sharing two adjacent atoms, and at least one ring atom is a heteroatom, wherein one of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and / or a sulfur atom, and optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxo-substituted, including but not limited to Limited to "8-9 membered fused heterocyclic group", "9-10 membered fused heterocyclic group", etc., the fusion mode can be 5-6 membered heterocyclic group and 5-6 membered heterocyclic group, 5-6 membered heterocyclic group and 5-6 membered cycloalkyl, benzo 5-6 membered heterocyclic group, benzo 5-6 membered saturated heterocyclic group, 5-6 membered heteroaryl and 5-6 membered heterocyclic group, 5-6 membered heteroaryl and 5-6 membered saturated heterocyclic group; 5-6 membered heteroaryl is as defined above; specific examples of the "8-10 membered fused heterocyclic group" include but are not limited to: pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine , pyrrolidinylcyclobutyl, pyrrolidinylpyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, pyrrolidinylmorpholinyl, piperidinylmorpholinyl, benzopyrrolidinyl, benzocyclopentyl, benzocyclohexyl, benzotetrahydrofuranyl, benzopyrrolidinyl, benzimidazolidinyl, benzoxazolidinyl, benzothiazolidinyl, benzisoxazolidinyl, benzisothiazolidinyl, benzopiperidinyl, benzomorpholinyl, benzopiperazinyl, benzotetrahydropyranyl, pyridocyclopentyl, pyridocyclohexyl, pyridotetrahydrofuranyl, pyridopyranyl pyrimidinyl, pyridoimidazolidinyl, pyridoxazolidinyl, pyridothiazolidinyl, pyridoisoxazolidinyl, pyridoisothiazolidinyl, pyridopiperdinyl, pyridomorpholinyl, pyridopiperazinyl, pyridotetrahydropyranyl, pyrimidocyclopentyl, pyrimidocyclohexyl, pyrimidotetrahydrofuranyl, pyrimidopyrrolidinyl, pyrimidoimidazolidinyl, pyrimidoxazolidinyl, pyrimidothiazolidinyl, pyrimidoisoxazolidinyl, pyrimidoisothiazolidinyl, pyrimidopiperdinyl, pyrimidomorpholinyl, pyrimidopiperazinyl, pyrimidotetrahydropyranyl;Tetrahydroimidazo[4,5-c]pyridinyl, 3,4-dihydroquinazolinyl, 1,2-dihydroquinoxalinyl, benzo[d][1,3]dioxolyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, 4H-1,3-benzoxazinyl, 4,6-dihydro-1H-furo[3,4-d]imidazolyl, 3a,4,6,6a-tetrahydro-1H- 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, hexahydrofuroimidazolyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, octahydrocyclopenta[c]pyrrolyl, 4H-1,3-benzoxazinyl, etc.;

[0217] The term "benzocyclopentyl" refers to the structure (also known as 2,3-dihydro-1H-indenyl); the term "benzopyrrolidine" includes etc.; the term "pyridotetrahydrofuranyl" includes Other specific examples of the aforementioned “other defined fused heterocyclic groups” have similar ring structures.

[0218] The "7-10 membered spiro heterocyclic group" of the present invention refers to a cyclic structure containing 7-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom) formed by two or more cyclic structures sharing a ring atom, including "7-10 membered saturated spiro heterocyclic groups" and "7-10 membered partially saturated spiro heterocyclic groups". Optionally, the ring atoms (such as carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxo-substituted. Specific examples include, but are not limited to:

[0219] wait.

[0220] The "7-10 membered bridged heterocyclic group" of the present invention refers to a cyclic structure containing 7-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom) formed by two or more cyclic structures sharing two non-adjacent ring atoms, including "7-10 membered saturated bridged heterocyclic groups" and "7-10 membered partially saturated bridged heterocyclic groups". Optionally, the ring atoms (such as carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxo-substituted. Specific examples include, but are not limited to:

[0221] wait.

[0222] The “6-10 membered aryl group” described in the present invention includes “6-8 membered monocyclic aryl group” and “8-10 membered condensed ring aryl group”.

[0223] The "6-8 membered monocyclic aromatic group" described in the present invention refers to a monocyclic aromatic group containing 6-8 ring carbon atoms, examples of which include but are not limited to phenyl, cyclooctatetraenyl, etc.; preferably phenyl.

[0224] The "8-10 membered fused ring aromatic group" described in the present invention refers to an unsaturated aromatic cyclic group containing 8-10 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms. It is preferably a "9-10 membered fused ring aromatic group", and specific examples include naphthyl.

[0225] The “5-10 membered heteroaryl group” described in the present invention includes “5-8 membered single heteroaryl group” and “8-10 membered fused heteroaryl group”.

[0226] The "5-8 membered single heteroaryl" of the present invention refers to a monocyclic cyclic group with aromaticity 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). Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxoed. The "5-8 membered single heteroaryl" includes, for example, "5-7 membered single heteroaryl", "5-6 membered single heteroaryl", "5-6 membered nitrogen-containing single heteroaryl", "6 membered nitrogen-containing single heteroaryl", etc. The heteroatom in the "nitrogen-containing heteroaryl" contains at least one nitrogen atom, for example, only 1 or 2 nitrogen atoms, or one nitrogen atom and one or two other heteroatoms (such as oxygen atoms and / or sulfur atoms), or two nitrogen atoms and one or two other 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, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, and the like. The "5- to 6-membered monoheteroaryl" refers to a specific example of a 5- to 8-membered heteroaryl containing 5 to 6 ring atoms.

[0227] The "8-10 membered fused heteroaryl" herein refers to an unsaturated aromatic cyclic structure containing 8-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom, or a sulfur atom) formed by two or more cyclic structures sharing two adjacent atoms. Optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms, or sulfur atoms) in the cyclic structure may be oxo-substituted. Including "9-10 membered fused heteroaryl", "8-9 membered fused heteroaryl", etc., and the fusion mode can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furathiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinonyl, 4-quinolinonyl, 1-isoquinolinonyl, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, purinyl, naphthyridinyl, etc.

[0228] The term "a carbon atom, a nitrogen atom or a sulfur atom is oxidized" as used in the present invention refers to the formation of a structure of C=O, N=O, S=O or SO2.

[0229] The term "optionally substituted" as used in the present invention refers to two situations in which one or more hydrogen atoms on the substituted group may be "substituted" or "not substituted" by one or more substituents.

[0230] The "pharmaceutically acceptable salt" of the present invention refers to a salt formed by an acidic functional group (e.g., -COOH, -OH, -SO3H, etc.) present in a compound and a suitable inorganic or organic cation (base), including salts formed with alkali metals or alkaline earth metals, ammonium salts, and salts formed with nitrogen-containing organic bases; and a salt formed by a basic functional group (e.g., -NH2, etc.) present in a compound and a suitable inorganic or organic anion (acid), including salts formed with inorganic acids or organic acids (e.g., carboxylic acids, etc.). Examples include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, bismuth salts, hydrochlorides, sulfates, nitrates, phosphates, hydrobromides, hydroiodides, formates, acetates, propionates, oxalates, malonates, succinates, maleates, fumarates, lactates, malates, citrates, tartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, tetrafluoroborate, arginine salts, aspartates, and glutamic acid.

[0231] The term "isomer" as used herein refers to compounds of the present invention that contain one or more asymmetric centers and can therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers. The compounds of the present invention may have asymmetric centers, each of which independently produces two optical isomers. The scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefinic 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 isomers) that have different hydrogen attachment points due to the displacement of one or more double bonds. For example, a ketone and its enol form are keto-enol tautomers. The compounds of the present invention contain a spirocyclic structure. Due to the influence of the three-dimensional structure of the ring, substituents on the ring may exist on both sides of the ring to form relative cis (cis) and trans (trans) isomers. Each tautomer and its mixture are included in the scope of the present invention. All enantiomers, diastereomers, racemates, mesomers, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds are included within the scope of the present invention.

[0232] The compounds of the present invention can be prepared by enantiospecific synthesis or by resolution from a mixture of enantiomers to obtain individual enantiomers. Conventional resolution techniques include forming salts of the free bases of each isomer of the enantiomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming salts of the acid forms of each enantiomer of the enantiomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming esters or amides of each enantiomer of the enantiomer pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving mixtures of enantiomers of the starting material or final product using various well-known chromatographic methods.

[0233] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to the other stereoisomers. When a single isomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Optical purity by weight is the ratio of the weight of an enantiomer to the weight of the enantiomer plus the weight of its optical isomers.

[0234] The "dosage form" mentioned in the present invention refers to a form of a drug suitable for clinical use, including but not limited to powders, tablets, granules, capsules, solutions, emulsions, suspensions, injections (including injections, sterile powders for injection and concentrated solutions for injection), sprays, aerosols, powder mists, lotions, liniments, ointments, plasters, pastes, patches, gargles or suppositories, more preferably powders, tablets, granules, capsules, solutions, injections, ointments, gargles or suppositories.

[0235] Advantageous Effects of the Invention

[0236] 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, good liver microsomal stability, exposure, and bioavailability, and are capable of treating and / or preventing diseases mediated by HPK1.

[0237] 2. The compounds of the present invention, their pharmaceutically acceptable salts or stereoisomers thereof have a good therapeutic effect on HPK1-mediated cancers.

[0238] 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

[0239] The technical solutions of the present invention will be described below in conjunction with specific embodiments, and the above contents of the present invention will be further described in detail. However, this should not be understood as limiting the scope of the above subject matter of the present invention to the following embodiments. All technologies implemented based on the above contents of the present invention fall within the scope of the present invention.

[0240] The abbreviations used in the following experiments have the following meanings:

[0241] LiAlH4: lithium aluminum hydride

[0242] LDA: lithium diisopropylamide

[0243] DCC: dicyclohexylcarbodiimide

[0244] Preparation Example 1: Preparation of 7-amino-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)-one (Compound 1)

[0245]

[0246] 1. Preparation of 2,2'-(1,2-phenylene)bis(ethane-1-ol)

[0247] Dissolve 2,2'-(1,2-phenylene)diacetic acid (10.0 g, 51.5 mmol) in tetrahydrofuran (200 mL). Add LiAlH4 (5.9 g, 0.15 mol) in portions at 0°C. After addition, react at 15°C for 18 hours. LCMS confirms the reaction is complete. Quench the reaction by adding 5.9 mL of water at 0°C. A solid precipitates, which is filtered through Celite and washed with tetrahydrofuran. The filtrate is dried and concentrated to yield 7.0 g of the title compound in an 81.8% yield.

[0248] 2. Preparation of 1,2-phenylenebis(ethane-2,1-diyl) dimethanesulfonate

[0249] Dissolve 2,2'-(1,2-phenylene)bis(ethane-1-ol) (7.0 g, 42.2 mmol) in dichloromethane (150 mL). Add triethylamine (8.5 g, 84.4 mmol) and methanesulfonyl chloride (9.8 g, 84.4 mmol) at 0°C. After addition, react at 0°C for 1 hour. Quench the reaction with 1 M dilute hydrochloric acid, separate the layers, and use the organic phase directly in the next step after drying and concentration.

[0250] 3. Preparation of 2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0251] Dissolve 1,2-phenylenebis(ethane-2,1-diyl) dimethanesulfonate (N / A, 42.2 mmol) in acetonitrile (50 mL), add aqueous ammonia (50 mL), and react in a sealed container at 90°C for 2 hours. Cool to 15°C, concentrate the solvent, dilute with water, adjust the pH to 4 with concentrated hydrochloric acid, extract with ethyl acetate, adjust the aqueous phase to pH 11 with aqueous sodium hydroxide, and extract with a mixed solvent (dichloromethane:methanol = 10:1). The organic phase is dried and concentrated to obtain 3.0 g of the title compound, with a two-step yield of 48.4%.

[0252] 4. Preparation of 2,2,2-trifluoro-1-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl-1-one

[0253] Dissolve 2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.0 g, 20.4 mmol) in dichloromethane (100 mL), add pyridine (2.4 g, 30.6 mmol), and add trifluoroacetic anhydride (5.4 g, 25.5 mmol) dropwise at 0°C. After addition, react at 15°C for 15 hours. LCMS indicates completion of the reaction. The mixture is quenched with water, extracted with dichloromethane, and the organic phase is dried, concentrated, and purified on a silica gel column (petroleum ether:ethyl acetate = 3:1) to afford 4.0 g of the title compound in an 80.8% yield.

[0254] 5. Preparation of 2,2,2-trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethan-1-one

[0255] Dissolve 2,2,2-trifluoro-1-(1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethyl-1-one (4.0 g, 16.5 mmol) in concentrated sulfuric acid (30 mL). Add potassium nitrate (1.7 g, 16.5 mmol) in portions at 0°C. After addition, react at 15°C for 16 hours. LCMS indicates completion of the reaction. Pour the reaction solution into ice water and extract with ethyl acetate. The organic phase is dried, concentrated, and purified on a silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain 3.0 g of the title compound in a yield of 63.3%.

[0256] 6. Preparation of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0257] Dissolve 2,2,2-trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethan-1-one (3.0 g, 10.4 mmol) in methanol (50 mL). Add potassium carbonate (2.9 g, 20.8 mmol). React at 15°C for 15 hours. LCMS indicates completion of the reaction. Filter through Celite, concentrate the solvent, and purify on a C18 column (methanol = 0-70%) to obtain 1.9 g of the title compound in a 95.5% yield.

[0258] 7. Preparation of 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0259] Dissolve 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (65 mg, 0.19 mmol) in formaldehyde (37%) (10 mL). Add formic acid (5 mL) and let it react at 15°C for 1 hour. Then, raise the temperature to 70°C and let it react for 1 hour. LCMS confirmed the reaction was complete. Adjust the pH to 9 with saturated sodium bicarbonate solution. Extract the organic phase with ethyl acetate, dry it, and concentrate it to obtain 1.9 g of the title compound in a 93.1% yield.

[0260] 8. Preparation of 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0261] Dissolve 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.9 g, 9.2 mmol) in methanol (30 mL) and add Pd / C (1.0 g). Hydrogenate at 15°C for 1 hour. LCMS confirms the reaction is complete. Filter through Celite, dry, and concentrate the filtrate to obtain 1.6 g of the title compound in a 98.6% yield.

[0262] 9. Preparation of N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0263] Dissolve 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.6 g, 9.1 mmol) in acetic acid (5 mL) and add acetic anhydride (1.5 mL). After addition, react at 15°C for 12 hours. LCMS indicates the reaction is complete. Dilute with water, adjust the pH to 9 with saturated sodium bicarbonate solution, extract with dichloromethane, and concentrate the aqueous phase. Purify with a C18 column (methanol = 0-80%) to obtain 1.9 g of the title compound in a 96.0% yield.

[0264] 10. Preparation of N-(3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0265] Dissolve N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.9 g, 8.7 mmol) in concentrated sulfuric acid (16 mL). Add fuming nitric acid (799.0 mg, 11.3 mmol) dropwise at 0°C. Incubate at 0°C for 10 minutes. LCMS confirms the reaction is complete. Pour the mixture into ice water and adjust the pH to 7 with aqueous sodium hydroxide. Concentrate the solvent, wash the solid with dichloromethane and methanol, and concentrate the organic phase to obtain the crude product, which is used directly in the next step.

[0266] 11. Preparation of 3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0267] Dissolve N-(3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (N / A, 8.7 mmol) in methanol (20 mL). Add potassium carbonate (2.4 g, 17.4 mmol). After addition, react at 55°C for 36 hours. LCMS indicates completion of the reaction. Filter through Celite, concentrate the filtrate, and purify on a C18 column (methanol = 0-80%) to obtain 1.6 g of the title compound in an 83.2% yield.

[0268] 12. Preparation of ethyl 2-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0269] Dissolve 3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.6 g, 7.2 mmol) in ethanol (30 mL) and add Pd / C (1.0 g). After addition, hydrogenate at 15°C for 2 hours. LCMS indicates the reaction is complete. Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (3.4 g, 17.4 mmol) and heat the temperature to 50°C for 2 hours. LCMS indicates the reaction is complete. Filter through celite, concentrate the filtrate, and purify on a silica gel column (dichloromethane:methanol = 8:1) to obtain 1.2 g of the title compound in a 57.7% yield.

[0270] 13. Preparation of 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

[0271] Ethyl 2-(7-methyl-1,5,6,7,8,9-hexahydroimidazolylbenzo[1,2-d]azepin-2-yl)acetate (200 mg, 0.7 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (221.5 mg, 0.77 mmol) were dissolved in tetrahydrofuran (5 mL). LDA (1.4 mL, 2.8 mmol) was added and the mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the completion of the reaction. The reaction was quenched with saturated ammonium chloride and extracted with dichloromethane. The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 4:1) to afford 60 mg of the title compound in a yield of 17.7%.

[0272] 14. Preparation of 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]pyridin-7-yl trifluoromethanesulfonate

[0273] Dissolve 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 (60 mg, 0.12 mmol) in dichloromethane (10 mL). Add pyridine (189.8 mg, 2.4 mmol) and trifluoromethanesulfonic anhydride (203.1 mg, 0.72 mmol) at 0°C. Allow to react at 0°C for 1 hour. LCMS indicates the reaction is complete. Dilute with dichloromethane, wash with aqueous sodium bicarbonate, and use the organic phase directly in the next step after drying and concentration.

[0274] 15. Preparation of 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

[0275] Dissolve 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]pyridin-7-yl trifluoromethanesulfonate (N / A, 0.12 mmol) in acetonitrile (5 mL). Add 2,4-dimethoxybenzylamine (60.1 mg, 0.36 mmol). After addition, heat the temperature to 45°C and react for 2 hours. LCMS analysis confirmed the reaction was complete. The solvent was concentrated and the mixture was purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 90.0 mg of the title compound, with a two-step yield of 95.0%.

[0276] 16. Preparation of 7-amino-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)-one

[0277] 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). The temperature was raised to 110°C and allowed to react for 24 hours. LCMS confirmed the completion of the reaction. The pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution, the solvent was concentrated, and the product was purified by Pre-HPLC (acetonitrile = 0-40%) to afford 10.0 mg of the title compound in a 23.4% yield.

[0278] Molecular formula: C 19 H 19 N5OS molecular weight: 365.5 LC-MS (M / e): 366.1 (M+H + )

[0279] 1H-NMR (400MHz, DMSO-d6) 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).

[0280] Preparation Example 2: Preparation of 4-amino-5-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound 2)

[0281]

[0282] Ethyl 2-(7-methyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (100 mg, 0.35 mmol) and 2-aminothiophene-3-carbonitrile (47.5 mg, 0.38 mmol) were dissolved in tetrahydrofuran (5 mL). The mixture was heated to 40°C and LDA (0.53 mL, 1.05 mmol) was added dropwise. The mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the reaction was complete. The reaction was quenched with saturated ammonium chloride, extracted with ethyl acetate, and the organic phase was dried, concentrated, and purified on a C18 column (acetonitrile = 0-60%) to afford 6.6 mg of the title compound in a 5.2% yield.

[0283] Molecular formula: C 19 H 19 N5OS molecular weight: 365.5 LC-MS (M / e): 366.1 (M+H + )

[0284] 1 H-NMR (400MHz, DMSO-d6)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).

[0285] Preparation Example 3: Preparation of 4-amino-5-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-d]azocin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound 4)

[0286]

[0287] 1. Preparation of 2,3,5,6-tetrahydrobenzo[d]azocine-4(1H)-one

[0288] Dissolve 5,6,8,9-tetrahydro-7H-benzo[7]annulene-7-one (8.0 g, 49.9 mmol) in trifluoroacetic acid (60 mL) and add sodium azide (4.9 g, 75.4 mol). React at 65°C for 7 hours. Extract with saturated sodium bicarbonate (200 mL) and ethyl acetate (100 mL). The organic phase is dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 5.0 g of the title compound in a yield of 57.1%.

[0289] 2. Preparation of 1,2,3,4,5,6-Hexahydrobenzo[d]azocine

[0290] Dissolve 2,3,5,6-tetrahydrobenzo[d]azecin-4(1H)-one (5.0 g, 28.5 mmol) in tetrahydrofuran (200 mL). Add lithium aluminum tetrahydride (4.3 g, 113.2 mmol) at 0°C and react at 75°C for 1 hour. Quench the reaction by adding water (4.3 mL). Add 10% sodium hydroxide solution (4.3 mL) and water (12.9 mL). Remove the solid by filtration and extract with water (100 mL) and ethyl acetate (200 mL) to obtain 4.2 g of crude product.

[0291] 3. Preparation of 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocine

[0292] Dissolve 1,2,3,4,5,6-hexahydrobenzo[d]azocine (2.0 g) in formic acid (10 mL), add formaldehyde (37%) (20 mL), 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.

[0293] 4. Preparation of 3-methyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azocine

[0294] Dissolve 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocine (2.0 g) in concentrated sulfuric acid (15 mL), cool to 0°C, and add potassium nitrate (1.2 g, 11.9 mmol). React at 15°C for 15 hours. Adjust the pH to 12 with 2N sodium hydroxide, and extract with dichloromethane / methanol (9:1) (100 mL). The organic phase is dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 9:1) to obtain 1.3 g of the title compound.

[0295] 5. Preparation of 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocine-8-amine

[0296] Dissolve 3-methyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azocine (1.2 g, 5.4 mmol) in methanol (40 mL). Add Pd / C (1.0 g). After addition, hydrogenate at 15°C for 1 hour. Filter through celite, dry, and concentrate the filtrate to obtain 1.0 g of the title compound in a 96.46% yield.

[0297] 6. Preparation of N-(3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocine-8-yl)acetamide

[0298] Dissolve 3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocine-8-amine (1.0 g, 5.2 mmol) in acetic acid (8 mL). Add acetic anhydride (2 mL). After addition, react at 15°C for 12 hours. LCMS indicates the reaction is complete. Dilute with water, adjust the pH to 9 with saturated sodium bicarbonate solution, and extract with 9:1 dichloromethane (100 mL). Concentrate and purify on a C18 column (methanol = 0-60%) to obtain 1.0 g of the title compound in an 81.9% yield.

[0299] 7. Preparation of N-(3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azocine-8-yl)acetamide

[0300] Dissolve N-(3-methyl-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)acetamide (1.0 g, 4.3 mmol) in concentrated sulfuric acid (15 mL). Add fuming nitric acid (339 mg, 5.4 mmol) dropwise at 0°C. After addition, react at 0°C for 10 min. LCMS confirms the reaction is complete. Pour the mixture into ice water, adjust the pH to 10 with 2N sodium hydroxide solution, and extract with dichloromethane / methanol (9:1) (100 mL). Concentrate the organic phase to yield 1.8 g of the crude product.

[0301] 8. Preparation of 3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azocine-8-amine

[0302] Dissolve N-(3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl)acetamide (1.8 g) in methanol (50 mL) and add potassium carbonate (1.7 g, 12.3 mmol). After addition, react at 55°C for 48 hours. Concentrate the mixture, extract with dichloromethane / methanol (9:1) (100 mL), and purify with a C18 column (methanol = 0-70%) to obtain 800 mg of the title compound, with a two-step yield of 79.0%.

[0303] 9. Preparation of ethyl 2-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-d]azocine-2-yl)acetate

[0304] Dissolve 3-methyl-9-nitro-1,2,3,4,5,6-hexahydrobenzo[d]azocine-8-amine (800 mg, 3.4 mmol) in ethanol (30 mL) and add Pd / C (320 mg). After addition, hydrogenate the mixture at 15°C for 1 hour. Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (1.66 g, 8.5 mmol) and heat to 50°C for 2 hours. Filter through celite, concentrate the filtrate, and purify on a silica gel column (dichloromethane:methanol = 6:1) to obtain 500 mg of the title compound in a yield of 48.8%.

[0305] 10. Preparation of 4-amino-5-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-d]azocin-2-yl)thieno[2,3-b]pyridin-6(7H)-one

[0306] Ethyl 2-(7-methyl-5,6,7,8,9,10-hexahydro-1H-imidazo[4',5':4,5]benzo[1,2-d]azocin-2-yl)acetate (70 mg, 0.23 mmol) and 2-aminothiophene-3-carbonitrile (32 mg, 0.26 mmol) were dissolved in tetrahydrofuran (10 mL). LDA (0.3 mL, 0.9 mmol) was added at 40°C and the mixture was allowed to react for 2 hours. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (50 mL). The organic phase was dried, concentrated, and purified on a preparative plate (dichloromethane:methanol = 6:1) to obtain 40 mg of the crude title compound. This was then purified again on a preparative plate (dichloromethane:methanol = 6:1) to obtain 2.8 mg of the title compound, in a yield of 3.2%.

[0307] Molecular formula: C 20 H 21 N5OS molecular weight: 379.5 LC-MS (M / e): 380.1 (M+H+)

[0308] 1 H-NMR(400MHz,DMSO-d6)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).

[0309] Preparation Example 4: Preparation of 7-amino-6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diacin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 7)

[0310]

[0311] 1. Preparation of 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)ethan-1-ol

[0312] 2-(2-chloro-4-fluoro-5-nitrophenyl)ethan-1-ol (4.0 g, 18.3 mmol) was dissolved in NMP (50 mL). 2,4-Dimethoxybenzylamine (3.7 g, 21.9 mmol) and N,N-diisopropylethylamine (4.7 g, 36.4 mmol) were added. The mixture was allowed to react at 50°C for 0.5 hour. LCMS confirmed the completion of the reaction. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified on a silica gel column (petroleum ether:ethyl acetate = 3:1) to afford 4.0 g of the title compound in a yield of 68.1%.

[0313] 2. Preparation of 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)acetaldehyde

[0314] 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)ethan-1-ol (4.0 g, 10.9 mmol) was dissolved in dichloromethane (100 mL). Dess-Martin reagent (5.6 g, 13.1 mmol) was added at 0°C. The mixture was allowed to react at 15°C for 1 hour. LCMS confirmed the reaction was complete. Dichloromethane was added to the reaction solution, followed by quenching with saturated sodium bicarbonate solution. The reaction was extracted with dichloromethane, and the organic phase was dried, concentrated, and purified on a silica gel column (petroleum ether:ethyl acetate = 5:1) to afford 3.9 g of the title compound in a 98.3% yield.

[0315] 3. Preparation of tert-butyl (2-((2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenylethyl)(methyl)amino)ethyl)(methyl)carbamate

[0316] Dissolve 2-(2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenyl)acetaldehyde (2.5 g, 6.9 mmol) in dichloromethane (50 mL). Add tert-butyl methyl(2-(methylamino)ethyl)carbamate (1.6 g, 8.2 mmol). After addition, react at 15°C for 10 minutes. Then, add sodium acetate borohydride (3.2 g, 15.0 mmol) and acetic acid (900 mg, 15.0 mmol). React at 15°C for 16 hours. LCMS indicates the reaction is complete. Add 1 M aqueous sodium hydroxide solution, extract with dichloromethane, collect the organic phase, dry it, concentrate the solvent, and perform column chromatography (methanol / dichloromethane = 0-8%) to obtain 3.1 g of the title compound in an 83.8% yield.

[0317] 4. N 1 -(4-amino-2-chloro-5-nitrophenylethyl)-N 1 ,N 2 - Preparation of dimethylethane-1,2-diamine

[0318] Dissolve tert-butyl (2-((2-chloro-4-((3,4-dimethylbenzyl)amino)-5-nitrophenethyl)(methyl)amino)ethyl)(methyl)carbamate (3.1 g, 5.8 mmol) in dichloromethane (30 mL) and trifluoroacetic acid (10 mL). Incubate at 10°C for 1 hour. LCMS indicates completion of the reaction. Concentrate the mixture and proceed directly to the next step.

[0319] 5. Preparation of 1,4-dimethyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[e][1,4]diazocine-9-amine

[0320] Dissolve the crude N1-(4-amino-2-chloro-5-nitrophenylethyl)-N1,N2-dimethylethane-1,2-diamine in N,N-dimethylacetamide (50 mL) and add potassium carbonate (3.3 g, 23.8 mmol). The mixture is allowed to react at 110°C for 2 hours. LCMS indicates the reaction is complete. Water is added to quench the reaction, followed by extraction with ethyl acetate. The organic phase is collected, dried, and concentrated by column chromatography (methanol / dichloromethane = 0-8%) to afford 0.3 g of the title compound, with a two-step yield of 20.6%.

[0321] 6. Preparation of 1,4-dimethyl-1,2,3,4,5,6-hexahydrobenzo[e][1,4]diazacin-8,9-diamine

[0322] Dissolve 1,4-dimethyl-8-nitro-1,2,3,4,5,6-hexahydrobenzo[e][1,4]diazacin-9-amine (300 mg, 1.2 mmol) in ethanol (10 mL). Add Pd / C (150 mg). Incubate at 10°C under nitrogen for 2 hours. LCMS confirms the reaction is complete. Filter through Celite and concentrate the solvent to obtain the desired compound, which is then used directly in the next step.

[0323] 7. Preparation of ethyl 2-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diacin-2-yl)acetate

[0324] Dissolve the crude 1,4-dimethyl-1,2,3,4,5,6-hexahydrobenzo[e][1,4]diazacin-8,9-diamine in ethanol (10 mL). Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (704 mg, 3.6 mmol). Incubate at 50°C for 3 hours. LCMS confirms the reaction is complete. Column chromatography (methanol / dichloromethane = 0-15%) of the concentrated solvent afforded 300 mg of the title compound, yielding 79.1% over two steps.

[0325] 8. Preparation of 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione

[0326] Dissolve 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (5.0 g, 29.5 mmol) in N,N-dimethylformamide (50 mL). Add p-methoxybenzyl chloride (7.9 g, 50.2 mmol), potassium carbonate (4.9 g, 35.5 mmol), and potassium iodide (2.0 g, 12.0 mmol). After addition, react at 10°C for 2 hours. LCMS indicates the reaction is complete. Water is added to the reaction solution, and a solid precipitates. Filter and obtain 3.0 g of the title compound in a 35.1% yield.

[0327] 9. Preparation of 6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diazocin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-1-one

[0328] Ethyl 2-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diacin-2-yl)acetate (350 mg, 1.1 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (415 mg, 1.4 mmol) were dissolved in tetrahydrofuran (10 mL), heated to 40°C, and LDA (1.7 mL, 3.3 mmol) was added dropwise under nitrogen protection. The mixture was reacted at 40°C for 2 hours after the addition was completed. The reaction was quenched with saturated ammonium chloride and extracted with dichloromethane. The organic phase was dried, concentrated, and column chromatography (methanol / dichloromethane = 0-15%) was performed to obtain the intermediate. Tetrahydrofuran (10 mL) was added, and LDA (1.2 mL) was added dropwise under nitrogen protection. The reaction was repeated for two hours to obtain 150 mg of the target compound in a yield of 26.5%.

[0329] 10. Preparation of 6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diacin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-1-one

[0330] Dissolve 6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diazacin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-1-one (150 mg, 0.29 mmol) in dichloromethane (10 mL). Add pyridine (460 mg, 5.8 mmol) and trifluoromethanesulfonic anhydride (490 mg, 1.74 mmol) at 0°C. Allow to react at 0°C for 1 hour. LCMS indicates the reaction is complete. Dilute with dichloromethane, wash with aqueous sodium bicarbonate, and dry, concentrate the organic phase for use in the next step.

[0331] 11. Preparation of 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]diacin-2-yl)-7-((3,4-dimethylbenzyl)amino)-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one

[0332] Dissolve 6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diazacin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-1-one (N / A, 0.29 mmol) in acetonitrile (5 mL). Add 2,4-dimethoxybenzylamine (130 mg, 0.78 mmol). After addition, heat the temperature to 45°C and react for 2 hours. LCMS analysis indicates the reaction is complete. Concentrate the solvent and purify on a silica gel column (dichloromethane:methanol = 20:1) to obtain 200 mg of the title compound, with a two-step yield of 90.2%.

[0333] 12. Preparation of 7-amino-6-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diazoin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

[0334] Dissolve 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]diacin-2-yl)-7-((3,4-dimethylbenzyl)amino)-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (200 mg, 0.25 mmol) in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (7 mL). Heat the temperature to 110°C and react for 24 hours. LCMS confirms the reaction is complete. Adjust the pH to 7, concentrate the solvent, and purify by Pre-HPLC (acetonitrile = 0-40%) to obtain 20 mg of the title compound in a 20.1% yield.

[0335] Molecular formula: C 20 H 22 N6OS molecular weight: 394.5 LC-MS (M / e): 395.1 (M+H + )

[0336] 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. 2Hz,1H),3.10-3.12(m,2H),2.89-2.90(m,7H),2.48(s,3H),2.21-2.37(m,2H).

[0337] Preparation Example 5: Preparation of 4-amino-5-(5,8-dimethyl-5,6,7,8,9,10-hexahydro-3H-imidazo[4',5':4,5]benzo[1,2-e][1,4]diazoin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound 8)

[0338]

[0339] Dissolve ethyl 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)acetate (100 mg, 0.32 mmol) in tetrahydrofuran (5 mL). Add 2-aminothiophene-3-carbonitrile (40 mg, 0.32 mmol) and LDA (0.32 mL, 0.64 mmol) under nitrogen. After addition, react at 40°C for 2 hours. LCMS indicates completion of the reaction. Quench the reaction with saturated ammonium chloride, extract with dichloromethane, dry, concentrate the organic phase, and mix with C18. Purify by reverse-phase column chromatography (methanol / water = 0-45%) to obtain 30.0 mg of the title compound in a 23.7% yield.

[0340] Molecular formula: C 20 H 22 N6OS molecular weight: 394.5 LC-MS (M / e): 395.1 (M+H + )

[0341] 1 H-NMR (400MHz, DMSO-d6)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).

[0342] Preparation Example 6: Preparation of 4-amino-5-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one hydrochloride (hydrochloride salt of compound 9)

[0343]

[0344] 1. Preparation of 1-(7-amino-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-2,2,2-trifluoroethane-1-one

[0345] Dissolve 2,2,2-trifluoro-1-(7-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)ethan-1-one (3.0 g, 10.4 mmol) in methanol (50 mL). Add Pd / C (1.0 g). React at 15°C for 15 hours. LCMS indicates completion of the reaction. Filter through Celite and concentrate the solvent to obtain 2.6 g of the title compound in a 96.7% yield.

[0346] 2. Preparation of N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0347] Dissolve 1-(7-amino-1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)-2,2,2-trifluoroethane-1-one (2.6 g, 10.1 mmol) in acetic acid (30 mL). Add acetic anhydride (1.5 mL) and react at 15°C for 16 hours. LCMS indicates the reaction is complete. Add water and continue stirring for 1 hour. A solid precipitates, which is filtered, washed with water, and dried to obtain 2.3 g of the title compound in a yield of 76.2%.

[0348] 3. Preparation of N-(8-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0349] Dissolve N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.3 g, 7.7 mmol) in concentrated sulfuric acid (16 mL). Add fuming nitric acid (700.0 mg, 10.0 mmol) at 0°C. After addition, react at 0°C for 2 hours. LCMS indicates completion of the reaction. Pour the mixture into ice water, extract with dichloromethane, and dry and concentrate the organic phase to obtain 2.3 g of the title compound in an 86.9% yield.

[0350] 4. Preparation of tert-butyl 7-amino-8-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate

[0351] Dissolve N-(8-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.3 g, 6.7 mmol) in methanol (30 mL). Heat to 55°C and add potassium carbonate (2.8 g, 20.1 mmol). React at 55°C for 16 hours. Filter through celite, add Boc2O (2.2 g, 10.1 mmol) to the filtrate, and react at 15°C for 2 hours. Purify on a silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain 1.7 g of the title compound in an 82.9% yield.

[0352] 5. Preparation of tert-butyl 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate

[0353] Dissolve tert-butyl 7-amino-8-nitro-1,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate (1.7 g, 5.5 mmol) in ethanol (100 mL), add Pd / C (800 mg), and hydrogenate at 15°C for 2 hours. LCMS detection shows that the reaction is complete. Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (2.6 g, 13.3 mmol), and heat to 50°C for 2 hours. LCMS detection shows that the reaction is complete. Filter with celite, concentrate the filtrate, and purify with silica gel column (ethyl acetate) to obtain 1.6 g of the target compound, with a yield of 60.4%.

[0354] 6. Preparation of tert-butyl 2-(4-amino-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-5-yl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine 7(1H)-carboxylate

[0355] Dissolve tert-butyl 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate (300 mg, 0.8 mmol) and 2-aminothiophene-3-carbonitrile (109.9 mg, 0.88 mmol) in tetrahydrofuran (5 mL). Heat to 40°C under nitrogen. Add LDA (1.2 mL, 2.4 mmol) dropwise. After addition, incubate at 40°C for 2 hours. LCMS indicates the reaction is complete. Quench the reaction with saturated ammonium chloride, extract with ethyl acetate, and dry, concentrate the organic phase. Purify on a silica gel column (petroleum ether:ethyl acetate = 5:1) to obtain 260 mg of the title compound in a yield of 71.7%.

[0356] 7. Preparation of 4-amino-5-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one hydrochloride

[0357] Dissolve tert-butyl 2-(4-amino-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-5-yl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine 7(1H)-carboxylate (45.0 mg, 0.1 mmol) in ethanol (2 mL). Add HCl / ethanol (1.5 mL). After addition, react at 15°C for 4 hours. LCMS indicates the reaction is complete. Add 0.5 mL of water, filter, and dry the solid to obtain 12.0 mg of the title compound in a 31.0% yield.

[0358] Molecular formula: C 18 H 17 N5OS molecular weight: 351.4 LC-MS (M / e): 352.1 (M+H + )

[0359] 1 H-NMR (400MHz, DMSO-d6)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).

[0360] Preparation Example 7: Preparation of 7-amino-6-(7-ethyl-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 (Compound 10)

[0361]

[0362] 1. Preparation of 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0363] Dissolve 2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.0 g, 34.0 mmol) in trifluoroacetic acid (20 mL), cool to 0°C, add concentrated sulfuric acid (7.5 mL) and potassium nitrate (5.5 g, 56.7 mmol), and 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.

[0364] 2. Preparation of 3-ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0365] 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5.0 g, crude) was dissolved in tetrahydrofuran (100 mL). A 40% aqueous acetaldehyde solution (15.75 g, 142.9 mmol), acetic acid (3.1 g, 51.6 mmol), and sodium triacetoxyborohydride (9.65 g, 45.5 mmol) were added and reacted at 15°C for 2 hours. The pH was adjusted to approximately 10 with 1N sodium hydroxide, and the mixture was extracted with dichloromethane / methanol (9:1) (200 mL). The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 2.0 g of the title compound, with a two-step reaction yield of 26.8%.

[0366] 3. Preparation of 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0367] Dissolve 3-ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.0 g, 9.1 mmol) in methanol (40 mL), add Pd / C (500 mg), purge with hydrogen three times, and hydrogenate under hydrogen at 15°C for 2 hours. Filter through celite, dry, and concentrate the filtrate to obtain 1.9 g of the title compound.

[0368] 4. Preparation of N-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0369] 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.9 g, crude) was dissolved in acetic acid (16 mL), and acetic anhydride (4 mL) was added. The mixture was reacted at 15°C for 1 hour. The mixture was diluted with water, adjusted to pH 11 with sodium hydroxide, and extracted with 9:1 dichloromethane (100 mL). Purification was performed on a C18 column (methanol = 0-60%) to obtain 1.5 g of the title compound, with a two-step yield of 71.4%.

[0370] 5. Preparation of N-(3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0371] Dissolve N-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.5 g, 6.5 mmol) in concentrated sulfuric acid (30 mL). Add fuming nitric acid (470 mg, 7.5 mmol) dropwise at 0°C. Incubate at 0°C for 10 minutes. LCMS confirms the reaction is complete. Pour the mixture into ice water, adjust the pH to 10 with 2N sodium hydroxide, and extract with 9:1 dichloromethane (100 mL). Purify on a C18 column (methanol = 0-65%) to obtain 1.2 g of the title compound in a 66.7% yield.

[0372] 6. Preparation of 3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0373] Dissolve N-(3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.2 g, 4.33 mmol) in methanol (150 mL) and add potassium carbonate (2.3 g, 16.6 mmol). After addition, react at 50°C for 2 hours. Concentrate and purify by silica gel column chromatography (dichloromethane:methanol = 8:1) to obtain 1.0 g of the title compound in a 98.2% yield.

[0374] 7. Preparation of ethyl 2-(7-ethyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0375] Dissolve 3-ethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (1.0 g, 4.2 mmol) in ethanol (100 mL), add Pd / C (300 mg), purify with hydrogen three times, and hydrogenate under hydrogen at 15°C for 4 hours. Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (2.0 g, 10.2 mmol), and heat to 50°C for 2 hours. Filter through celite, concentrate the filtrate, and extract with saturated sodium bicarbonate (10 mL), water (20 mL), and dichloromethane / methanol (9:1) (100 mL). Purify on a silica gel column (dichloromethane:methanol = 15:1) to obtain 800 mg of the title compound in a yield of 63.5%.

[0376] 8. Preparation of 7-amino-6-(7-ethyl-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

[0377] Ethyl 2-(7-ethyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (50 mg, 0.17 mmol) and 3-aminothiophene-2-carbonitrile (21 mg, 0.17 mmol) were dissolved in tetrahydrofuran (10 mL). LDA (0.43 mL, 0.86 mmol) was added at 40°C and the mixture was allowed to react for 3 hours. The reaction was quenched with saturated ammonium chloride, extracted with water (15 mL) and ethyl acetate (15 mL), and methanol (3 mL) was added. The mixture was filtered and dried to obtain 21 mg of the title compound in a yield of 32.6%.

[0378] Molecular formula: C 20 H 21 N5OS molecular weight: 379.5 LC-MS (M / e): 380.1 (M+H + )

[0379] 1 H-NMR(400MHz,DMSO-d6)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).

[0380] Preparation Example 8: Preparation of 7-amino-6-(7-cyclobutyl-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 (Compound 11)

[0381]

[0382] 1. Preparation of 8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0383] Dissolve N-(8-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.0 g, 2.9 mmol) in methanol (10.0 mL), add potassium carbonate (600.0 mg, 4.3 mmol), and react at 20°C for 2.0 h. After the reaction is completed, filter, wash with water, extract and concentrate with dichloromethane, and the crude product is directly used in the next reaction.

[0384] 2. Preparation of 3-cyclobutyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0385] 8-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (crude product from the previous step) was dissolved in 10.0 mL of methanol. Sodium cyanoborohydride (550.0 mg, 8.8 mmol) and acetic acid (1.7 g, 28.3 mmol) were added dropwise. Cyclobutanone (410.0 mg, 5.8 mmol) was added dropwise at 0°C. The mixture was reacted at 20°C for 2.0 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then spin-dried to afford 300 mg of the title compound, with a two-step yield of 39.6%.

[0386] 3. Preparation of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine

[0387] 3-Cyclobutyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (250 mg) was dissolved in ethanol (10 mL), and Pd / C (50.0 mg) was added. The reaction was carried out at 25°C under hydrogen atmosphere for 1.5 h, and the reaction solution was directly used in the next reaction.

[0388] 4. Preparation of ethyl 2-(7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0389] To the reaction mixture from the previous step, ethyl 3-ethoxy-3-iminopropionate hydrochloride (330.0 mg, 1.7 mmol) was added. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 h. After filtration, the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was concentrated and purified by column chromatography (dichloromethane:methanol = 10:1) to afford 200 mg of the title compound, a two-step yield of 63.9%.

[0390] 5. Preparation of 7-amino-6-(7-cyclobutyl-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

[0391] Ethyl 2-(7-cyclobutyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepin-2-yl)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, LDA (0.3 mL, 0.60 mmol) was added dropwise at 40°C. The reaction was continued for 2.0 h. After completion, the reaction was quenched by pouring into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was spin-dried to dryness, and the crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1). Purification with methanol slurry afforded 12.0 mg of the product in a 32.3% yield.

[0392] Molecular formula: C 22 H 23 N5OS molecular weight: 405.5 LC-MS (M / e): 406.0 (M+H + )

[0393] 1 H-NMR(400MHz,DMSO-d6)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).

[0394] Preparation Example 9: Preparation of 7-amino-6-(7-cyclopropyl-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 (Compound 12)

[0395]

[0396] 1. Preparation of 3-cyclopropyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0397] 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.2 g, 21.8 mmol), sodium cyanoborohydride (8.7 g, 139.5 mmol), and acetic acid (13.6 g, 230.6 mmol) were dissolved in methanol (120 mL). (1-Ethoxycyclopropyloxy)trimethylsilane (8.7 g, 50.1 mmol) was added dropwise at 0°C. The mixture was reacted at 60°C for 4 h. LCMS detected the completion of the reaction. Water (100 mL) was added to the reaction solution to quench the reaction. The reaction was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to afford 4 g of the title compound in a yield of 78.7%.

[0398] 2. Preparation of 3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0399] 3-Cyclopropyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3.8 g, 16.3 mmol) was dissolved in methanol (50 mL), Pd / C (1.9 g) was added, and the mixture was reacted at 25°C under hydrogen atmosphere for 16 h. The reaction was completed after LCMS detection. The mixture was filtered and the filtrate was dried to obtain 3.5 g of a crude product.

[0400] 3. Preparation of N-(3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0401] 3-Cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (3.5 g, crude product) was dissolved in acetic acid (20 mL), and acetic anhydride (3 mL) was added. The mixture was reacted at 25°C for 4 h. The reaction was complete as determined by LCMS. The reaction solution was dried by rotary evaporation, and the pH was adjusted to 8-9 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, and the organic phase was dried by rotary evaporation. The mixture was separated by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain 2.12 g of the target compound in a yield of 53.1%.

[0402] 4. Preparation of N-(3-cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0403] N-(3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (2.12 g, 8.65 mmol) was dissolved in concentrated sulfuric acid (22 mL). Fuming nitric acid (849 mg, 13 mmol) was added at 0°C and reacted at 25°C for 0.5 h. The reaction was completed after LCMS detection. The pH was adjusted to 8-9 with 5 M sodium hydroxide solution, and the mixture was extracted with DCM. The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain 2 g of the product in a yield of 79.7%.

[0404] 5. Preparation of 3-cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0405] N-(3-Cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (1.96 g, 6.76 mmol) was dissolved in methanol (35 mL), and potassium carbonate (4.6 g, 33.4 mmol) was added. The mixture was reacted at 65°C for 8 h. The reaction was completed after LCMS detection. The product was filtered through celite and separated by silica gel column chromatography (methanol:dichloromethane = 1:15) to obtain 1.1 g of the title compound in a yield of 65.1%.

[0406] 6. Preparation of ethyl 2-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0407] 3-Cyclopropyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7-amine (1.1 g, 4.4 mmol) was dissolved in ethanol (25 mL) and reacted at 25°C for 2 h under hydrogen atmosphere. Ethyl 3-ethoxy-3-iminopropionate hydrochloride (1.7 g, 8.8 mmol) was added. The reaction was complete after LCMS detection. The mixture was filtered and the filtrate was dried. The product was separated by silica gel column chromatography (dichloromethane:methanol = 10:1) to give 900 mg of the product in a yield of 65.1%.

[0408] 7. Preparation of 7-amino-6-(7-cyclopropyl-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

[0409] Ethyl 2-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (200 mg, 0.64 mmol) and 3-aminothiophene-2-carbonitrile (76 mg, 0.61 mmol) were dissolved in tetrahydrofuran (5 mL). Under nitrogen, LDA (1.5 mL, 2.88 mmol) was added dropwise at 40°C. The reaction was continued for 6 h, and LCMS confirmed the reaction was complete. The mixture was quenched by pouring into saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried by rotary evaporation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 10:1). Purification with methanol slurry gave 77 mg of the product in a 30.7% yield.

[0410] Molecular formula: C 21 H 21 N5OS molecular weight: 391.5 LC-MS (M / e): 392.0 (M+H + )

[0411] 1 H-NMR(400MHz,DMSO-d6)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).

[0412] Preparation Example 10: Preparation of 6-(7-acetyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-aminothieno[3,2-b]pyridine-5(4H) (Compound 13)

[0413]

[0414] 1. Preparation of ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate hydrochloride

[0415] Dissolve tert-butyl 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate (373 mg, 1.0 mmol) in 4M HCl / dioxane (10 mL), react at 15°C for 2 hours, and concentrate to obtain 241 mg, which was used in the next step.

[0416] 2. Preparation of ethyl (7-acetyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0417] Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (210 mg, crude) was dissolved in dichloromethane (10 mL). Acetic anhydride (86 mg, 0.85 mmol) was added dropwise at 0°C. The mixture was allowed to react for 2 hours at 0°C. The organic phase was concentrated, dried, and purified on a silica gel column (dichloromethane:methanol = 10:1) to afford 200 mg of the title compound. The yield over two steps was 63.5%.

[0418] 3. Preparation of 6-(7-acetyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-aminothieno[3,2-b]pyridine-5(4H)

[0419] Ethyl 7-acetyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepin-2-yl) acetate (170 mg, 0.54 mmol) and 3-aminothiophene-2-carbonitrile (74 mg, 0.59 mmol) were dissolved in tetrahydrofuran (10 mL). LDA (1.1 mL, 2.16 mmol) was added at 40°C and the mixture was allowed to react for 5 hours. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate (15 mL). Methanol (1 mL) and ethyl acetate (1 mL) were added, and the mixture was filtered and dried to obtain 7.5 mg of the target compound in a 3.5% yield.

[0420] Molecular formula: C 20 H 19 N5O2S molecular weight: 393.13 LC-MS (M / e): 394.47 (M+H + )

[0421] 1 H-NMR(400MHz,DMSO-d6)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).

[0422] Preparation Example 11: Preparation of 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-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)-one (Compound 14-1)

[0423]

[0424] 1. Preparation of 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[3,2-b]pyridin-5(4H)-one

[0425] 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]pyridin-7-yl trifluoromethanesulfonate (N / A, 0.37 mmol) was dissolved in acetonitrile (20 mL). (1s,4s)-4-aminocyclohexan-1-ol (170.5 mg, 1.48 mmol) was added and the mixture was reacted at 45°C for 2 hours. LCMS confirmed the completion of the reaction. The reaction solution was concentrated and purified on a silica gel column (dichloromethane:methanol = 10:1) to afford 216 mg of the title compound, with a two-step yield of 81.8%.

[0426] 2. Preparation of 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-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)-one

[0427] Dissolve 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[3,2-b]pyridin-5(4H)-one (216 mg, 0.3 mmol) in concentrated hydrochloric acid (2 mL) and trifluoroacetic acid (14 mL). Heat the mixture to 110°C and react for 24 hours. LCMS analysis confirmed the completion of the reaction. Concentrate the solvent, dissolve in dichloromethane, wash with saturated sodium bicarbonate solution, and dry and concentrate the organic phase. Purify by pre-TLC (dichloromethane:methanol = 7:1) to obtain 12.7 mg of the title compound in a 9.1% yield.

[0428] Molecular formula: C 25 H 29 N5O2S molecular weight: 463.6 LC-MS (M / e): 464.0 (M+H + )

[0429] 1H-NMR (400MHz, DMSO-d6) 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).

[0430] Preparation Example 12: Preparation of 7-(isopropylamino)-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)-one (Compound 15)

[0431]

[0432] 1. Preparation of 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]pyridin-5(4H)-one

[0433] 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]pyridin-7-yl trifluoromethanesulfonate (N / A, 0.23 mmol) was dissolved in acetonitrile (10 mL). Isopropylamine (54.3 mg, 0.92 mmol) was added and the mixture was reacted at 40°C for 2 hours. LCMS confirmed the completion 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 title compound.

[0434] 2. Preparation of 7-(isopropylamino)-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)-one

[0435] Dissolve 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]pyridin-5(4H)-one (100 mg, 0.15 mmol) in concentrated hydrochloric acid (1.5 mL) and trifluoroacetic acid (10.5 mL). Heat the mixture to 110°C and react for 24 hours. LCMS confirms the reaction is complete. Concentrate the solvent, dissolve in dichloromethane, wash with saturated sodium bicarbonate solution, and dry and concentrate the organic phase. Purify by pre-TLC (dichloromethane:methanol = 7:1) to obtain 12.5 mg of the title compound in a 20.2% yield.

[0436] Molecular formula: C 22 H 25 N5OS molecular weight: 407.5 LC-MS (M / e): 408.0 (M+H + )

[0437] 1 H-NMR (400MHz, DMSO-d6) 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).

[0438] Preparation Example 13: Preparation of 4-amino-5-(8-methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one (Compound 19)

[0439]

[0440] 1. Preparation of N-(6-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0441] Dissolve N-(3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (5.5 g, 18.3 mmol) in concentrated sulfuric acid (50 mL). Add fuming nitric acid (1.5 g, 22.0 mmol) dropwise at 0°C. After addition, react at 0°C for 1.5 hours. LCMS confirms the reaction is complete. Pour the mixture into ice water and extract with dichloromethane. The organic phase is dried, concentrated, and separated by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain 800 mg of the title compound in a yield of 12.6%.

[0442] 2. Preparation of 6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0443] Dissolve N-(6-nitro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (800 mg, 2.3 mmol) in methanol (20 mL). Add potassium carbonate (960 mg, 6.9 mmol). After addition, react at 55°C for 24 hours. Filter through celite, concentrate the filtrate, and purify on a C18 column (methanol = 0-50%) to obtain 400 mg of the title compound in an 83.3% yield.

[0444] 3. Preparation of 3-methyl-6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0445] Dissolve 6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (400 mg, 1.9 mmol) in methanol (10 mL). Add formaldehyde (37%) (791.2 mg, 9.7 mmol) and acetic acid (114.0 mg, 1.9 mmol). React at 15°C for 1 hour. Add sodium cyanoborohydride (601.4 mg, 9.7 mmol). React at 15°C for 1 hour. LCMS confirms the reaction is complete. Concentrate the solvent, dissolve the solid in dichloromethane, wash with saturated sodium chloride and saturated sodium bicarbonate solutions, extract with dichloromethane, and dry the organic phase over anhydrous sodium sulfate, spin dry, and separate by silica gel column chromatography (methanol:dichloromethane = 1:10) to obtain 280 mg of the title compound, in a yield of 65.6%.

[0446] 4. Preparation of ethyl 2-(8-methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d]azepin-2-yl)acetate

[0447] Dissolve 3-methyl-6-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (280 mg, 1.3 mmol) in ethanol (10 mL) and add Pd / C (100 mg). After addition, hydrogenate at 15°C for 1 hour. Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (594.8 mg, 3.0 mmol) and react at 55°C for 1 hour. LCMS indicates the reaction is complete. Filter through Celite and concentrate the filtrate. The resulting solid is dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, separated, and extracted with dichloromethane. The organic phase is dried, concentrated, and separated by silica gel column chromatography (methanol:dichloromethane = 1:4) to afford 250 mg of the title compound in a 68.8% yield.

[0448] 5. Preparation of 4-amino-5-(8-methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d]azepin-2-yl)thieno[2,3-b]pyridin-6(7H)-one

[0449] Ethyl 2-(8-methyl-1,6,7,8,9,10-hexahydroimidazo[4',5':3,4]benzo[1,2-d]azepin-2-yl)acetate (100 mg, 0.35 mmol) and 2-amino-3-cyanothiophene (43.4 mg, 0.35 mmol) were dissolved in tetrahydrofuran (10 mL). LDA (0.7 mL, 1.4 mmol) was added dropwise at 40°C under nitrogen. The mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the reaction was complete. The reaction was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried and concentrated to obtain a solid, which was then slurried with methanol to afford 16.2 mg of the title compound in a 12.7% yield.

[0450] Molecular formula: C 19 H 19 N5OS molecular weight: 365.5 LC-MS (M / e): 366.0 (M+H + )

[0451] 1 H-NMR (400MHz, MeOD) δ: 7.28 (d, J = 8.0Hz, 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).

[0452] 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 salt of Compound 20)

[0453]

[0454] 1. Preparation of tert-butyl 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)-carboxylate

[0455] Tert-butyl 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)-carboxylate (500 mg, 0.60 mmol) was dissolved in acetonitrile (10 mL). Isopropylamine (141.8 mg, 2.4 mmol) was added and the mixture was allowed to react at 40°C for 2 hours. LCMS analysis confirmed the completion of the reaction. The reaction mixture was concentrated and purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to obtain 180 mg of the title compound in a 40.2% yield.

[0456] 2. Preparation of 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

[0457] Dissolve tert-butyl 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)-carboxylate (180 mg, 0.24 mmol) in concentrated hydrochloric acid (1.0 mL) and trifluoroacetic acid (7.0 mL) and react at 110°C for 48 hours. LCMS analysis indicated that the reaction was complete. Concentrate the solvent and use it directly in the next step.

[0458] 3. Preparation of 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

[0459] 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, 0.51 mmol) was dissolved in methanol (10 mL). 2-((tert-Butyldimethylsilyl)oxy)acetaldehyde (266.7 mg, 1.5 mmol) and acetic acid (30.6 mg, 0.51 mmol) were added at 25°C. Sodium cyanoborohydride (96.1 mg, 1.5 mmol) was also added, and the reaction was continued for 4 hours. The reaction was quenched by adding water, 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 title compound, with a two-step yield of 60.5%.

[0460] 4. Preparation of 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

[0461] 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 completion of the reaction, the filter cake was collected by filtration and washed with ethyl acetate and dichloromethane to obtain 19.4 mg of the title compound in a yield of 15.3%.

[0462] Molecular formula: C 23 H 27 N5O2S molecular weight: 437.6 LC-MS (M / e): 438.2 (M+H + )

[0463] 1H-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).

[0464] Preparation Example 15: Preparation of 7-(((1s,4s)-4-hydroxycyclohexyl)amino)-6-(7-(oxetane-3-yl)-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 (Compound 21-1)

[0465]

[0466] Dissolve 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 (80 mg, 0.18 mmol) in methanol (10 mL). Add 3-oxetanone (38.5 mg, 0.54 mmol) and acetic acid (10.8 mg, 0.18 mmol). The mixture is reacted at 20°C for 30 minutes. Sodium cyanoborohydride (33.5 mg, 0.54 mmol) is added and the mixture is allowed to react at 20°C for 17 hours. The reaction is complete by LCMS. The solvent was concentrated, and the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated sodium bicarbonate aqueous solutions, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane = 1:15) to obtain 13.6 mg of the title compound in a yield of 15.1%.

[0467] Molecular formula: C 27 H 31 N5O3S molecular weight: 505.6 LC-MS (M / e): 506.0 (M+H + )

[0468] 1H-NMR (400MHz, DMSO-d6) 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).

[0469] Preparation Example 16: Preparation of 7-(((1s,3s)-3-hydroxycyclobutyl)amino)-6-(7-(oxetane-3-yl)-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 (Compound 22-1)

[0470]

[0471] 1. Preparation of tert-butyl 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]benzo[1,2-d]azepine-7(1H)-carboxylate

[0472] tert-Butyl 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)-carboxylate (500 mg, 0.6 mmol) was dissolved in acetonitrile (10 mL). cis-3-aminocyclobutanol hydrochloride (295.7 mg, 2.4 mmol) was added and the mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the completion of the reaction. The solvent was concentrated and the product was separated by silica gel column chromatography (methanol:dichloromethane = 1:20) to obtain 400 mg of the title compound in an 86.6% yield.

[0473] 2. Preparation of 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

[0474] Tert-butyl 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]benzo[1,2-d]azepine-7(1H)-carboxylate (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. The solvent was concentrated, and the solid was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and separated by C18 column chromatography (methanol = 0-60%) to obtain 150 mg of the title compound in a yield of 68.8%.

[0475] 3. Preparation of 7-(((1s,3s)-3-hydroxycyclobutyl)amino)-6-(7-(oxetane-3-yl)-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

[0476] Dissolve 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 (150 mg, 0.36 mmol) in methanol (15 mL). Add 3-oxetanone (77.1 mg, 1.1 mmol) and acetic acid (21.6 mg, 0.36 mmol). React at 20°C for 30 minutes. Then, add sodium cyanoborohydride (68.2 mg, 1.1 mmol). After addition, react at 20°C for 17 hours. The reaction is complete by LCMS. The solvent was concentrated, and the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated sodium bicarbonate aqueous solutions, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane = 1:15) to obtain 16.9 mg of the title compound in a yield of 9.9%.

[0477] Molecular formula: C 25 H 27 N5O3S molecular weight: 477.6 LC-MS (M / e): 478.0 (M+H + )

[0478] 1 H-NMR(400MHz, DMSO-d6)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).

[0479] Preparation Example 17: Preparation of 6-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[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 (Compound 23-1)

[0480]

[0481] 1. Preparation of ethyl 2-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0482] Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate hydrochloride (1.7 g, 5.5 mmol), triethylamine (3.9 g, 38.5 mmol), and cyclopropionyl chloride (600 mg, 5.7 mmol) were dissolved in 40 mL of dichloromethane and reacted at 0°C for 1.5 hours. After completion of the reaction, the mixture was concentrated and purified on a silica gel column (methanol:dichloromethane = 10%) to obtain 1.5 g of the title compound in a yield of 71.8%.

[0483] 2. Preparation of ethyl (E)-2-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-3-hydroxy-3-(3-((4-methoxybenzyl)amino)thiophen-2-yl)propanoate

[0484] Ethyl 2-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (850 mg, 2.5 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (790 mg, 2.7 mmol) were dissolved in tetrahydrofuran (10 mL). LDA (5.0 mL, 10.0 mmol) was added at 40°C and allowed to react for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction, followed by extraction with dichloromethane. The organic phase was concentrated, and the crude product was used directly in the next step.

[0485] 3. Preparation of 6-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one

[0486] The crude product from the previous step was dissolved in 15 mL of tetrahydrofuran, and LDA (5.0 mL) was added dropwise at 40°C. The reaction was continued for 1.5 h. Afterwards, saturated aqueous ammonium chloride solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the organic phase was concentrated to obtain 650 mg of a crude product of the target compound.

[0487] 4. Preparation of 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]pyridin-7-yl trifluoromethanesulfonate

[0488] 6-(7-(Cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (600 mg, 1.1 mmol) was dissolved in dichloromethane (15 mL), cooled to -15°C, pyridine (1.8 g, 22.8 mmol) and trifluoromethanesulfonic anhydride (3.0 g, 10.6 mmol) were added, and the reaction was completed for 1.0 hour. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried and concentrated to obtain the crude target compound, which was directly used in the next reaction.

[0489] 5. Preparation of 6-(7-(cyclopropanecarbonyl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one

[0490] Dissolve the crude product from the previous step in 10 mL of acetonitrile and add (1s,4s)-4-aminocyclohexan-1-ol (160 mg, 1.4 mmol). After addition, react at 50°C for 1 hour. Filter through celite, dry the filtrate, concentrate, and purify it by column chromatography (methanol:dichloromethane = 10%) to obtain 300 mg of the title compound, a two-step yield of 35.1%.

[0491] 6. Preparation of (1s,4s)-4-((6-(7-(cyclopropanecarbonyl)-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-2,2,2-trifluoroacetate

[0492] 6-(7-(Cyclopropanecarbonyl)-1-((trifluoromethyl)sulfonyl)-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-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one (300 mg, 0.39 mmol) was dissolved in trifluoroacetic acid (3 mL) and 1 mL of concentrated hydrochloric acid, reacted at 115°C for 22 h, concentrated, and directly carried out to the next step.

[0493] 7. Preparation of 6-(7-(cyclopropanecarbonyl)-1,5,6,7,8,9-hexahydroimidazole[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

[0494] The crude product from the previous step was dissolved in 10 mL of methanol, and 150 mg of potassium carbonate was added. The mixture was reacted at 25°C for 1 h. After the reaction, the solvent was concentrated and column chromatography was performed to obtain 16 mg of the desired product, with a two-step yield of 7.9%.

[0495] Molecular formula: C 28 H 31 N5O3S molecular weight: 517.6 LC-MS (M / e): 518.0 (M+H + )

[0496] 1 H-NMR(400MHz, CDCl3)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).

[0497] Preparation Example 18: Preparation of 7-amino-6-(7-(3-hydroxycyclobutyl)-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 (bromate salt of compound 24)

[0498]

[0499] 1. Preparation of ethyl 2-(7-(3-(benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0500] Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate hydrochloride (230 mg, 0.74 mmol), 3-(benzyloxy)cyclobutan-1-one (196 mg, 1.11 mmol), and acetic acid (44 mg, 0.74 mmol) were dissolved in dichloromethane (10 mL). Sodium acetate borohydride (314 mg, 1.48 mmol) was added at 0°C. The mixture was allowed to react at 25°C for 8 h. LCMS confirmed the reaction was complete. The reaction mixture was poured into saturated aqueous sodium hydroxide (50 mL) and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, dried by spin drying, and separated by silica gel column chromatography (methanol:dichloromethane = 1:10) to obtain 260 mg of the title compound in an 81.0% yield.

[0501] 2. Preparation of 7-amino-6-(7-(3-(benzyloxy)cyclobutyl)-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

[0502] Ethyl 2-(7-(3-(benzyloxy)cyclobutyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (150 mg, 0.35 mmol) and 3-aminothiophene-2-carbonitrile (43 mg, 0.35 mmol) were dissolved in tetrahydrofuran (5 mL). LDA (1.05 mL, 2.1 mmol) was added dropwise at 40°C. The reaction was continued for 4 h. LCMS analysis indicated that the reaction was complete. The reaction solution was poured into saturated aqueous ammonium chloride solution for quenching. The reaction was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and dried by spin drying. The resulting mixture was separated by silica gel column chromatography (methanol:dichloromethane = 1:10) to afford 100 mg of the title compound in a yield of 55.8%.

[0503] 3. Preparation of 7-amino-6-(7-(3-hydroxycyclobutyl)-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 bromide

[0504] 7-Amino-6-(7-(3-(benzyloxy)cyclobutyl)-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 (50 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL). Boron tribromide (100 mg, 0.40 mmol) was added dropwise at -40°C. The mixture was reacted at 25°C for 1 hour. LCMS confirmed the reaction was complete. Methanol was added to quench the reaction, the solvent was evaporated, and the crude product was slurried with methanol to obtain 19 mg of the title compound in a 37.8% yield.

[0505] Molecular formula: C 22 H 24 BrN5O2S molecular weight: 502.4 LC-MS (M / e): 422.0 (M+H + )

[0506] 1 H-NMR (400MHz, DMSO-d6)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),3.82-3.9 2(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).

[0507] Preparation Example 19: Preparation of 7-amino-6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride (hydrochloride salt of compound 25)

[0508]

[0509] 1. Preparation of ethyl 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)acetate

[0510] Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (240 mg, 0.88 mmol) was dissolved in methanol (10 mL). 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, sodium cyanoborohydride (352 mg, 6.4 mmol) was added. The reaction was continued at 20°C for 6 hours. After completion of the addition, the solvent was evaporated and the reaction was quenched by addition of saturated aqueous sodium bicarbonate (20 mL). The reaction was extracted with ethyl acetate (50 mL). The organic phase was concentrated and purified on a silica gel column (methanol / dichloromethane = 1:20) to obtain 250 mg of the title compound in a yield of 65.8%.

[0511] 2. Preparation of 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

[0512] Ethyl 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)acetate (250 mg, 0.58 mmol) and 3-aminothiophene-2-carbonitrile (71 mg, 0.57 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL). LDA (1.2 ml, 2.3 mmol) was added at 40°C. After completion of the reaction, saturated aqueous ammonium chloride 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 afford 80 mg of the title compound in a yield of 27.0%.

[0513] 3. Preparation of 7-amino-6-(7-(2-hydroxyethyl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-pyridin-2-yl)thieno[3,2-b]pyridin-5(4H)-one hydrochloride

[0514] 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 (50 mg, 0.1 mmol) was dissolved in 1 ml of tetrahydrofuran and 1 ml of concentrated hydrochloric acid and allowed to react for 0.5 hour. After completion of the reaction, the filter cake was collected by filtration and washed with ethyl acetate and dichloromethane to obtain 12.4 mg of the title compound in a yield of 26.4%.

[0515] Molecular formula: C 20 H 22 ClN5O2S molecular weight: 431.9 LC-MS (M / e): 396.5 (M+H + )

[0516] 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).

[0517] Preparation Example 20: Preparation of 7-amino-6-(7-(oxetan-3-yl)-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 (Compound 26)

[0518]

[0519] 1. Preparation of ethyl 2-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-acetate

[0520] Dissolve ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate hydrochloride (309.1 mg, 1.0 mmol) in methanol (30 mL). Add 3-oxetanone (216.3 mg, 3.0 mmol) and acetic acid (60.0 mg, 1.0 mmol). The mixture is allowed to react at 20°C for 30 minutes. Then, sodium cyanoborohydride (186.0 mg, 3.0 mmol) is added. The mixture is allowed to react at 20°C for 17 hours. LCMS confirms the reaction is complete. The solvent is concentrated, and the solid is dissolved in dichloromethane. The solid is washed with saturated sodium chloride and saturated sodium bicarbonate solutions, extracted with dichloromethane, and the organic phase is dried over anhydrous sodium sulfate, dried by spin drying, and separated by silica gel column chromatography (methanol:dichloromethane = 1:15) to obtain 200 mg of the title compound in a yield of 60.8%.

[0521] 2. Preparation of 7-amino-6-(7-(oxetan-3-yl)-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

[0522] Dissolve 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 (150 mg, 0.36 mmol) in methanol (15 mL). Add 3-oxetanone (77.1 mg, 1.1 mmol) and acetic acid (21.6 mg, 0.36 mmol). React at 20°C for 30 minutes. Then, add sodium cyanoborohydride (68.2 mg, 1.1 mmol). After addition, react at 20°C for 17 hours. The reaction is complete by LCMS. The solvent was concentrated, and the solid was dissolved in dichloromethane, washed with saturated sodium chloride and saturated sodium bicarbonate aqueous solutions, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, spin-dried, and separated by silica gel column chromatography (methanol:dichloromethane = 1:15) to obtain 16.9 mg of the title compound in a yield of 9.1%.

[0523] Molecular formula: C 21 H 21 N5O2S molecular weight: 407.5 LC-MS (M / e): 408.1 (M+H + )

[0524] 1H-NMR (400MHz, DMSO-d6) 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).

[0525] 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 salt of compound 27-1)

[0526]

[0527] 1. Preparation of 3-amino-4-methylthiophene-2-carboxylic acid

[0528] Dissolve methyl 3-amino-4-methylthiophene-2-carboxylate (1.71 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol) in water (20 mL) and react at 90°C for 1 hour. The reaction mixture is used directly in the next step.

[0529] 2. Preparation of 7-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione

[0530] Cool 3-amino-4-methylthiophene-2-carboxylic acid (reaction solution from the previous step) to 0°C and add trichloromethyl chloroformate (2.37 g, 12 mol). After addition, react at 20°C for 2 hours. Filter and collect the solid, spin-drying to obtain 1.6 g of the title compound (yield 87.3%).

[0531] 3. Preparation of 1-(4-methoxybenzyl)-7-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4-(1H)-dione

[0532] 7-Methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (1.6 g, 8.7 mmol), 1-(chloromethyl)-4-methoxybenzene (1.65 g, 10.5 mmol), potassium carbonate (1.45 g, 10.5 mmol), and potassium iodide (282 mg, 1.7 mmol) were dissolved in N,N-dimethylformamide (23 mL) and reacted at 20°C for 16 hours. The reaction solution was poured into water (100 mL) and filtered to collect the solid, which was then spin-dried and purified on a silica gel column (dichloromethane) to obtain 1.5 g of the title compound in a yield of 64.7%.

[0533] 4. Preparation of ethyl 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]azepin-2-yl)-3-oxopropanoate

[0534] Ethyl 2-(7-methyl-1,5,6,7,8,9-hexahydroimidazolyl[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (475 mg, 1.65 mmol) and 1-(4-methoxybenzyl)-7-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (500 mg, 1.65 mmol) were dissolved in tetrahydrofuran (20 mL). Under nitrogen, LDA (3.3 mL, 6.6 mmol) was added at 40°C. After addition, the mixture was allowed to react at 40°C for 4 hours. The reaction was quenched with saturated ammonium chloride at 0°C. The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to afford 480 mg of the title compound in a 53.3% yield.

[0535] 5. Preparation of 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

[0536] Ethyl 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]azepin-2-yl)-3-oxopropanoate (480 mg, 0.88 mmol) was dissolved in tetrahydrofuran (8 mL). Under nitrogen, LDA (1.76 mL, 3.52 mol) was added at 40°C. After addition, the mixture was allowed to react at 40°C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (8 mL). The organic phase was concentrated and purified on a silica gel column (dichloromethane:methanol = 4:1) to obtain 390 mg of the title compound in a yield of 88.7%.

[0537] 6. Preparation of 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]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate

[0538] 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 (390 mg, 0.78 mmol) was dissolved in dichloromethane (8 mL). Pyridine (1232 mg, 15.6 mmol) and trifluoromethanesulfonic anhydride (1318 mg, 4.68 mmol) were added at 0°C. The mixture was allowed to react for 1 hour at 0°C. The reaction was quenched with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phase was dried, concentrated, and used directly in the next step.

[0539] 7. Preparation of 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]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

[0540] 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]azepin-2-yl)-5-oxo-4,5-dihydrothieno[3,2-b]pyridin-7-yl trifluoromethanesulfonate (N / A, 0.39 mmol) was dissolved in acetonitrile (5 mL). (1s,4s)-4-aminocyclohexan-1-ol (179 mg, 1.56 mmol) was added and the mixture was allowed to react at 40°C for 2 hours. The reaction mixture was concentrated and purified on a silica gel column (dichloromethane:methanol = 10:1) to afford 180 mg of the title compound, with a two-step yield of 63.3%.

[0541] 8. Preparation of 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

[0542] 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]azepin-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 mixture was reacted for 24 hours. The solvent was concentrated, and the mixture was dissolved in dichloromethane (20 mL). NaOH (1N, 20 mL) was added and stirred for 0.2 hours. The organic phase was concentrated and purified by medium pressure reverse phase purification (0-50% methanol / water (0.5% concentrated hydrochloric acid)) to give 70 mg of the title compound in a yield of 59.4%.

[0543] Molecular formula: C 26 H 32 ClN5O2S molecular weight: 514.1 LC-MS (M / e): 478.0 (M+H + )

[0544] 1H-NMR(400MHz,DMSO-d6)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).

[0545] Preparation Example 22: 7-(((1S,4S)-4-hydroxycyclohexyl)amino)-2-methyl-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)-one (Compound 28-1)

[0546]

[0547] 1. Preparation of 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]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one

[0548] 3-Amino-5-methylthiophene-2-carboxylic acid methyl ester was used as the starting material and the method of Preparation Example 21 was used to prepare 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]azepin-2-yl)thieno[3,2-b]pyridine-5(4H)-one.

[0549] 2. Preparation of (1s,4s)-4-((2-methyl-6-(7-methyl-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]pyridin-7-yl)amino)cyclohexyl 2,2,2-trifluoroacetate

[0550] Dissolve 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]azepin-2-yl)thieno[3,2-b]pyridin-5(4H)-one (150 mg, 0.21 mmol) in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (4 mL). After addition, heat to 115°C and react for 5.0 hours. Concentrate the solvent and use it directly in the next reaction.

[0551] 3. Preparation of 7-(((1S,4S)-4-hydroxycyclohexyl)amino)-2-methyl-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)-one

[0552] The crude product from the previous step was dissolved in 5 mL of methanol, and potassium carbonate (300 mg, 2.2 mmol) was added. The mixture was reacted at 25°C for 1 hour, and the solvent was concentrated. Column chromatography (dichloromethane:methanol = 10:1) afforded 15 mg of the title compound, with a two-step yield of 15.3%.

[0553] Molecular formula: C 26 H 31 N5O2S molecular weight: 477.6 LC-MS (M / e): 478.0 (M+H + )

[0554] 1 H-NMR(400MHz,DMSO-d6)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).

[0555] 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]pyridin-5(4H)-one hydrochloride (hydrochloride salt of compound 29-1)

[0556]

[0557] 3-Amino-4,5-dimethylthiophene-2-carboxylic acid was selected as the starting material and 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)-one hydrochloride was prepared by referring to the method of Preparation Example 21.

[0558] Molecular formula: C 27 H 34 ClN5O2S molecular weight: 528.1 LC-MS (M / e): 492.0 (M+H + )

[0559] 1 H-NMR(400MHz,DMSO-d6)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).

[0560] Preparation Example 24: 7-((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-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)-one (Compound 30-1)

[0561]

[0562] 1. Preparation of tert-butyl 2-(7-hydroxy-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate

[0563] Dissolve tert-butyl 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate (1.8 g, 4.83 mmol) and 1-methyl-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (972 mg, 5.3 mmol) in tetrahydrofuran (50 mL). Under nitrogen, LDA (9.7 mL, 19.3 mmol) was added at 40°C. After addition, the mixture was allowed to react at 40°C for 4 hours. The reaction was quenched by addition of saturated aqueous ammonium chloride at 0°C, and the mixture was extracted with dichloromethane. The organic phase was concentrated to obtain a crude mixture of the product and the intermediate. The crude product from the previous step was dissolved in tetrahydrofuran (20 mL). Under nitrogen, LDA (9.7 mL, 19.3 mmol) was added at 40°C. After addition, the mixture was allowed to react at 40°C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride. The organic phase was concentrated and purified on a silica gel column (100% ethyl acetate) to afford 710 mg of the title compound in a 31% yield.

[0564] 2. Preparation of tert-butyl 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)-carboxylate

[0565] Tert-butyl 2-(7-hydroxy-4-methyl-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate (710 mg, 1.52 mmol) was dissolved in dichloromethane (15 mL). Pyridine (2.4 g, 30.4 mmol) and trifluoromethanesulfonic anhydride (2.6 g, 9.12 mmol) were added at 0°C. The mixture was allowed to react at 0°C for 1 hour. The reaction mixture was concentrated, extracted with dichloromethane, washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate and purified by column chromatography (ethyl acetate / n-heptane = 0-60%) to obtain 450 mg of the title compound in a 41% yield.

[0566] 3. Preparation of tert-butyl 2-(7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-5-oxo-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(1H)-carboxylate

[0567] Tert-butyl 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)-carboxylate (450 mg, 0.62 mmol) was dissolved in acetonitrile (10 mL). (1s,4s)-4-aminocyclohexan-1-ol (284 mg, 2.5 mmol) was added and the mixture was reacted at 40°C for 2 hours. The reaction mixture was concentrated and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 430 mg of the title compound in a 99% yield.

[0568] 4. Preparation of 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

[0569] Dissolve tert-butyl 2-(7-(((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-5-oxo-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(1H)-carboxylate (120 mg, 0.17 mmol) in trifluoroacetic acid (4 mL), react at 25°C for 1 hour, and concentrate. Add a mixture of tetrahydrofuran and water (5 / 5 mL) to the reaction solution, adjust the pH to 10 with NaOH, and react at 25°C for 1 hour. Concentrate and use directly in the next step.

[0570] 5. Preparation of 7-((1s,4s)-4-hydroxycyclohexyl)amino)-4-methyl-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)-one

[0571] 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-methylthiopheno[3,2-b]pyridin-5(4H)-one (the crude product from the previous step) was dissolved in 10 mL of methanol. 40% aqueous formaldehyde solution (0.1 mL) and sodium cyanoborohydride (70 mg, 1.1 mmol) were added. The reaction was carried out at 20°C for 3 hours, and the solvent was concentrated. The reaction was purified by column chromatography (dichloromethane:methanol = 7:1) (0.3% TFA in MeOH / H2O = 0-75%) to obtain 40 mg of the title compound, with a two-step yield of 49%.

[0572] Molecular formula: C 26 H 31 N5O2S molecular weight: 477.6 LC-MS (M / e): 478.2 (M+H + )

[0573] 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).

[0574] Preparation Example 25: Preparation of 7-amino-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 (Compound 33)

[0575]

[0576] 1. Preparation of tert-butyl 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)-carboxylate

[0577] Tert-butyl 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)-carboxylate (N / A, 0.26 mmol) was dissolved in acetonitrile (10 mL). 2,4-Dimethoxybenzylamine (130.3 mg, 0.78 mmol) was added and the mixture was reacted at 40°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated and purified on a silica gel column (dichloromethane:methanol = 20:1) to afford 80 mg of the title compound, with a two-step yield of 37.4%.

[0578] 2. Preparation of 7-amino-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

[0579] Tert-butyl 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)-carboxylate (80 mg, 98.3 μmol) was dissolved in concentrated hydrochloric acid (0.5 mL) and trifluoroacetic acid (3.5 mL) and reacted at 110°C for 48 hours. LCMS confirmed the completion of the reaction. The solvent was concentrated, the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the product was purified on a Pre-TLC plate (dichloromethane:methanol = 7:1) to afford 4.2 mg of the title compound in a yield of 12.8%.

[0580] Molecular formula: C 18 H 17 N5OS molecular weight: 351.4 LC-MS (M / e): 352.1 (M+H + )

[0581] 1 H-NMR (400MHz, DMSO-d6) 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).

[0582] Preparation Example 26: Preparation of 2-(7-amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid isopropyl ester (Compound 37)

[0583]

[0584] 1. Preparation of 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid isopropyl ester

[0585] Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (330 mg, 1.2 mmol) and triethylamine (607 mg, 6.0 mmol) were dissolved in dichloromethane (10 mL). The mixture was cooled to -10°C and isopropyl chloroformate (111 mg, 0.91 mmol) was added. The reaction was allowed to react at -10°C for 2 h. The reaction was quenched with methanol (1 mL). The solution was spin-dried and separated by silica gel column chromatography (methanol:dichloromethane = 1:15) to obtain 110 mg of the title compound in a yield of 25.5%.

[0586] 2. Preparation of 2-(7-amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylic acid isopropyl ester

[0587] Isopropyl 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate (90 mg, 0.25 mmol) and 3-aminothiophene-2-carbonitrile (32 mg, 0.26 mmol) were dissolved in tetrahydrofuran (8 mL). LDA (2 M, 0.63 mL, 1.26 mmol) was added dropwise at 40°C and the reaction was continued for 2 h. After completion of the reaction, saturated aqueous ammonium chloride (5 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate (20 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain 80 mg of the crude product. Methanol (5 mL) was then added for ultrasonic slurrying. The precipitated solid was filtered under reduced pressure to obtain 40 mg of the title compound in a yield of 36.6%.

[0588] Molecular formula: C 22 H 23 N5O3S molecular weight: 437.5 LC-MS (M / e): 438.0 (M+H + )

[0589] 1 H-NMR (400MHz, DMSO-d6) 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).

[0590] Preparation Example 27: Preparation of methyl 2-(7-amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate (Compound 40)

[0591]

[0592] 1. Preparation of methyl 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate

[0593] Ethyl 2-(1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (300 mg, 1.1 mmol) and triethylamine (445 mg, 4.4 mmol) were dissolved in dichloromethane (40 mL). The mixture was cooled to 0°C, and methyl chloroformate solution (0.3 M / L, 3.7 mL, 1.1 mmol) was added. The reaction was allowed to react at 0°C for 2 h. The reaction was quenched with methanol (2 mL). The solution was spin-dried and separated by silica gel column chromatography (methanol:dichloromethane = 1:20) to obtain 220 mg of the title compound in a 60.4% yield.

[0594] 2. Preparation of methyl 2-(7-amino-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-6-yl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate

[0595] Methyl 2-(2-ethoxy-2-oxoethyl)-5,6,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepine-7(1H)-carboxylate (100 mg, 0.30 mmol) and 3-aminothiophene-2-carbonitrile (45 mg, 0.36 mmol) were dissolved in tetrahydrofuran (15 mL). LDA (2 M, 0.75 mL, 1.5 mmol) was added dropwise at 40°C and the reaction was continued for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (3 mL) and then extracted with ethyl acetate (20 mL) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the crude product. Methanol (10 mL) was added and ultrasonically slurried. The precipitated solid was filtered under reduced pressure to obtain 35 mg of the title compound in a yield of 28.5%.

[0596] Molecular formula: C 20 H 19 N5O3S molecular weight: 409.5 LC-MS (M / e): 409.9 (M+H + )

[0597] 1 H-NMR(400MHz,DMSO-d6)δ:12.77(s,1H),11.77(s,1H),10.70-10.55(m,1H),7.92-7.85(m,2 H),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).

[0598] Preparation Example 28: Preparation of 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-(oxa-3-cyclobutylamino)thiophene[3,2-b]pyridin-5(4H)-one (Compound 42)

[0599]

[0600] 1. Preparation of 7-chloro-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

[0601] Dissolve 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 (510 mg, 2.35 mmol), and ferric chloride (1.5 g, 9.4 mmol) in 1,4-dioxane (30 mL). Heat to 110°C and react for 1 hour. LCMS confirms the reaction is complete. Cool the temperature to 25°C and adjust the pH to 9 with saturated sodium bicarbonate solution. Extract with dichloromethane. The organic phase is dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 220 g of the title compound in a yield of 22.9%.

[0602] 2. Preparation of 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-(oxa-3-cyclobutylamino)thiophene[3,2-b]pyridin-5(4H)-one

[0603] 7-Chloro-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (220 mg, 0.54 mmol), 3-aminooxetane (59.2 mg, 0.81 mmol), 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). The mixture was heated to 60°C and allowed to react for 16 hours. LCMS confirmed the reaction was complete. The mixture was cooled to 25°C, diluted with dichloromethane, and washed with water. The organic phase was dried and concentrated to obtain a solid. The solid was slurried with methanol to obtain 14.5 mg of the title compound in a 6.0% yield.

[0604] Molecular formula: C 24 H 25 N5O2S molecular weight: 447.6 LC-MS (M / e): 448.0 (M+H + )

[0605] 1 H-NMR (400MHz, DMSO-d6) 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).

[0606] Preparation Example 29: Preparation of 7-(((1r,4r)-4-hydroxycyclohexyl)amino)-6-(7-methyl-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 (Compound 44)

[0607]

[0608] 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 4Preparation of tert-butyl imidazole [4', 5': 4, 5] benzo [1, 2-d] azepine-7-carboxylate

[0609] 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 tert-Butyl imidazo[4',5':4,5]benzo[1,2-d]azepine-7-carboxylate (200.0 mg, 0.24 mmol) was dissolved in acetonitrile (5 mL), and (1r,4r)-4-aminocyclohexane-1-ol (110.1 mg, 0.96 mmol) was added. After addition, the mixture was allowed to react at 45°C for 2 hours. The reaction solution was concentrated and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 200.0 mg of the crude title compound.

[0610] 2. Preparation of 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

[0611] 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 Tert-butyl imidazo[4',5':4,5]benzo[1,2-d]azepine-7-carboxylate (200.0 mg crude, N / A) was dissolved in concentrated hydrochloric acid (4 mL) and trifluoroacetic acid (28 mL). After addition, the temperature was raised to 110°C and the reaction was allowed to react for 24 hours. The solvent was concentrated, the mixture was dissolved in dichloromethane (20 mL), and stirred with 1N NaOH (20 mL) for 0.2 hours. The organic phase was concentrated and subjected to medium-pressure reverse phase preparative (0-50% methanol / water (0.5% concentrated hydrochloric acid)) to afford 75.0 mg of the title compound, with a two-step yield of 70.8%.

[0612] 3. Preparation of 7-(((1r,4r)-4-hydroxycyclohexyl)amino)-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)-one

[0613] 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 (75.0 mg, 0.17 mmol) was dissolved in 10.0 mL of methanol, and 1.0 mL of formaldehyde and sodium cyanoborohydride (21.0 mg, 0.33 mmol) were added. The mixture was stirred at 25°C for 1 h, the solvent was concentrated, and the product was separated by normal phase column (methanol:dichloromethane = 1:99) to obtain 7.6 mg, with a yield of 9.8%.

[0614] Molecular formula: C 25 H 29 N5O2S molecular weight: 463.2 LC-MS (M / e): 464.0 (M+H + )

[0615] 1 H-NMR(400MHz,DMSO-d6)δ:12.99(s,1H),12.17(s,1H),11.85(s,1H),8.0 2(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).

[0616] Preparation Example 30: Preparation of 7-(azetidin-1-yl)-6-(7-(oxetane-3-yl)-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 (Compound 45)

[0617]

[0618] 1. Preparation of tert-butyl 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]azepine-7(1H)-carboxylate

[0619] Dissolve tert-butyl 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-carboxylate (200 mg, 0.24 mmol) in acetonitrile (5 mL). Add azetidine (55 mg, 0.96 mmol). After addition, react at 40°C for 2 hours. LCMS analysis indicates the reaction is complete. The reaction solution is concentrated and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain the crude title compound.

[0620] 2. Preparation of 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

[0621] Dissolve tert-butyl 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]azepine-7(1H)-carboxylate (crude product) in concentrated hydrochloric acid (1 mL) and trifluoroacetic acid (7 mL). After addition, heat to 110°C and react for 24 hours. LCMS analysis confirmed the completion of the reaction. Concentrate the solvent, dissolve in dichloromethane, wash with saturated sodium bicarbonate, and dry and concentrate the organic phase. Purify by pre-TLC (dichloromethane:methanol = 7:1) to obtain 40 mg of the title compound, with a two-step reaction yield of 43%.

[0622] 3. Preparation of 7-(azetidin-1-yl)-6-(7-(oxetane-3-yl)-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

[0623] 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). 3-Oxetanone (22 mg, 0.3 mmol) and glacial acetic acid (6 mg, 0.1 mmol) were added and reacted at 20°C for 30 min. Sodium cyanoborohydride (19 mg, 0.3 mmol) was added and reacted at 20°C for 4 h. After completion of the reaction, the mixture was extracted three times with dichloromethane and saturated sodium bicarbonate solution. The organic phase was spin-dried and separated by forward preparative separation (dichloromethane:methanol = 5:1) to obtain 5 mg of the title compound.

[0624] Molecular formula: C 24 H 25 N5O2S molecular weight: 447.5 LC-MS (M / e): 448.2 (M+H + )

[0625] 1 H-NMR (400MHz, DMSO-d6) 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).

[0626] Preparation Example 31: Preparation of 7-amino-6-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 46)

[0627]

[0628] 1. Preparation of 3-(6-chloropyrazin-3-yl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0629] 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (961 mg, 5 mmol), triethylamine (1012 mg, 10 mmol), and 3,6-dichloropyrazine (894 mg, 6 mmol) were dissolved in dimethyl sulfoxide (50 mL) and reacted at 110°C for 1 hour. After completion, the reaction was quenched with water (50 mL) and extracted with dichloromethane (50 mL). The organic phase was concentrated and purified on a silica gel column (ethyl acetate / dichloromethane = 1:9) to obtain 500 mg of the title compound in a 32.8% yield.

[0630] 2. Preparation of 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0631] Dissolve 3-(6-chloropyrazin-3-yl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.64 mmol), ammonium chloride (351 mg, 6.56 mmol), and iron powder (275 mg, 4.92 mmol) in ethanol (15 mL) and water (15 mL) and react at 95°C for 3 hours. Extract with dichloromethane (50 mL), and the organic phase is concentrated and used directly in the next step.

[0632] 3. Preparation of N-(3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0633] Dissolve 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (crude product from the previous step) in acetic anhydride (2 mL) and acetic acid (5 mL) and react at 25°C for 1 hour. Quench the reaction by adding water (50 mL), extract with dichloromethane (50 mL), and concentrate the organic phase to yield 400 mg of the title compound, a two-step yield of 76.9%.

[0634] 4. Preparation of N-(3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0635] Dissolve N-(3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (400 mg, 1.26 mmol) in concentrated sulfuric acid (4 mL). Add fuming nitric acid (95 mg, 1.52 mmol) dropwise at 0°C. After completion, react at 0°C for 1 hour. After completion, dilute with dichloromethane (50 mL) and wash with water (50 mL). The organic phase is concentrated and purified on a silica gel column (ethyl acetate / dichloromethane = 1:4) to obtain 230 mg of the title compound in a 50.3% yield.

[0636] 5. Preparation of 3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0637] N-(3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (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. The reaction was quenched with water (30 mL), filtered, and the solid collected and dried to afford 200 mg of the title compound in a 98.4% yield.

[0638] 6. Preparation of 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine

[0639] 3-(6-chloropyrazin-3-yl)-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-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. The mixture was extracted with dichloromethane (50 mL) and washed with water (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 180 mg of the title compound in a 99.3% yield.

[0640] 7. Preparation of ethyl 2-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0641] Dissolve 3-(6-chloropyrazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-7,8-diamine (180 mg, 0.62 mmol) and ethyl 3-ethoxy-3-iminopropionate hydrochloride (292 mg, 1.49 mmol) in ethanol (10 mL). React at 55°C for 1 hour. The mixture is spin-dried, diluted with dichloromethane (50 mL), and washed with aqueous ammonia (10 mL). The organic phase is dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 19:1) to afford 160 mg of the title compound in a 66.8% yield.

[0642] 8. Preparation of 7-amino-6-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

[0643] Ethyl 2-(7-(6-chloropyrazin-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (60 mg, 0.16 mmol) and 3-aminothiophene-2-carbonitrile (20 mg, 0.16 mmol) were dissolved in tetrahydrofuran (4 mL). Under nitrogen, LDA (0.32 mL, 0.64 mol) was added at 40°C. After addition, the mixture was allowed to react at 40°C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (8 mL). The organic phase was concentrated and purified via reverse-phase column chromatography (acetonitrile:water (0.5% hydrochloric acid) = 30%) to afford 7 mg of the title compound in a 9.7% yield.

[0644] Molecular formula: C 22 H 18 ClN7OS molecular weight: 463.9 LC-MS (M / e): 464.0 (M+H + )

[0645] 1 H-NMR(400MHz,DMSO-d6)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)

[0646] Preparation Example 32: Preparation of 7-amino-6-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 47)

[0647]

[0648] 1. Preparation of ethyl 2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0649] To an ethanol solution of 3-methyl-8-amino-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol was added ethyl 3-ethoxy-3-iminopropionate hydrochloride (3.75 g, 19.3 mmol), and the temperature was raised to 50°C for 16 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was adjusted to pH 8 by adding sodium bicarbonate solution. The filtrate was extracted with dichloromethane (100 mL). The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 820 mg of the title compound, with a reaction yield of 59.0%.

[0650] 2. Preparation of 2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetic acid

[0651] Ethyl 2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepin-2-yl)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 reacted at 25°C for 3 hours. After the reaction, 2M dilute hydrochloric acid solution was added to adjust the pH to neutral. The system was concentrated and dried to obtain the crude target compound, which was used directly in the next reaction.

[0652] 3. Preparation of N-(2-cyanothiophene-3-yl)-2-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetamide

[0653] 2-(7-Methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetic acid (N / A, 2.6 mmol) was dissolved in dichloromethane (50 mL). 2-Aminothiophene-3-carbonitrile (387.5 mg, 3.1 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.5 g, 3.9 mmol), and triethylamine (526.2 mg, 5.2 mmol) were added sequentially. The reaction was allowed to proceed at 25°C for 8 hours. After completion of the reaction, the system was quenched with water and extracted with dichloromethane (100 mL). The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 9:1) to obtain 700 mg of the crude target compound, which was used directly in the next step.

[0654] 4. Preparation of 7-amino-6-(7-methyl-6,7,8,9-tetrahydro-5H-oxazolo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

[0655] 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 (600 mg, 1.6 mmol) was dissolved in methanol (50 mL). Sodium methoxide (5.2 g, 28.9 mmol) was added and the reaction mixture was allowed to react at 70°C for 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to neutral by adding 2M dilute hydrochloric acid solution. The mixture was concentrated and dried. The mixture was purified on a silica gel column (dichloromethane:methanol = 7:3), the solvent was dried, the mixture was slurried with methanol, filtered, washed, and dried to obtain 19.0 mg of the title compound. The three-step reaction yield was 2.3%.

[0656] Molecular formula: C 19 H 18 N4O2S molecular weight: 366.4 LC-MS (M / e): 367.4.1 (M+H + )

[0657] 1 H-NMR (400MHz, CDCl3) 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).

[0658] Preparation Example 33: Preparation of 6-(7-(2,2-difluoroethyl)-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 (Compound 48)

[0659]

[0660] 1. Preparation of tert-butyl 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)-carboxylate

[0661] Dissolve tert-butyl 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)-carboxylate (500 mg, 0.60 mmol) in acetonitrile (10 mL). Add isopropylamine (106 mg, 1.80 mmol) and heat to 40°C for 2 hours. LCMS analysis indicates the reaction is complete. The reaction solution is concentrated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 300 mg of the title compound in a yield of 67.1%.

[0662] 2. Preparation of 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

[0663] Dissolve tert-butyl 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)-carboxylate (300 mg, 0.4 mmol) in dichloromethane (10 mL). Add trifluoroacetic acid (2 mL) and react for 1 hour. LCMS indicates the reaction is complete. Dilute with dichloromethane, wash with saturated sodium bicarbonate, and use the organic phase directly in the next step after drying, concentration, and direct use.

[0664] 3. Preparation of 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

[0665] 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, 0.4 mmol) was dissolved in acetonitrile (5 mL). N,N-diisopropylethylamine (155 mg, 1.2 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (256 mg, 1.2 mmol) were added and the reaction was allowed to proceed for 2 hours. LCMS analysis indicated that the reaction was complete. The reaction solution was concentrated and purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to afford 150 mg of the title compound, with a two-step yield of 52.9%.

[0666] 4. Preparation of 6-(7-(2,2-difluoroethyl)-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

[0667] 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 mixture was allowed to react at 110°C for 48 hours. LCMS confirmed the completion of the reaction. The solvent was concentrated, and the pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was purified by Pre-TLC (dichloromethane:methanol = 7:1) to afford 17 mg of the title compound in a yield of 14.9%.

[0668] Molecular formula: C 23 H 25 F2N5OS molecular weight: 457.5 LC-MS (M / e): 458.0 (M+H + )

[0669] 1H-NMR (400MHz, DMSO-d6) 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).

[0670] Preparation Example 34: Preparation of 6-(7-(2,2-difluoroethyl)-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 (Compound 49)

[0671]

[0672] 1. Preparation of 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]pyridin-5(4H)-one

[0673] 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]pyridin-5(4H)-one (400 mg, 0.53 mmol) was dissolved in acetonitrile (5 mL). N,N-diisopropylethylamine (206 mg, 1.6 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (342 mg, 1.6 mmol) were added and the reaction was allowed to proceed for 2 hours. LCMS confirmed the completion of the reaction. The reaction solution was concentrated and purified on a silica gel column (ethyl acetate:petroleum ether = 1:1) to afford 250 mg of the title compound in a yield of 70.7%.

[0674] 2. Preparation of 6-(7-(2,2-difluoroethyl)-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

[0675] 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]pyridin-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 mixture was allowed to react at 110°C for 48 hours. LCMS confirmed the completion of the reaction. The solvent was concentrated, and the pH of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was purified on a Pre-TLC plate (dichloromethane:methanol = 7:1) to afford 20 mg of the title compound in a yield of 17.8%.

[0676] Molecular formula: C 20 H 19 F2N5OS molecular weight: 415.5 LC-MS (M / e): 416.0 (M+H + )

[0677] 1 H-NMR (400MHz, DMSO-d6) 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).

[0678] Preparation Example 35: Preparation of 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-((2,2-difluoroethyl)amino)thiophene[3,2-b]pyridin-5(4H)-one (Compound 50)

[0679]

[0680] 1. Preparation of 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]pyridin-7-yl trifluoromethanesulfonate

[0681] Dissolve 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thiophene[3,2-b]pyridin-5(4H)-one (600 mg, 1.2 mmol) in dichloromethane (12 mL). Add pyridine (1.90 g, 24 mmol) and trifluoromethanesulfonic anhydride (2.03 g, 7.2 mmol) at 0°C. After addition, react at 0°C for 30 minutes. Quench the reaction with saturated aqueous sodium bicarbonate solution, extract with dichloromethane, and dry, concentrate the organic phase for direct use in the next step.

[0682] 2. Preparation of 6-(7-cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzo[1,2-d]azepin-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thiophene[3,2-b]pyridin-5(4H)-one

[0683] 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzo[1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-7-yl trifluoromethanesulfonate (crude product from the previous step) was dissolved in acetonitrile (10 mL). 2,2-Difluoroethylamine (389 mg, 4.8 mmol) was added and the mixture was allowed to react at 40°C for 1 hour. The reaction mixture was concentrated and purified on a silica gel column (dichloromethane:methanol = 13:1) to obtain 300 mg of the title compound, with a two-step yield of 36.2%.

[0684] 3. Preparation of 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-((2,2-difluoroethyl)amino)thiophene[3,2-b]pyridin-5(4H)-one

[0685] Dissolve 6-(7-cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzo[1,2-d]azepinepyridin-2-yl)-7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)thiophen[3,2-b]pyridin-5(4H)-one (150 mg, 0.21 mmol) in concentrated hydrochloric acid (1 mL). Add trifluoroacetic acid (7 mL). After addition, warm to 110°C and react for 24 hours. Concentrate the solvent, dissolve in dichloromethane, wash with saturated sodium bicarbonate solution, dry the organic phase, and purify by medium-pressure reverse phase purification (40% methanol / water (0.5% concentrated hydrochloric acid)) to obtain 40 mg of the title compound in a 41.4% yield.

[0686] Molecular formula: C 23 H 23 F2N5OS molecular weight: 455.5 LC-MS (M / e): 456.1 (M+H + )

[0687] 1 H-NMR (400MHz, DMSO-d6) 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).

[0688] Preparation Example 36: Preparation of 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)thiophene[3,2-b]pyridin-5(4H)-one hydrochloride (hydrochloride salt of compound 52)

[0689]

[0690] 1. Preparation of 6-(7-cyclopropyl-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

[0691] 6-(7-Cyclopropyl-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzo[1,2-d]azepin-2-yl)-4-(4-methoxybenzyl)-5-oxo-4,5-dihydrothiophene[3,2-b]pyridin-7-yl trifluoromethanesulfonate was dissolved in acetonitrile (30 mL). Isopropylamine (141.6 mg, 2.4 mmol) was added and the mixture was allowed to react at 45°C for 1 hour. The reaction mixture was concentrated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 200 mg of the title compound.

[0692] 2. Preparation of 6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-7-(isopropylamino)thiophene[3,2-b]pyridin-5(4H)-one hydrochloride

[0693] 6-(7-cyclopropyl-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 (200 mg, 0.29 mmol) was dissolved in concentrated hydrochloric acid (2 mL), and trifluoroacetic acid (14 mL) was added. After the addition was complete, the temperature was raised to 110°C and the reaction was allowed to proceed for 16 hours. The solvent was concentrated and the mixture was purified by C 18 Column purification (acetonitrile = 0-30%) afforded 11.5 mg of the target compound in a yield of 8.4%.

[0694] Molecular formula: C 24 H 28 N5OSCl molecular weight: 469.2 LC-MS (M / e): 434.0 (M+H + )

[0695] 1 H-NMR(400MHz,DMSO-d6)δ:13.11(m,1H),12.09(m,1H),11.87(s,1H),9.0 3(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).

[0696] Preparation Example 37: Preparation of 7-amino-6-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 53)

[0697]

[0698] 1. Preparation of 1,5-dihydrobenzo[d]oxepin-2,4-dione

[0699] 2,2'-(1,2-phenylene)diacetic acid (12 g, 61.9 mmol) was dissolved in dichloromethane (200 mL), and DCC (12.8 g, 61.9 mmol) was added at 25°C. The mixture was reacted at 25°C for 4 h. The reaction was completed after LCMS detection. The mixture was filtered and the filter cake was dried to obtain 12 g of a crude target compound.

[0700] 2. Preparation of 2-(2-(2-(ethylamino)-2-oxoethyl)phenyl)acetic acid

[0701] 1,5-Dihydrobenzo[d]oxepin-2,4-dione (12 g, crude product) was dissolved in dichloromethane (200 mL). Ethylamine hydrochloride (2.7 g, 33 mmol) and triethylamine (13.7 g, 136 mmol) were added at 0°C and reacted at 25°C for 4 h. LCMS detected the completion of the reaction. Water was added to the system to quench the reaction. The organic phase was extracted with dichloromethane, concentrated, and purified on a silica gel column (methanol / dichloromethane = 1:10) to obtain 7 g of the title compound. The two-step yield was 50.9%.

[0702] 3. Preparation of N-ethyl-2-(2-(2-hydroxyethyl)phenyl)acetamide

[0703] 2-(2-(2-(Ethylamino)-2-oxoethyl)phenyl)acetic acid (7 g, 31.5 mmol) was dissolved in tetrahydrofuran (10 mL), and borane (37.8 mL, 37.8 mmol) was added dropwise at 0°C. After the addition was complete, the system was reacted at 25°C for 3 h. LCMS detected the reaction was complete, and methanol was added to quench the reaction. The reaction was washed with water, extracted with ethyl acetate, and the organic phase was concentrated and purified on a silica gel column (methanol / dichloromethane = 1:10) to obtain 5 g of the title compound in a yield of 76.3%.

[0704] 4. Preparation of 2-(2-(ethylamino)-2-oxoethyl)phenethyl methanesulfonate

[0705] N-Ethyl-2-(2-(2-hydroxyethyl)phenyl)acetamide (5 g, 24 mmol) was dissolved in tetrahydrofuran (10 mL). Methanesulfonyl chloride (5.6 g, 48 mmol) and triethylamine (7.3 g, 72 mmol) were added dropwise at 0°C. After the addition was complete, the system was reacted at 0°C for 3 h. LCMS detected the reaction completion. Water was added to quench the reaction. The product 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 title compound in a yield of 71.4%.

[0706] 5. Preparation of 3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one

[0707] 2-(2-(Ethylamino)-2-oxoethyl)phenethyl methanesulfonate (4.5 g, 15.7 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (1.2 g, 31.4 mmol) was added dropwise at 0°C. After the addition was complete, the system was reacted at 0°C for 2 h. LCMS detected that the reaction was complete. Water was added to the system to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified on a silica gel column (ethyl acetate / petroleum ether = 1:1) to obtain 2.35 g of a crude product.

[0708] 6. Preparation of 3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one

[0709] 3-Ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (2.35 g, crude) was dissolved in concentrated sulfuric acid (10 mL). Potassium nitrate (1.4 g, 13.8 mmol) was added dropwise at 0°C. After the addition was complete, the system was reacted at 0°C for 2 h. LCMS confirmed the reaction was complete. The reaction solution was added dropwise to ice water to quench the reaction. The product was extracted with ethyl acetate, the organic phase was concentrated, and purified on a silica gel column (ethyl acetate / petroleum ether = 1:3) to obtain 1 g of the title compound. The yield for the two steps was 27.1%.

[0710] 7. Preparation of 8-amino-3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one

[0711] Dissolve 3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (1 g, 4.3 mmol) in methanol (20 mL). Add Pd / C (500 mg). Incubate at 25°C for 2 h. LCMS confirms the reaction is complete. Filter and dry the filtrate to obtain 860 mg of the title compound in a 90.4% yield.

[0712] 8. Preparation of N-(3-ethyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0713] 8-Amino-3-ethyl-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (860 mg, 4.20 mmol) was dissolved in acetic acid (10 mL) and acetic anhydride (2 mL) was added. The mixture was reacted at 25°C for 2 h. LCMS confirmed the reaction was complete. The reaction solution was dried by rotary evaporation, diluted with dichloromethane, washed with saturated sodium bicarbonate solution, and the organic phase was dried by rotary evaporation. The mixture was then purified by silica gel column chromatography (methanol / dichloromethane = 1:1) to obtain 650 mg of the target compound in a yield of 62.7%.

[0714] 9. Preparation of N-(3-ethyl-8-nitro-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide

[0715] N-(3-Ethyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (580 mg, 2.35 mmol) was dissolved in concentrated sulfuric acid (10 mL). Fuming nitric acid (181 mg, 2.82 mmol) was added dropwise at 0°C and allowed to react at 25°C for 2 h. The reaction was complete after LCMS analysis. The reaction solution was added dropwise to ice-cold water to quench the reaction. The organic phase was extracted with dichloromethane, concentrated, and purified on a silica gel column (methanol / dichloromethane = 1:10) to obtain 230 mg of the title compound in a yield of 33.5%.

[0716] 10. Preparation of 7-amino-3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one

[0717] N-(3-Ethyl-8-nitro-4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)acetamide (230 mg, 0.79 mmol) was dissolved in methanol (10 mL), and potassium carbonate (327 mg, 2.37 mmol) was added. The mixture was reacted at 25°C for 4 h. The reaction was complete after LCMS detection. The reaction solution was dried and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain 190 mg of the target compound in a yield of 96.54%.

[0718] 11. Preparation of ethyl 2-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0719] 7-Amino-3-ethyl-8-nitro-1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one (190 mg, 0.76 mmol) was dissolved in ethanol (10 mL), and Pd / C (120 mg) was added. The mixture was allowed to react at 25°C for 2 h. LCMS confirmed the reaction was complete. 3-Ethoxy-3-iminopropionic acid ethyl ester hydrochloride (297 mg, 1.52 mmol) was added and the mixture was allowed to react at 50°C for 2 h. LCMS confirmed the reaction was complete. The mixture was filtered, the filtrate was dried, diluted with dichloromethane, and washed with saturated sodium bicarbonate. The organic phase was dried and separated by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain 150 mg of the title compound in a yield of 62.4%.

[0720] 12. Preparation of 7-amino-6-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

[0721] Ethyl 2-(7-ethyl-6-oxo-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (100 mg, 0.32 mmol) and 3-aminothiophene-2-carbonitrile (40 mg, 0.32 mmol) were dissolved in tetrahydrofuran (10 mL). LDA (1 mL, 1.92 mmol) was added at 40°C and allowed to react for 2 h at 40°C. LCMS confirmed the reaction was complete. The reaction solution was quenched by pouring into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was spin-dried and slurried with methanol to obtain 18.5 mg of the title compound in a 14.7% yield.

[0722] Molecular formula: C 20 H 19 N5O2S molecular weight: 393.5 LC-MS (M / e): 394.0 (M+H+)

[0723] 1 H-NMR (400MHz, DMSO-d6) δ: 12.80 (d, J = 6.0Hz, 1H), 11.79 (d, J = 6.8Hz, 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).

[0724] Preparation Example 38: Preparation of 7-amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydro-5,9-methanoimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 54)

[0725]

[0726] 1. Preparation of 7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methanolbenzo[d]azepine

[0727] Dissolve 1-(7,8-dinitro-1,2,4,5-tetrahydro-3H-1,5-methoxybenzo[d]azepin-3-yl)-2,2,2-trifluoroethane-1-one (200.0 mg, 0.58 mol) in methanol (8 mL) and water (3 mL). Add sodium carbonate (127.2 mg, 1.2 mmol) and continue the reaction for 16 hours. Quench the reaction by adding water and extract with dichloromethane (100 mL). The organic phase is dried and concentrated to yield 170 mg of the crude target compound, which is used directly in the next reaction.

[0728] 2. Preparation of 3-cyclopropyl-7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine

[0729] 7,8-Dinitro-2,3,4,5-tetrahydro-1H-1,5-methanolbenzo[d]azepine (crude product) (170.0 mg, 0.68 mmol) was dissolved in methanol (10.0 mL). Acetic acid (432.0 mg, 7.2 mmol), sodium cyanoborohydride (276.3 mg, 4.4 mmol), and (1-ethoxycyclopropyloxy)trimethylsilane (278.9 mg, 1.6 mmol) were added, and the reaction was incubated at 65°C for 3 h. The reaction was quenched by adding water, and the organic phase was extracted with dichloromethane. The organic phase was concentrated and purified on a silica gel column (ethyl acetate / petroleum ether = 2:3) to obtain 127.0 mg of the title compound, with a two-step yield of 75.7%.

[0730] 3. Preparation of 3-cyclopropyl-7,8-diamino-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine

[0731] Dissolve 3-cyclopropyl-7,8-dinitro-2,3,4,5-tetrahydro-1H-1,5-methylbenzo[d]azepine (320.0 mg, 1.1 mmol) in ethanol (10 mL). Add Pd / C (200.0 mg). Hydrogenate the mixture at 25°C under a hydrogen atmosphere for 40 minutes. The reaction mixture is used directly in the next step.

[0732] 4. Preparation of ethyl 2-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0733] To the reaction mixture from the previous step, ethyl 3-ethoxy-3-iminopropionate hydrochloride (508.6 mg, 2.6 mmol) was added, and the temperature was raised to 50°C for 2 hours. The mixture was filtered through celite, concentrated, and spun down to dryness. The filtrate was diluted with water, and the pH was adjusted to alkaline with sodium bicarbonate solution. The mixture was extracted with dichloromethane (100 mL). The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 250.0 mg of the title compound, with a yield (two steps) of 69.4%.

[0734] 5. Preparation of 7-amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydro-5,9-methanoimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

[0735] Ethyl 2-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (250 mg, 0.66 mmol) was dissolved in tetrahydrofuran (15 mL), and 2-aminothiophene-3-carbonitrile (113.1 mg, 0.91 mmol) was added. The mixture was placed at 40°C under a nitrogen atmosphere, and lithium diisopropylamide (1.5 mL, 3.0 mmol) was added and stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride solution and 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 title compound in a 7.1% yield.

[0736] Molecular formula: C 22 H 21 N5OS molecular weight: 403.5 LC-MS (M / e): 404.0 (M+H + )

[0737] 1 H-NMR(400MHz, CDCl3)δ:12.75(s,1H),11.75(s,1H),10.72-10.52(m,1H),7.9 4(d,J=8.8HZ,1H),7.91-7.67(m,1H),7.36(s,1H),7.28(s,1H),7.01(d,J=5.2H Z,1H),3.20-3.10(m,2H),2.92-2.82(m,2H),2.64-2.50(m,2H),2.25-2.15(m,1 H),1.85-1.75(m,1H),1.70-1.60(m,1H),0.30-0.20(m,2H),-0.1--0.2(m,2H).

[0738] Preparation Example 39: Preparation of 7-amino-6-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazole[4',5]:4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 55)

[0739]

[0740]

[0741] 1. Preparation of ethyl 2-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0742] 1,5-Dihydrobenzo[d]oxepin-2,4-dione and cyclopropylamine were selected as starting materials and the preparation method of Preparation Example 37 was referred to to prepare ethyl 2-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate.

[0743] 2. Preparation of 7-amino-6-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazole[4',5]:4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one

[0744] Ethyl 2-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepinpyridin-2-yl)acetate (32.7 mg, 0.1 mmol) and 2-cyano-3-aminothiophene (12.4 mg, 0.1 mmol) were dissolved in tetrahydrofuran (5 mL). The temperature was raised to 40°C under nitrogen. 2M lithium diisopropylamide solution (0.25 mL, 0.5 mmol) was added dropwise at 40°C. After addition, the mixture was allowed to react at 40°C for 3 hours. LCMS confirmed the completion of the reaction. The temperature was lowered to 25°C and the reaction was quenched with saturated ammonium chloride aqueous solution. The organic phase was extracted with ethyl acetate, dried, and concentrated. The resulting solid was slurried with methanol and filtered to obtain the solid. The solid was dried to afford 14.5 mg of the title compound in a yield of 35.8%.

[0745] Molecular formula: C 21 H 19 N5O2S molecular weight: 405.5 LC-MS (M / e): 406.1 (M+H + )

[0746] 1H-NMR (400MHz, DMSO-d6) 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).

[0747] Preparation Example 40: Preparation of 7-((2,2-difluoroethyl)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]pyridin-5(4H)-one trifluoroacetate (Trifluoroacetate salt of Compound 58)

[0748]

[0749] 1. Preparation of tert-butyl 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)-carboxylate

[0750] Tert-butyl 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)-carboxylate (500 mg, 0.60 mmol) was dissolved in acetonitrile (5 mL), and 2,2-difluoroethyl-1-amine (388 mg, 4.78 mmol) was added. The mixture was reacted at 40°C for 2 h. LCMS analysis indicated that the reaction was complete, and the solvent was evaporated. The product was separated by silica gel column chromatography (ethyl acetate:petroleum ether = 1:1) to obtain 300 mg of the title compound in a yield of 65.4%.

[0751] 2. Preparation of 7-((2,2-difluoroethyl)amino)-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

[0752] Tert-butyl 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)-carboxylate (300 mg, 0.39 mmol) was dissolved in trifluoroacetic acid (3.5 ml) and hydrochloric acid (0.5 mL). The mixture was heated to 110°C and reacted for 24 hours. LCMS confirmed the reaction was complete. The reaction solution was dried and adjusted to pH 8 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane, dried, and concentrated to obtain 200 mg of the crude target compound.

[0753] 3. Preparation of 7-((2,2-difluoroethyl)amino)-6-(7-(oxetane-3-yl)-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 trifluoroacetate

[0754] 7-((2,2-difluoroethyl)amino)-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 (200 mg, N / A) was dissolved in methanol (5 mL), and oxetane-3-one (30 mg, 0.40 mmol) and acetic acid (144 mg, 2.4 mmol) were added. After reacting at 25°C for 1 hour, sodium cyanoborohydride (150 mg, 2.4 mmol) was added and the reaction was continued for 8 hours. LCMS confirmed the reaction was complete. Aqueous sodium bicarbonate was added to the system, and the mixture was extracted with dichloromethane. The organic phase was collected and the solvent was dried by spin drying. The title compound (19 mg) was obtained in a 37.8% yield by reverse-phase column chromatography (methanol / water = 0-40%, with each phase containing 0.3% trifluoroacetic acid).

[0755] Molecular formula: C 25 H 24 F5N5O3S molecular weight: 569.15 LC-MS (M / e): 472.5 (M+H + )

[0756] 1H-NMR(400MHz,DMSO-d6)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).

[0757] Preparation Example 41: Preparation of 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptanyl[4,5]benzo[1,2-d]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)thieno[3,2-b]pyridin-5(4H)-one (Compound 59)

[0758]

[0759] 1. Preparation of 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptanyl[4,5]benzo[1,2-d]imidazol-2-yl)-7-hydroxy-4-(4-methoxybenzyl)thieno[3,2-b]pyridin-5(4H)-one

[0760] Ethyl 2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptanyl[4,5]benzo[1,2-d]imidazol-2-yl)acetate (130 mg, 0.4 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (173 mg, 0.6 mmol) were dissolved in tetrahydrofuran (20 mL). The temperature was raised to 40°C. LDA (2 mL, 4 mmol) was added under nitrogen and allowed to react for 2 hours. LCMS confirmed the reaction was complete. The mixture was quenched by addition of saturated ammonium chloride solution and extracted with a mixture of ethyl acetate and methanol (ethyl acetate:methanol = 10:1 (100 mL x 4)). The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to afford 190 mg of the title compound in a 90% yield.

[0761] 2. Preparation of 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-b]pyridin-7-yl trifluoromethanesulfonate

[0762] 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptanyl[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) was dissolved in dichloromethane (100 mL) at 0°C. Pyridine (285 mg, 3.3 mmol) and trifluoromethanesulfonic anhydride (620 mg, 2 mmol) were added and allowed to react for 1 hour. LCMS confirmed the reaction was complete. The solvent was concentrated, and the reaction was quenched by the addition of saturated sodium bicarbonate. The reaction was extracted with dichloromethane (100 mL x 4). The organic phase was dried and concentrated to afford 390 mg of the crude title compound, which was used in the next step without further processing.

[0763] 3. Preparation of 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[3,2-b]pyridin-5(4H)-one

[0764] Dissolve 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-b]pyridin-7-yl trifluoromethanesulfonate (390 mg) in acetonitrile (100 mL), add difluoroethylamine (291 mg, 3.6 mmol), and heat to 40°C for 4 hours. LCMS indicates the reaction is complete. The organic phase is dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to afford 140 mg of the title compound, with a two-step yield of 66%.

[0765] 4. Preparation of 6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptanyl[4,5]benzo[1,2-d]imidazol-2-yl)-7-((2,2-difluoroethyl)amino)thieno[3,2-b]pyridin-5(4H)-one

[0766] Place 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[3,2-b]pyridin-5(4H)-one (140 mg, 0.24 mmol) in a 100 mL single-necked flask. Add trifluoroacetic acid (6 mL) and concentrated hydrochloric acid (1 mL). Heat to 110°C and react for 24 hours. LCMS indicates completion of the reaction. The organic phase is concentrated and purified by reverse-phase column chromatography (water:methanol = 10:3) to afford 52 mg of the title compound in a 57% yield.

[0767] Molecular formula: C 24 H 25 F2N5OS molecular weight: 469.6 LC-MS (M / e): 470.2 (M+H + )

[0768] 1 H-NMR(400MHz,DMSO-d6)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).

[0769] Preparation Example 42: Preparation of 7-amino-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 (Compound 60)

[0770]

[0771] 1. Preparation of 7-amino-1,2,4,5-tetrahydrobenzo[d]oxepin

[0772] Dissolve 7-nitro-1,2,4,5-tetrahydrobenzo[d]oxepin (140 mg, 0.73 mmol) in methanol (5 mL) and add palladium on carbon (100 mg, N / A). Incubate under a hydrogen atmosphere for 2 hours. LCMS confirms the reaction is complete. Filter, collect, and concentrate the filtrate to obtain the crude target compound, which is used directly in the next step.

[0773] 2. Preparation of N-(1,2,4,5-tetrahydrobenzo[d]oxepin-7-yl)acetamide

[0774] Dissolve 7-amino-1,2,4,5-tetrahydrobenzo[d]oxepin (crude product from the previous step) in acetic acid (2 mL) and add acetic anhydride (2 mL). After addition, react at 15°C for 1 hour. LCMS indicates the reaction is complete. Dilute with water, adjust the pH to 9 with saturated sodium bicarbonate solution, extract with dichloromethane, concentrate the aqueous phase, and purify on a C18 column (methanol = 0-80%) to obtain 100 mg of the title compound, with a two-step yield of 66.8%.

[0775] 3. Preparation of N-(8-nitro-1,2,4,5-tetrahydrobenzo[d]oxepin-7-yl)acetamide

[0776] Dissolve N-(1,2,4,5-tetrahydrobenzo[d]oxepin-7-yl)acetamide (100 mg, 0.49 mmol) in concentrated sulfuric acid (2 mL). Add fuming nitric acid (38 mg, 0.61 mmol) dropwise at 0°C. After addition, react at 0°C for 10 min. LCMS confirms the reaction is complete. Pour the mixture into ice water and adjust the pH to 7 with aqueous sodium hydroxide. Concentrate the solvent, wash the solid with dichloromethane and methanol, and concentrate the organic phase to obtain the crude target compound, which is used directly in the next step.

[0777] 4. Preparation of 8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazepine-7-amine

[0778] Dissolve N-(8-nitro-1,2,4,5-tetrahydrobenzo[d]oxepin-7-yl)acetamide (N / A, 0.49 mmol) in methanol (5 mL) and add potassium carbonate (166 mg, 1.2 mmol). After addition, react at 55°C for 8 hours. LCMS indicates completion of the reaction. Filter through Celite, concentrate the filtrate, and purify on a C18 column (methanol = 0-80%) to obtain 80 mg of the title compound in a 78.1% yield.

[0779] 5. Preparation of ethyl 2-(5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)acetate

[0780] Dissolve 8-nitro-1,2,4,5-tetrahydrobenzo[d]oxazepine-7-amine (80 mg, 0.38 mmol) in ethanol (3 mL) and add Pd / C (100 mg). After addition, hydrogenate the mixture at 15°C for 2 hours. LCMS indicates the reaction is complete. Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (149 mg, 0.76 mmol) and heat the temperature to 50°C for 2 hours. LCMS indicates the reaction is complete. Filter through celite, concentrate the filtrate, and purify on a silica gel column (dichloromethane:methanol = 15:1) to obtain 100 mg of the title compound in a 94.9% yield.

[0781] 6. Preparation of 7-amino-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

[0782] Ethyl 2-(5,6,8,9-tetrahydro-1H-oxazepamo[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 mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the reaction was complete. The reaction was quenched by adding saturated ammonium chloride and extracted with dichloromethane. The organic phase was dried, concentrated, and then slurried with methanol to obtain 5 mg of the title compound in a yield of 7.98%.

[0783] Molecular formula: C 18 H 16 N4O2S molecular weight: 352.1 LC-MS (M / e): 353.1 (M+H + )

[0784] 1 H-NMR(400MHz,DMSO-d6)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).

[0785] Preparation Example 43: Preparation of 7-((2,2-difluoroethyl)amino)-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 (Compound 61)

[0786]

[0787] 1. Preparation of 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

[0788] Ethyl 2-(5,6,8,9-tetrahydro-1H-oxazelo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)acetate (500 mg, 1.8 mmol) and 1-(4-methoxybenzyl)-2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (686 mg, 2.4 mmol) were dissolved in tetrahydrofuran (10 mL). Under nitrogen, LDA (4.5 mL, 5 mol) was added at 40°C. The mixture was allowed to react for 1 hour at 40°C. LCMS confirmed the reaction was complete, and the temperature was lowered to 15°C. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the organic phase was dried and concentrated to obtain the crude target compound. The crude target compound was again added to tetrahydrofuran (10 mL), and LDA (4.5 mL, 5 mol) was added under nitrogen. The reaction was allowed to react for 1 hour at 40°C. The temperature was lowered to 15° C., and saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with dichloromethane. The organic phase was dried, concentrated, and purified on a silica gel column (dichloromethane:methanol=20:1) to obtain 320 mg of the target compound in a yield of 37.1%.

[0789] 2. Preparation of 4-(4-methoxybenzyl)-5-oxo-6-(1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydro-1H-oxazo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)-4,5-dihydrothieno[3,2-b]pyridin-7-yl trifluoromethylsulfonate

[0790] Dissolve 7-hydroxy-4-(4-methoxybenzyl)-6-(5,6,8,9-tetrahydro-1H-oxazepino[4',5':4,5]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (320 mg, 0.68 mmol) in dichloromethane (10 mL). Add pyridine (1.1 g, 13.6 mmol) and trifluoromethanesulfonic anhydride (1.2 g, 4.1 mmol) at 0°C. After addition, react at 0°C for 30 minutes. LCMS indicates the reaction is complete. Quench the reaction by adding saturated aqueous sodium bicarbonate solution, extract with dichloromethane, dry and concentrate the organic phase, and use it directly in the next step.

[0791] 3. Preparation of 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]pyridin-5(4H)-one

[0792] 4-(4-Methoxybenzyl)-5-oxo-6-(1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydro-1H-oxazepamo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)-4,5-dihydrothieno[3,2-b]pyridin-7-yl trifluoromethylsulfonate (N / A, 0.68 mmol) was dissolved in acetonitrile (10 mL). 2,2-difluoroethane-1-amine (440 mg, 5.4 mmol) was added and the mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated and purified on a silica gel column (dichloromethane:methanol = 20:1) to obtain 130 mg of the title compound, with a two-step yield of 28.6%.

[0793] 4. Preparation of 7-((2,2-difluoroethyl)amino)-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

[0794] 7-((2,2-difluoroethyl)amino)-4-(4-methoxybenzyl)-6-(1-((trifluoromethyl)sulfonyl)-5,6,8,9-tetrahydro-1H-oxazepamo[4',5':4,5]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (130 mg, 0.19 mmol) was dissolved in concentrated hydrochloric acid (1.5 mL). Trifluoroacetic acid (10.5 mL) was added. After addition, the temperature was raised to 110°C and the reaction mixture was allowed to react for 24 hours. LCMS confirmed the completion of the reaction. The solvent was concentrated, the mixture was dissolved in dichloromethane, and saturated aqueous sodium bicarbonate solution was added. The mixture was filtered, and the filter cake was slurried with methanol to obtain 40 mg of the title compound in a yield of 50.5%.

[0795] Molecular formula: C 20 H 18 F2N4O2S molecular weight: 416.4 LC-MS (M / e): 417.1 (M+H + )

[0796] 1H-NMR (400MHz, DMSO-d6) 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).

[0797] Preparation Example 44: Preparation of 7-amino-6-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)-1-methyl-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (Compound 62)

[0798]

[0799] Ethyl 2-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (50 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL). 4-Amino-1-methyl-1H-pyrazole-5-carbonitrile (20 mg, 0.16 mmol) was added under nitrogen. Lithium diisopropylamide (0.40 mL, 0.80 mmol) was added at 40°C. After addition, the mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the reaction was complete. The reaction was quenched by addition of saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried, concentrated, and then slurried with methanol to obtain 33 mg of the title compound in a 53.0% yield.

[0800] Molecular formula: C 21 H 23 N7O molecular weight: 389.5 LC-MS (M / e): 390.2 (M+H + )

[0801] 1 H-NMR(400MHz,DMSO-d6)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).

[0802] Preparation Example 45: Preparation of 7-amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one (Compound 63)

[0803]

[0804] 1. Preparation of 2-nitro-5,6,8,9-tetrahydro-7H-benzo[7]annulene-7-one

[0805] Dissolve 5,6,8,9-tetrahydro-7H-benzo[7]annulene-7-one (2.0 g, 12.4 mmol) in concentrated sulfuric acid (20 mL). After stirring for 1 hour, slowly add potassium nitrate (1.5 g, 14.9 mmol) in batches. After addition, react at 0°C for 2 hours. LCMS confirms the completion of the reaction. Pour the mixture into ice water (200 mL) and extract with ethyl acetate (100 mL x 4). The organic phase is dried, concentrated, and purified on a silica gel column (n-heptane:ethyl acetate = 5:1) to obtain 2.0 g of the title compound in a 79% yield.

[0806] 2. Preparation of 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)azetidine

[0807] Dissolve 2-nitro-5,6,8,9-tetrahydro-7H-benzo[7]annulene-7-one (2.0 g, 9.7 mmol) in methanol (100 mL), add sodium cyanoborohydride (1.6 g, 23.5 mmol) and azetidine (673 mg, 11.8 mmol), and react at 35°C for 12 hours. LCMS indicates the reaction is complete. Concentrate the solvent, quench the reaction by adding saturated sodium bicarbonate, extract with ethyl acetate (100 mL x 4), dry and concentrate the organic phase, and purify on a silica gel column (dichloromethane:methanol = 10:1) to obtain 2.3 g of the title compound in a 96% yield.

[0808] 3. Preparation of 7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine

[0809] Dissolve 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)azetidine (2.3 g, 9.3 mmol) in methanol (100 mL) and add Raney nickel (790 mg, 9.3 mmol). Allow to react at 30°C for 4 hours. LCMS confirms the reaction is complete. Filter through Celite and concentrate to obtain 1.6 g of the title compound, with a crude yield of 80%.

[0810] 4. Preparation of N-(7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)acetamide

[0811] 7-(Azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine (1.6 g, 7.5 mmol) was placed in a 100 mL single-necked flask, acetic acid (5 mL) and acetic anhydride (5 mL) were added, and the mixture was allowed to react at 25°C for 1 hour. LCMS confirmed the completion of the reaction. The mixture was concentrated to dryness, quenched with saturated sodium bicarbonate, and extracted with a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol = 5:1) (100 mL x 4 times). The organic phase was dried and concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 1.5 g of the title compound in a yield of 78%.

[0812] 5. Preparation of N-(7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)acetamide

[0813] Dissolve N-(7-(azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)acetamide (1.5 g, 5.9 mmol) in concentrated sulfuric acid (15 mL) and stir at 0°C for 1 hour. Add potassium nitrate (656 mg, 6.5 mmol) in batches. After addition, react at 0°C for 1 hour. LCMS indicates the reaction is complete. Pour the mixture into ice water and quench with saturated sodium carbonate. Extract with a mixed solution of ethyl acetate and methanol (ethyl acetate:methanol = 10:1) (200 mL x 4). The organic phase is dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 1.6 g of the title compound in an 89% yield.

[0814] 6. Preparation of 7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-amine

[0815] Dissolve N-(7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetamide (1.6 g, 5.3 mmol) in methanol (100 mL). Add potassium carbonate (2.2 g, 15.8 mmol). Continue the reaction at 50°C for 4 hours. LCMS indicates the reaction is complete. Filter through celite, dry, concentrate, and purify on a silica gel column (dichloromethane:methanol = 10:1) to obtain 854 mg of the title compound in a 62% yield.

[0816] 7. Preparation of ethyl 2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazol-2-yl)acetate

[0817] Dissolve 7-(azetidin-1-yl)-3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]cycloalkene-2-amine (854 mg, 3.3 mmol) in ethanol (50 mL) and add Pd / C (489 mg, 1.7 mmol). After addition, hydrogenate at 25°C for 8 hours. LCMS indicates the reaction is complete. Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (1.5 g, 7.9 mmol), heat to 50°C, stir under reflux for 3 hours, and determine the reaction is complete by LCMS. Add celite and filter. The organic phase is dried, concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 755 mg of the title compound, with a two-step yield of 70.6%.

[0818] 8. Preparation of 7-amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazol-2-yl)thieno[3,2-b]pyridin-5(4H)-one

[0819] Ethyl 2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazol-2-yl)acetate (755 mg, 2.3 mmol) and 2-cyano-3-aminothiophenol (682 mg, 5.5 mmol) were dissolved in tetrahydrofuran (15 mL). The temperature was raised to 40°C under nitrogen. LDA (1.2 mmol, 0.6 mL) was slowly added. After addition, the mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the completion of the reaction. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated, and then extracted with a mixture of ethyl acetate and methanol (ethyl acetate:methanol = 10:1) (200 mL x 4). The organic phase was dried and concentrated, and purified on a silica gel column (dichloromethane:methanol = 10:1) to obtain 401 mg of the title compound in a yield of 43%.

[0820] Molecular formula: C 22 H 23 N5OS molecular weight: 405.5 LC-MS (M / e): 406.1 (M+H + )

[0821] 1H-NMR (400MHz, DMSO-d6)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).

[0822] Preparation Example 46: Preparation of 7-(isopropylamino)-6-(7-(oxetan-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5:4,5]benzo[1,2-d]azepin-2-yl)thiophene[3,2-b]pyridin-5(4H)-one (Compound 64)

[0823]

[0824] Dissolve 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) in methanol (10 mL). Add 3-oxetanone (90 mg, 0.54 mmol) and acetic acid (186 mg, 0.18 mmol). After reacting at 25°C for 30 minutes, sodium cyanoborohydride (96 mg, 0.54 mmol) was added. After addition, the mixture was allowed to react at 35°C for 16 hours. LCMS confirmed the completion of the reaction. Saturated sodium bicarbonate was added to adjust the pH to 8, and the mixture was extracted with dichloromethane (40 mL). Separate the mixture by silica gel column chromatography (methanol:dichloromethane = 1:15) to obtain 60 mg of the title compound in a 43.8% yield.

[0825] Molecular formula: C 24 H 27 N5O2S molecular weight: 449.6 LC-MS (M / e): 450.2 (M+H + )

[0826] 1H-NMR (400MHz, DMSO-d6) 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).

[0827] 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)

[0828]

[0829] 1. Preparation of 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]pyridin-5(4H)-one

[0830] Dissolve 6-(7-(azetidin-1-yl)-1-((trifluoromethyl)sulfonyl)-1,5,6,7,8,9-hexahydrocyclohepta[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) in acetonitrile (50 mL), warm to 40°C, and react for 3 hours. LCMS analysis confirmed the completion of the reaction. The product was separated by column chromatography and purified on a silica gel column (dichloromethane:methanol = 10:1) to afford 157 mg of the title compound in a 56.5% yield.

[0831] 2. Preparation of 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

[0832] 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]pyridin-5(4H)-one (157 mg, 0.22 mmol) was placed in a 100 mL single-necked flask. Trifluoroacetic acid (6 mL) and concentrated hydrochloric acid (1 mL) were added, and the mixture was heated to 110°C and reacted for 24 hours. LCMS confirmed the reaction was complete. The organic phase was concentrated and purified by reverse-phase column chromatography (water:methanol = 10:3) to obtain 38 mg of the title compound in a 39% yield.

[0833] Molecular formula: C 25 H 29 N5OS molecular weight: 447.6 LC-MS (M / e): 480.2 (M+H + )

[0834] 1 H-NMR(400MHz,DMSO-d6)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).

[0835] Preparation Example 48: 2-(7-amino-1-methyl-5-oxo-4,5-dihydro-1H-pyrazolo[4,3-b]pyridin-6-yl)-7-cyclopropyl-5,7,8,9-tetrahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-6(1H)-one (Compound 66)

[0836]

[0837] Ethyl 2-(7-cyclopropyl-6-oxo-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (200 mg, 0.61 mmol) was dissolved in tetrahydrofuran (10 mL), and 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (89 mg, 0.73 mmol) was added dropwise at 40°C. LDA (2.44 mL, 4.88 mmol) was added dropwise and the reaction was continued for 6 h. LCMS confirmed the reaction was complete. The mixture was quenched by pouring into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was then spin-dried and slurried with methanol to obtain 40 mg of the crude target compound. This was purified by reverse-phase chromatography (methanol:water = 0-50%) to afford 2.4 mg of the target compound in a 1.0% yield.

[0838] Molecular formula: C 21 H 21 N7O2 molecular weight: 403.4 LC-MS (M / e): 404.1 (M+H + )

[0839] 1 H-NMR(400MHz,DMSO-d6)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).

[0840] Preparation Example 49: Preparation of 7-amino-1-methyl-6-(7-(oxetane-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 (Compound 67)

[0841]

[0842] 1. Preparation of 8-nitro-3-(oxetane-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine

[0843] 8-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (500 mg, 5.42 mmol) and oxetanone (523 mg, 7.26 mmol) were dissolved in methanol (20 mL). Acetic acid (1.5 g, 24.2 mmol) and sodium cyanoborohydride (900 mg, 14.5 mmol) were added and reacted at 25°C for 16 h. LCMS confirmed the reaction was complete. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The organic phase was then dried and purified on a silica gel column (dichloromethane:methanol = 15:1) to afford 420 mg of the title compound in a 66.0% yield.

[0844] 2. Preparation of ethyl 2-(7-(oxetane-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate

[0845] Dissolve 8-nitro-3-(oxetane-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-amine (420 mg, 1.6 mmol) in ethanol (10 mL) and add Pd / C (200 mg). Hydrogenate at 25°C for 2 hours. Add ethyl 3-ethoxy-3-iminopropionate hydrochloride (657 mg, 3.36 mmol) and heat to 50°C before continuing for 4 hours. LCMS indicates completion of the reaction. Filter through Celite, spin-dry the filtrate, dilute with dichloromethane, and wash with saturated sodium bicarbonate. The organic phase is then spin-dried and purified on a silica gel column (dichloromethane:methanol = 10:1) to afford 370 mg of the title compound in a 70.1% yield.

[0846] 3. Preparation of 7-amino-1-methyl-6-(7-(oxetane-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

[0847] Ethyl 2-(7-(oxetane-3-yl)-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (80 mg, 0.24 mmol) was dissolved in tetrahydrofuran (5 mL), and 4-amino-1-methyl-1H-pyrazole-5-carbonitrile (29 mg, 0.24 mmol) was added dropwise. LDA (0.96 mL, 1.92 mmol) was added dropwise at 45°C. The reaction was continued for 5 h, and the reaction was complete by LCMS. The mixture was quenched by pouring into saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and the organic phase was spin-dried and slurried with methanol to obtain 17.5 mg of the title compound in a yield of 17.8%.

[0848] Molecular formula: C21 H 23 N7O2 molecular weight: 405.5 LC-MS (M / e): 406.2 (M+H + )

[0849] 1 H-NMR(400MHz,DMSO-d6)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).

[0850] Preparation Example 50: Preparation of 7-amino-6-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocyclohepta[4,5]benzo[1,2-d]imidazol-2-yl)-1-methyl-1,4-dihydro-5H-pyrazolo[4,3-b]pyridin-5-one (Compound 68)

[0851]

[0852] Ethyl 2-(7-(azetidin-1-yl)-1,5,6,7,8,9-hexahydrocycloheptyl[4,5]benzo[1,2-d]imidazol-2-yl)acetate (200 mg, 0.61 mmol) and 3-amino-1,5-dimethyl-1H-pyrrol-2-cyanoacetate (112 mg, 0.92 mmol) were dissolved in tetrahydrofuran (50 mL). The temperature was raised to 40°C under nitrogen. LDA (3.1 mL, 6.1 mmol) was slowly added. After addition, the mixture was allowed to react at 40°C for 2 hours. LCMS confirmed the completion of the reaction. The reaction was quenched by addition of saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried and concentrated, and then extracted with a mixed solvent of ethyl acetate / methanol (ethyl acetate:methanol = 10:1, 200 mL x 4). The organic phase was dried and concentrated, and purified by reverse-phase column chromatography (water:methanol = 10:4) to obtain 100 mg of the title compound in a yield of 40.6%.

[0853] Molecular formula: C 22 H 25 N7O molecular weight: 403.5 LC-MS (M / e): 404.2 (M+H + )

[0854] 1H-NMR(400MHz,DMSO-d6)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).

[0855] Preparation Example 51: Preparation of 4-amino-5-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazole[4',5':4,5]benzo[1,2-d]azepin-2-yl)-1-methyl-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (Compound 69)

[0856]

[0857] Ethyl 2-(7-cyclopropyl-1,5,6,7,8,9-hexahydroimidazo[4',5':4,5]benzo[1,2-d]azepin-2-yl)acetate (100 mg, 0.32 mmol) was dissolved in tetrahydrofuran (5 mL). 6-Methyl-1-methyl-1H-pyrazole-4-carbonitrile (39 mg, 0.32 mmol) was added under nitrogen. LDA (2 M, 1.3 mL, 2.6 mmol) was added at 40°C. After addition, the mixture was allowed to react at 40°C for 3 hours. LCMS confirmed the reaction was complete. The reaction was quenched by pouring into saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried, concentrated, and then slurried with methanol and dichloromethane to obtain 10 mg of the title compound in an 8.1% yield.

[0858] Molecular formula: C 21 H 23 N7O2 molecular weight: 389.5 LC-MS (M / e): 390.2 (M+H + )

[0859] 1 H-NMR(400MHz,DMSO-d6)δ:12.17(s,1H),10.71(s,1H),10.55(s,1H),7.60(s,1H),7.33(s,1H),7.2 5(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).

[0860] The compounds shown in the following table were prepared using the same or similar methods as the above preparation examples:

[0861]

[0862]

[0863] Experimental plan

[0864] The following provides exemplary experimental schemes of some compounds of the present invention to show the beneficial activities and beneficial technical effects of the compounds of the present invention. However, it should be understood that the following experimental schemes are merely examples of the content of the present invention, rather than limitations on the scope of the present invention.

[0865] Experimental Example 1 Inhibition of the Compounds of the Invention on In Vitro Kinase Activity

[0866] Test substances: some compounds of the present invention, whose structural formulas and preparation methods are shown in the preparation examples of the present invention.

[0867] The abbreviations used in the following experiments have the following meanings:

[0868] DMSO: dimethyl sulfoxide;

[0869] HEPES: Hydroxyethylpiperazine ethylsulfonic acid

[0870] Experimental Methods: Compounds were evaluated on six kinases in vitro using the Lantha screen assay.

[0871] Experimental steps:

[0872] 1. Prepare 1× kinase buffer containing 50 mM HEPES solution, 10 mM MgCl2, 4 mM dithiothreitol, 0.01% bovine serum albumin, and 0.01% Tween-20:

[0873] 2. Compound dilution:

[0874] 1) Add 10 μl of 10 mM compound solution to 90 μl of 100% DMSO to prepare a 1 mM compound solution. Add 90 μl of 100% DMSO to the second well of a 96-well plate, followed by 10 μl of the 1 mM compound solution to prepare a 100 μM compound solution. Add 60 μl of 100% DMSO to the remaining wells. Add 30 μl of compound from the second well to the third well. Repeat this process for a total of 10 dilutions, performing 3-fold dilutions.

[0875] Transfer 40 μl of the 100 μM compound solution prepared above to a 384-well Echo plate;

[0876] 2) Transfer 40 μl of 100% DMSO to two empty wells as a positive control without compound and a negative control without enzyme;

[0877] 3) Use Echo 550 to transfer 100 nl of compound to a 384-well assay plate. The starting concentration of the compound is 1 μM.

[0878] 3. Prepare 2× kinase solution with 1× kinase buffer. Transfer 5 μl of 2× kinase solution to the reaction wells of a 384-well plate. Add 1× kinase buffer to the negative control wells. Vortex at 450 rpm to mix thoroughly. Incubate at room temperature for 10 minutes.

[0879] 4. Prepare 2× substrate solution with 1× kinase buffer, transfer 5 μl of 2× substrate solution to the reaction wells of a 384-well plate, and shake at 450 rpm to mix.

[0880] 5. The reaction was carried out at room temperature for 90 minutes.

[0881] 6. Prepare 2× stop reaction solution containing antibody, transfer 10 μl of 2× stop reaction solution to the reaction wells of 384-well plate, centrifuge at 1000 rpm for 1 minute, let it stand at room temperature for 60 minutes, and then detect.

[0882] 7. Data reading: The data were read on Envision2104 Multilable Reader with excitation at 340 nm and emission at 520 nm and 495 nm.

[0883] 8. Data calculation

[0884] 1) Convert the ratio of the fluorescence readings (Lantha signal (520 nm / 495 nm)) to the inhibition percentage using the formula:

[0885] Inhibition percentage = (maximum value - Lantha signal) / (maximum value - minimum value) * 100

[0886] 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.

[0887] 2) Import data into MS Excel, IC 50 The results were curve fitted using XLFit Excel add-in version 5.4.0.8.

[0888] Experimental results

[0889] Table 1 In vitro enzyme inhibitory activity of the compounds of the present invention

[0890]

[0891]

[0892]

[0893] Experimental Conclusion

[0894] The compounds of the present invention have good inhibitory activity on MAP4K1 / HPK1 and have excellent selectivity for HPK1.

[0895] Experimental Example 2 Inhibition experiment of the compound of the present invention on in vitro cytological activity

[0896] Test substances: some compounds of the present invention, whose structural formulas and preparation methods are shown in the preparation examples of the present invention.

[0897] The abbreviations used in the following experiments have the following meanings:

[0898] ELISA: enzyme-linked immunosorbent assay;

[0899] Jurkat: human acute T-cell leukemia cells;

[0900] SLP76: 76 kDa leukocyte protein containing SH2 domain;

[0901] CD3: cluster of differentiation 3 (leukocyte differentiation antigen);

[0902] PBS buffer: phosphate-balanced saline;

[0903] TMB: 3,3',5,5'-tetramethylbenzidine.

[0904] Experimental method: The 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.

[0905] Experimental steps:

[0906] 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.

[0907] 2. Drug dilution and dosing:

[0908] 1) Prepare 10x drug solution with a maximum concentration of 3 μM, 3x dilution, and 6 concentrations;

[0909] 2) Add 9 μL of drug solution to each well of a 96-well plate seeded with cells, with two replicates for each drug concentration. Incubate the cells in the 96-well plate at 37°C and 5% CO2 for 1 hour.

[0910] 3. Cell stimulation: Add 10 μL of 50 μg / mL CD3 antibody to each well and treat for 30 minutes. Lyse the cells for pSLP76 detection.

[0911] 4. Cell Collection and Lysis

[0912] 1) Blow up the cells and transfer them to a centrifuge tube. Centrifuge at 3000 rpm and 4°C for 3 min.

[0913] 2) Discard the supernatant, add 100 μL / well of pre-chilled PBS buffer to resuspend, and centrifuge at 3000 rpm at 4°C for 3 min;

[0914] 3) Discard the supernatant and add 100 μL / tube of cell lysis buffer;

[0915] 4) Ultrasonic lysis for 5 min, and centrifugation at 14,000 rpm for 5 min.

[0916] 5. pSLP76 Detection

[0917] 1) Transfer 50 μL / well sample supernatant to a 96-well plate;

[0918] 2) Add 50 μL / well of mixed antibodies;

[0919] 3) Shake at room temperature for 1 hour;

[0920] 4) Discard the supernatant and wash three times with washing solution, 200 μL / well;

[0921] 5) Add 100 μL / well TMB substrate and shake at room temperature for 15 minutes;

[0922] 6) Add 100 μL / well of stop solution and detect at 450 nm within 30 min.

[0923] 6. Data processing

[0924] Data were analyzed using GraphPad Prism 5.0 software, and nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, from which the IC 50 value.

[0925] pSLP76 inhibition (%) = (number of test substance wells - average number of cells without CD3) / (average number of cells with CD3 - average number of cells without CD3) × 100%

[0926] Experimental Conclusion

[0927] The experimental results show that the compounds of the present invention have good inhibitory activity on the phosphorylation of serine 376 of the downstream protein SLP76 of MAP4K1 / HPK1, such as compound 1, compound 10, compound 11, compound 12, compound 14-1, compound 15, compound 23-1, compound 26, compound 49, compound 50, compound 53, compound 55, compound 58, compound 63, compound 64, etc. 50The values ​​were all less than 100 nM, indicating that the compounds of the present invention have good inhibitory activity against HPK1.

Claims

1. A compound represented by formula (II-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in, X 1 Selected from -N(R 4 ); Y 1 Selected from -O-, -N(R 4 )-or-S-; X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-N-、-N(R 4 )-or-S-; Y 2 Selected from -N-; Y 4 Selected from -C(R 2 ); Y 3 Selected from -C(R 5 ); Each R 2 、R 5 are independently selected from hydrogen, halogen, hydroxyl, thiol, amino, nitro, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkoxy; Each R 4 are independently selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; R 1 Selected from hydrogen, halogen, hydroxy, 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 、-NR a -C(O)-R b - or the following groups optionally substituted by substituents: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; Ring A is selected from a 7-8 membered monocycloalkyl group or a 7-8 membered monoheterocyclic group; 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 group optionally substituted by 1-3 Q2: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group, -(CH2) m -5-6 membered heteroaryl or -(CH2) m -phenyl; said Q2 are independently selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 alkyl; Each R a , each R b are independently selected from hydrogen, halogen, hydroxy, 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 or the following groups optionally substituted by substituents: -(CH2) m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; Each m, each n, and each p are independently selected from 0, 1, 2, or 3.

2. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein Each R 2 、R 5 are independently selected from hydrogen, halogen, hydroxyl, thiol, amino, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkoxy; Each R 4 are independently selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 Alkyl; R 1 Selected from hydrogen, halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl, amino C 1-4 Alkyl, -NR a R b 、-NR a -C(O)-R b - or the following groups optionally substituted by substituents: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; Ring A is selected from a 7-8 membered monocycloalkyl group or a 7-8 membered monoheterocyclic group; 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 group optionally substituted by 1-3 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group, -(CH2) m -5-6 membered heteroaryl or -(CH2) m -phenyl; said 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, hydroxy C 1-4 alkyl; Each R a , each R b are independently selected from hydrogen, halogen, hydroxy, 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 or the following groups optionally substituted by substituents: -(CH2) m -3-8 membered cycloalkyl, -(CH2) m -3-8 membered heterocyclic group; the substituent is selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; Each m, each n, and each p are independently selected from 0, 1, 2, or 3.

3. A compound of formula (III-1), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in, Y 1 Selected from -O-, -N(R 4 )-or-S-; Y 4 Selected from -C(R 2 ); Y 3 Selected from -C(R 5 ); X 2 、X 3 、X 4 are independently selected from -C(R 2 )-、-N-、-N(R 4 )-or-S-; Each R 2 、R 5 are independently selected from hydrogen, halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; Each R 4 are independently selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; R 1 Selected from hydrogen, halogen, nitro, cyano, C 1-4 Alkyl, halogenated C 1-4 Alkyl, -NR a -C(O)-R b -、-NR a R b or the following groups optionally substituted by substituents: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; 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 oxidized; Each Q1 is independently selected from halogen, nitro, amino, cyano, carboxyl, -C(O)R a 、-C(O)OR a 、-C(O)NR a or the following group optionally substituted by 1-2 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 Alkyl, -(CH2) m -3-6 membered cycloalkyl, -(CH2) m -3-6 membered heterocyclic group, -(CH2) m -5-6 membered heteroaryl or -(CH2) m -phenyl; said 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 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, aziridine, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl; Each R b are 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.

4. The compound according to claim 3, its pharmaceutically acceptable salt or its stereoisomer, wherein: Each R 2 、R 5 are independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or trifluoromethyl; Each R 4 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or trifluoromethyl; R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxirane, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, -NR a -C(O)-R b -or-NR a R b ; Ring A is selected from wherein each ring atom in ring A is optionally oxidized; 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, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, isopropoxymethyl, isopropoxyethyl, -(CH2) m -cyclopropyl, -(CH2) m -cyclobutyl, -(CH2) m -cyclopentyl, -(CH2) m -cyclohexyl, -(CH2) m -Oxypropyl, -(CH2) m -oxetanyl, -(CH2) m -aziridine, -(CH2) m -azetidinyl, -(CH2) m -tetrahydrofuranyl, -(CH2) m -Oxyheterocyclohexyl, -(CH2) m -tetrahydropyranyl, -(CH2) m -pyrrolidinyl, -(CH2) m -piperidinyl, -(CH2) m -piperazinyl, -(CH2) m -pyridyl, -(CH2) m -pyrimidinyl, -(CH2) m -pyridazinyl, -(CH2) m -pyrazinyl; said Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, hydroxyethyl or hydroxypropyl; Each R a are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituents are selected from halogen, hydroxyl, nitro, amino, cyano, carboxyl, methyl, ethyl, propyl, isopropyl or trifluoromethyl; Each R b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl; Each m and each n are independently selected from 0, 1, 2 or 3.

5. The compound according to claim 4, its pharmaceutically acceptable salt or its stereoisomer, wherein Ring A is selected from Each ring atom in ring A is optionally substituted with oxo.

6. The compound according to claim 4, its pharmaceutically acceptable salt or its stereoisomer, wherein Ring A is selected from Each ring atom in ring A is optionally substituted with oxo.

7. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein X 2 、X 3 、X 4 One of S, N or -N(R 4 )-, and the other two are independently -C(R 2 )-.

8. The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, which has a structure represented by general formula (IV-1): in, X 2 、X 3 、X 4 , Ring A, R 1 , Q1, n are defined as described in claim 1.

9. The compound according to claim 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having a structure represented by general formula (VII-1), general formula (VII-3), general formula (VII-5) or general formula (VII-6): in, Ring A, R 1 、R 4 , Q1, n are defined as described in claim 3.

10. The compound according to claim 9, its pharmaceutically acceptable salt or its stereoisomer, wherein R 1 Selected from-NR a R b 、-NH-C(O)-R b - or the following groups optionally substituted by substituents: -(CH2) p -3-6 membered cycloalkyl, -(CH2) p -3-6 membered heterocyclic group; the substituent is selected from halogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; Each R 4 are independently selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl; Ring A is selected from wherein each ring atom in ring A is optionally oxidized; Each Q1 is independently selected from -C(O)R a 、-C(O)OR a 、-C(O)NR a or the following group optionally substituted by 1-2 Q2: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy-C 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl; said Q2 are independently selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy or hydroxy C 1-4 alkyl; Each R a Each of the following groups is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxetanyl, aziridine, azetidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl, or imidazolidinyl; the substituent is selected from halogen, hydroxy, methyl, ethyl, propyl, isopropyl, or trifluoromethyl; Each R b are independently selected from hydrogen or C 1-4 alkyl; Each n and each p are independently selected from 0, 1 or 2.

11. The compound according to claim 10, its pharmaceutically acceptable salt or its stereoisomer, wherein R 1 Selected from azetidinyl, oxetanyl, -NR a -C(O)-R b -or-NR a R b ; Each R 4 are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl or trifluoromethyl; Ring A is selected from wherein each ring atom in ring A is optionally oxidized; 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, oxapropyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, tetrahydropyranyl, aziridine, azetidinyl, pyrrolidinyl, pyridyl or pyridazinyl; said Q2 are independently selected from fluorine, chlorine, bromine, hydroxyl, amino, cyano, carboxyl, nitro, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; Each R a are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, trifluoroethoxy, trifluoromethoxy, or the following groups optionally substituted with substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolidinyl or imidazolidinyl; the substituents are selected from halogen, hydroxy, methyl, ethyl, propyl, isopropyl or trifluoromethyl; Each R b are independently selected from hydrogen, methyl, ethyl, propyl or isopropyl.

12. The compound described below, its pharmaceutically acceptable salt or its stereoisomer:

13. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer thereof, selected from the following compounds:

14. A pharmaceutical preparation containing the compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized in that: Containing one or more pharmaceutically acceptable excipients, the pharmaceutical preparation is in any pharmaceutically acceptable dosage form.

15. Use of the compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical preparation according to claim 14 in the preparation of a medicament for treating and / or preventing diseases and related conditions mediated by HPK1, wherein the diseases and related conditions mediated by HPK1 are selected from cancer or benign tumors, and the cancer is selected from 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, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma, or sarcoma.

16. The use according to claim 15, wherein the lung cancer is selected from small cell lung cancer and non-small cell lung cancer.

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