Selenium-containing heterocyclic compound and use thereof

Abstract

Disclosed in the present invention are a POLQ inhibitor, i.e., a selenium-containing heterocyclic compound, and synthesis and use methods for the compound. Specifically, the present invention describes a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and synthesis and use methods for the compound.

Description

Selenium-containing heterocyclic compounds and their applications Technical Field

[0001] The present invention belongs to the field of medicine and relates to a class of POLQ inhibitor compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use as POLQ inhibitors in preventing or treating related diseases. Background Art

[0002] DNA double-strand break repair is crucial for maintaining genomic stability and cell survival. There are three major DNA double-strand break repair pathways: homologous recombination (HR), nonhomologous end joining (NHEJ), and alternative nonhomologous end joining (alt-MEJ). Microhomology-mediated end joining (MMEJ) is the most common form of nonhomologous end joining and alternative nonhomologous end joining. Homologous recombination is a high-fidelity, accurate repair mechanism that maintains genomic stability and prevents the development of cancer. However, nonhomologous end joining and microhomology-mediated end joining are error-prone repair pathways that can lead to mutations at the repair site.

[0003] Unlike normal cells, the survival of tumor cells often depends on the misregulation of DNA double-strand break repair. At the same time, abnormal DNA double-strand break repair can make tumor cells more sensitive to specific types of DNA damage. Therefore, defects in DNA double-strand break repair can be used to develop targeted tumor treatments. Tumor cells with impaired homologous recombination or non-homologous joining repair will be more dependent on microhomology-mediated end-joining repair. Multiple lines of evidence from genetics, cell biology and biochemistry indicate that DNA polymerase Theta (POLQ or POL theta) is a key protein in the microhomology-mediated end-joining repair process (Kent et al., Nature Structural & Molecular Biology (2015), 22(3), 230-237, Mateos-Gomez et al. Nature (2015), 518(7538), 254-257).

[0004] POLQ is a multifunctional enzyme composed of an N-terminal helicase domain (SF2HEL308-type) and a C-terminal low-fidelity DNA polymerase binding domain (A-type) (Wood & Doublie DNA Repair (2016), 44, 22-32). The helicase domain mediates the removal of the RPA protein from single-stranded DNA and promotes annealing, while the polymerase domain can extend the ends of single-stranded DNA and fill the gaps. These two domains work together to function in the microhomology-mediated end-joining repair process.

[0005] Studies have shown that POLQ is essential for cells with homologous recombination defects (e.g., synthetic lethality with FA / BRCA defects), and that POLQ protein levels are upregulated in homologous recombination-deficient tumor cells (Ceccaldi et al. Nature (2015), 518(7538), 258-262). In vivo studies have also shown that POLQ is overexpressed in a range of homologous recombination-deficient ovarian, uterine, and breast cancers with poor prognosis (Higgins et al. Oncotarget (2010), 1, 175-184, Lemee et al. PNAS (2010), 107(30), 13390-13395, Ceccaldi et al. (2015), 518(7538), 258-262). More importantly, POLQ expression is suppressed in normal tissues compared to tumor tissues (Kawamura et al. International Journal of Cancer (2004), 109(1), 9-16).

[0006] In summary, POLQ is crucial for cells with homologous recombination defects, and there is currently an unmet need for the treatment of homologous recombination-deficient tumors. Inhibiting POLQ function can inhibit microhomology-mediated end-joining repair in cells. The development of POLQ inhibitors may provide a novel strategy for the targeted treatment of homologous recombination-deficient tumors. Summary of the Invention

[0007] Disclosed herein are certain selenazole derivatives that inhibit POLQ activity, particularly through the ATP-dependent helicase domain activity of POLQ. Also disclosed are pharmaceutical compositions comprising the compounds and methods for treating and / or preventing diseases treatable by POLQ inhibition, such as cancer, including homologous recombination (HR)-deficient cancers.

[0008] Specifically, the present invention provides a compound having the structure of formula (I):

[0009] in,

[0010] L is selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b )m -、-(CR a R a ) m -S-, -NR a -(CR a R b ) m -、-(CR a R b ) m -NR a - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-,

[0011] m is 0, 1, 2, 3, 4, 5, or 6;

[0012] X is selected from C or N;

[0013] Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace;

[0014] Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace;

[0015] Ring B is selected from a 5-10 membered heteroaryl group containing at least one Se atom, wherein the ring B optionally contains 1, 2, 3, or 4 N atoms, and the ring B is optionally surrounded by 0, 1, 2, 3, or 4 R yx replace;

[0016] Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring;

[0017] Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a Rb, -SF5, -SF3, -C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO) Ra 、-NR a(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace;

[0018] R 1 Selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace;

[0019] Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR aR b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace;

[0020] R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace;

[0021] or R a and R bTogether with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace;

[0022] Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)R a’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl;

[0023] Among them, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

[0024] Preferably, the ring B has the following structure:

[0025] or

[0026] Wherein, @ indicates the site connected to the amide bond; * indicates the site connected to L;

[0027] Wherein, Y is selected from CR Y or N;

[0028] Where M is selected from CR M or N;

[0029] Where X1 represents R X1 or N; X2 represents R X2 or N; X3 represents R X3 or N; X4 is selected from R X4 or N;

[0030] Among them, R M , R Y 、R X1 、R X2 、R X3 、R X4 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R yx replace.

[0031] In addition, the present invention provides a compound having a structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof,

[0032] in,

[0033] Y is selected from CR Y or N;

[0034] M is selected from CR M or N;

[0035] L is selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m -、-(CR a R a ) m -S-, -NR a -(CR a R b ) m -、-(CR a R b ) m -NR a - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-,

[0036] m is 0, 1, 2, 3, 4, 5, or 6;

[0037] X is selected from C or N;

[0038] X1 represents R X1 or N;

[0039] X2 represents R X2 or N;

[0040] X3 represents R X3 or N;

[0041] X4 is selected from R X4 or N;

[0042] R M 、R Y 、R X1 、R X2 、R X3 、R X4 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R yx replace;

[0043] Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace;

[0044] Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace;

[0045] Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring;

[0046] Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a Rb, -SF5, -SF3, -C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO) Ra 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace;

[0047] R 1 Selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace;

[0048] Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace;

[0049] R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace;

[0050] or R a and R b Together with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace;

[0051] Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NRa’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)R a’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl;

[0052] Among them, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

[0053] In addition, the present invention provides a compound having the following structure or a pharmaceutically acceptable salt thereof, wherein, has the following structure:

[0054] Wherein, L is selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m-、-(CR a R a ) m -S-, -NR a -(CR a R b ) m -、-(CR a R b ) m -NR a - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-,

[0055] m is 0, 1, 2, 3, 4, 5, or 6;

[0056] X is selected from C or N;

[0057] M stands for CR M or N;

[0058] X1 represents R X1 or N;

[0059] X2 represents R X2 or N;

[0060] X3 represents R X3 or N;

[0061] R M 、R X1 、R X2 、R X3 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2Ra 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R yx replace;

[0062] Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace;

[0063] Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NRa S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace;

[0064] Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring;

[0065] Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a Rb, -SF5, -SF3, -C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO) Ra、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace;

[0066] R 1 Selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace;

[0067] Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace;

[0068] R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace;

[0069] or R a and R bTogether with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace;

[0070] Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)R a’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl;

[0071] Among them, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

[0072] In addition, the present invention provides a compound having the following structure or a pharmaceutically acceptable salt thereof, wherein the compound has any one of the following structures:

[0073] wherein G represents CH, C(Cl), C(Br), C(F), C(CH3) or N;

[0074] Wherein, L is selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m -、-(CR a R a ) m -S-, -NR a -(CR a R b ) m -、-(CR a R b ) m -NR a - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-,

[0075] m is 0, 1, 2, 3, 4, 5, or 6;

[0076] X is selected from C or N;

[0077] M represents CH or N;

[0078] Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace;

[0079] Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NRa R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace;

[0080] Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring;

[0081] Every R2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a Rb, -SF5, -SF3, -C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO) Ra 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace;

[0082] R 1 Selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace;

[0083] Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace;

[0084] R a and R b independently selected from hydrogen, deuterium, C3-C10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace;

[0085] or R a and R b Together with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace;

[0086] Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)R a’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl;

[0087] Among them, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

[0088] In addition, the present invention provides a compound having the following structure or a pharmaceutically acceptable salt thereof, wherein, has the following structure:

[0089] Wherein, L is selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m -、-(CR a R a ) m -S-, -NR a -(CR a R b ) m -、-(CR a R b ) m -NR a - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-,

[0090] m is 0, 1, 2, 3, 4, 5, or 6;

[0091] X is selected from C or N;

[0092] M represents CH or N;

[0093] Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R1a replace;

[0094] Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace;

[0095] Cy represents 0, 1, 2, or 3 R 2aa substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring;

[0096] Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a Rb, -SF5, -SF3, -C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO) Ra 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace;

[0097] R 1 Selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace;

[0098] Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace;

[0099] R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace;

[0100] or R a and R b Together with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace;

[0101] Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)R a’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl;

[0102] Among them, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

[0103] In addition, the present invention provides a compound having the following structure or a pharmaceutically acceptable salt thereof, wherein, has the following structure:

[0104] Wherein, L is selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m -、-(CR a R a ) m -S-, -NR a -(CR a R b ) m -、-(CR a R b ) m -NR a - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-,

[0105] m is 0, 1, 2, 3, 4, 5, or 6;

[0106] X is selected from C or N;

[0107] M represents CH or N;

[0108] Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace;

[0109] Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace;

[0110] Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring;

[0111] Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a Rb, -SF5, -SF3, -C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO) Ra 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace;

[0112] R 1 Selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace;

[0113] Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace;

[0114] R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace;

[0115] or R a and R b Together with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace;

[0116] Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)Ra’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl;

[0117] Among them, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

[0118] In a preferred embodiment of the present invention, ring A represents the following groups: phenyl or 5-6 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O and S, and the ring A can be arbitrarily replaced by 0, 1, 2 or 3 groups selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NRa R b , -SF5, -SF3 substituents.

[0119] In a preferred embodiment of the present invention, wherein ring A represents phenyl or pyridyl, and said ring A may be arbitrarily replaced by 0, 1, 2, or 3 groups selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0120] In a preferred technical solution of the present invention, wherein ring A represents the following group:

[0121] Wherein, Cy has the same meaning as defined above;

[0122] Where W1 represents CR W1 or N, W2 means CR W2 or N, W3 means CR W3 or N, W4 means CR W4 or N;

[0123] R W1 、R W2 、R W3 、R W4Each independently represents hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3;

[0124] Alternatively, the bond between W1 and W2 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following:

[0125] Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3Ra 、-NR a R b , -SF5, -SF3;

[0126] Alternatively, the bond between W2 and W3 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following:

[0127] Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(O)R a 、-S(=O)(=NH)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3;

[0128] Alternatively, the bond between W1 and W4 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following:

[0129] Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0130] In a preferred technical solution of the present invention, wherein ring A represents the following group:

[0131] Among them, R W1 、R W2 、R W3 、R W4 , Cy are as defined above.

[0132] In the preferred technical solution of the present invention, R W1 represents hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0133] In the preferred technical solution of the present invention, R W1represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

[0134] In the preferred technical solution of the present invention, R W2 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

[0135] In the preferred technical solution of the present invention, R W3 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

[0136] In a preferred technical solution of the present invention, wherein ring A represents the following group:

[0137] Further, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0138] In a preferred technical solution of the present invention, wherein ring A represents the following group:

[0139] Further, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0140] In the preferred technical solution of the present invention, Cy represents a 3-18 membered monocycloalkyl, a 3-18 membered spirocycloalkyl, a 3-18 membered bridged cycloalkyl, a 3-18 membered fused cycloalkyl, a 3-18 membered monoheterocycloalkyl, a 3-18 membered spiroheterocycloalkyl, a 3-18 membered bridged heterocycloalkyl, a 3-18 membered fused heterocycloalkyl, a 6-14 membered aryl or a 3-18 membered heteroaryl, and the Cy is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a Rb , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0141] In the preferred technical solution of the present invention, Cy represents phenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, 2-oxo-1,2-dihydropyridinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl, and the Cy is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0142] In a preferred technical solution of the present invention, Cy represents any one of the following groups:

[0143] and Cy is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0144] In the preferred technical solution of the present invention, wherein L represents -CH2O-, -C(CH3)O-, -OCH2-, CH2S-, -C(CH3)S-, -SCH2-,

[0145] In the preferred technical solution of the present invention, R 1 represents a C1-C6 alkyl group, a 3-18-membered monocycloalkyl group, a 3-18-membered spirocycloalkyl group, a 3-18-membered bridged cycloalkyl group, a 3-18-membered fused cycloalkyl group, a 3-18-membered monoheterocycloalkyl group, a 3-18-membered spiroheterocycloalkyl group, a 3-18-membered bridged heterocycloalkyl group, a 3-18-membered fused heterocycloalkyl group, a 6-14-membered aryl group or a 3-18-membered heteroaryl group, wherein R 1 Can be arbitrarily selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0146] In the preferred technical solution of the present invention, R 1 represents a C1-C6 alkyl group, wherein R 1 It may be arbitrarily substituted with 0, 1, 2, or 3 OH groups, halogen, -COOH, or -P(=O)(OH)2.

[0147] In the preferred technical solution of the present invention, R 1 represents a 6-14 membered aryl group, preferably a phenyl group, and said R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0148] In the preferred technical solution of the present invention, R1 represents a 3-18 membered heteroaryl group, preferably a pyridyl group, and said R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0149] In the preferred technical solution of the present invention, R 1 represents a 3-18 membered spirocycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a Rb , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0150] In the preferred technical solution of the present invention, R 1 represents a 3-18 membered bridged cycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0151] In the preferred technical solution of the present invention, R 1 represents a 3-18 membered fused cycloalkyl group, and said R 1It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0152] In the preferred technical solution of the present invention, R 1 represents a 3-18 membered monoheterocyclic alkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0153] In the preferred technical solution of the present invention, R 1 represents a 3-18 membered spiroheterocycloalkyl group, and said R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0154] In the preferred technical solution of the present invention, R 1 represents a 3-18 membered bridged heterocyclic alkyl group, and the R 1It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0155] In the preferred technical solution of the present invention, wherein X1 represents CR X1 , where R X1 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0156] In a preferred technical solution of the present invention, X1 represents N.

[0157] In the preferred technical solution of the present invention, wherein X2 represents CR X2 , where R X2 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0158] In a preferred technical solution of the present invention, X2 represents N.

[0159] In the preferred technical solution of the present invention, X3 represents CR X3 , where R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0160] In a preferred technical solution of the present invention, X3 represents N.

[0161] In the preferred technical solution of the present invention, wherein X4 represents CR X4 , where R X4 represents C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0162] In a preferred technical solution of the present invention, X4 represents N.

[0163] In addition, the present invention provides a compound or a pharmaceutically acceptable salt thereof having the following structure:

[0164] in,

[0165] L1 and L2 are each independently selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m -、-(CR a R a ) m -S-、-NRL-(CR L R L’ ) m -、-(CR L R L’) m -NR L - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-,

[0166] m is 0, 1, 2, 3, 4, 5, or 6;

[0167] X is selected from C or N;

[0168] Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace;

[0169] Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace;

[0170] Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring;

[0171] Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace;

[0172] R 1 、R 2 Each independently selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace;

[0173] Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace;

[0174] R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace;

[0175] or R a and R b Together with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace;

[0176] Every R 1b 、R 2b 、R 3b 、R 4b 、R 5bindependently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl.

[0177] In a preferred embodiment of the present invention, ring A represents the following groups: phenyl or 5-6 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O and S, and the ring A can be arbitrarily replaced by 0, 1, 2 or 3 groups selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)Ra 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0178] In a preferred embodiment of the present invention, wherein ring A represents phenyl or pyridyl, and said ring A may be arbitrarily replaced by 0, 1, 2, or 3 groups selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(O)R a 、-S(=O)(=NH)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0179] In a preferred technical solution of the present invention, wherein ring A represents the following group:

[0180] Wherein, Cy has the above definition;

[0181] Where W1 represents CR W1 or N, W2 means CR W2 or N, W3 means CR W3 or N, W4 means CR W4 or N;

[0182] R W1 、R W2 、R W3 、RW4 Each independently represents hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3;

[0183] Alternatively, the bond between W1 and W2 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following:

[0184] Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b、-OSO3R a 、-NR a R b , -SF5, -SF3;

[0185] Alternatively, the bond between W2 and W3 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following:

[0186] Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3;

[0187] Alternatively, the bond between W1 and W4 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following:

[0188] Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0189] In a preferred technical solution of the present invention, wherein ring A represents the following group:

[0190] Among them, R W1 、R W2 、R W3 、R W4 , Cy has the above definition.

[0191] In the preferred technical solution of the present invention, R W1 represents hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0192] In the preferred technical solution of the present invention, R W1represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

[0193] In the preferred technical solution of the present invention, R W2 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

[0194] In the preferred technical solution of the present invention, R W3 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

[0195] In a preferred technical solution of the present invention, wherein ring A represents the following group:

[0196] Further, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0197] In a preferred technical solution of the present invention, wherein ring A represents the following group:

[0198] Further, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0199] In the preferred technical solution of the present invention, Cy represents a 3-18 membered monocycloalkyl, a 3-18 membered spirocycloalkyl, a 3-18 membered bridged cycloalkyl, a 3-18 membered fused cycloalkyl, a 3-18 membered monoheterocycloalkyl, a 3-18 membered spiroheterocycloalkyl, a 3-18 membered bridged heterocycloalkyl, a 3-18 membered fused heterocycloalkyl, a 6-14 membered aryl or a 3-18 membered heteroaryl, and the Cy is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a Rb , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0200] In the preferred technical solution of the present invention, Cy represents phenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, 2-oxo-1,2-dihydropyridinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl, and the Cy is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0201] In a preferred technical solution of the present invention, Cy represents any one of the following groups:

[0202] and Cy is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

[0203] In the preferred technical solution of the present invention, wherein L1 represents -CH2O-, -C(CH3)O-, -OCH2-, CH2S-, -C(CH3)S-, -SCH2-,

[0204] In the preferred technical solution of the present invention, wherein L2 represents -CH2O-, -C(CH3)O-, -OCH2-, CH2S-, -C(CH3)S-, -SCH2-,

[0205] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a C1-C6 alkyl group, a 3-18-membered monocycloalkyl group, a 3-18-membered spirocycloalkyl group, a 3-18-membered bridged cycloalkyl group, a 3-18-membered fused cycloalkyl group, a 3-18-membered monoheterocycloalkyl group, a 3-18-membered spiroheterocycloalkyl group, a 3-18-membered bridged heterocycloalkyl group, a 3-18-membered fused heterocycloalkyl group, a 6-14-membered aryl group or a 3-18-membered heteroaryl group, wherein R 1Can be arbitrarily selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

[0206] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a C1-C6 alkyl group, and the R 1 It may be arbitrarily substituted with 0, 1, 2, or 3 OH groups, halogen, -COOH, or -P(=O)(OH)2.

[0207] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a 6-14 membered aryl group, preferably a phenyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)Ra 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0208] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a 3-18 membered heteroaryl group, preferably a pyridyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0209] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a 3-18 membered spirocycloalkyl group, and the R 1It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0210] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a 3-18 membered bridged cycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR aR b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0211] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a 3-18 membered fused cycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0212] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a 3-18 membered monoheterocyclic alkyl group, and the R 1It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0213] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a 3-18 membered spiro heterocycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR aR b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0214] In the preferred technical solution of the present invention, R 1 、R 2 Each independently represents a 3-18 membered bridged heterocyclic alkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

[0215] Specifically, the present invention provides a compound or a pharmaceutically acceptable salt thereof having the following structure:

[0216] Unless otherwise indicated, the compounds of the present invention may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.

[0217] Preferably, the pharmaceutical composition of the present invention may further include a second active substance, wherein the second active substance is an anti-tumor drug, and the anti-tumor drug includes one or more of a chemotherapy drug, a targeted tumor treatment drug or a tumor treatment antibody drug.

[0218] In addition, the present invention also provides a method for treating a disease by inhibiting the action of POLQ using a compound of the present invention, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, wherein the disease is preferably a tumor.

[0219] definition:

[0220] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight chain (i.e., unbranched) or branched chain, or cyclic hydrocarbon radical, or combinations thereof, which may be saturated, mono- or polyunsaturated, and may include divalent or polyvalent groups, having the specified number of carbon atoms (i.e., C1-C 10 Refers to one to ten carbon atoms). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl, and homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are referred to as "homoalkyl". The alkyl group is optionally substituted with one or more halogen atoms.

[0221] The term "haloalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen atom.

[0222] The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkyl group, for example, but not limited to, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-. Alkyl (or alkylene) groups typically have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred. "Lower alkyl" or "lower alkylene" refers to shorter chain alkyl or alkylene groups, typically having eight or fewer carbon atoms. The alkylene group is optionally substituted with one or more halogen atoms.

[0223] The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be linear or branched, or a combination thereof. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. The alkynyl group may be optionally substituted with one or more halogen atoms.

[0224] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, each having 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl refers to a monocyclic ring fused to an aryl or heteroaryl group, wherein the point of attachment is on the non-aromatic portion. Examples of cycloalkyls and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, and dihydroindanyl. The cycloalkyl group is optionally substituted with one or more halogen atoms. Furthermore, the term "cycloalkyl" as used herein includes bridged ring systems and spirocyclic ring systems.

[0225] The term "alkoxy" refers to a straight or branched chain alkoxy group having the indicated number of carbon atoms. 1-6 The alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy and the like.

[0226] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or cyclic hydrocarbon radical consisting of at least one carbon atom and at least one heteroatom selected from O, N, P, Si, S, or combinations thereof, wherein the nitrogen, phosphorus, or sulfur atom may be optionally oxidized and the nitrogen atom may be optionally quaternized. The heteroatoms O, N, P, S, and Si may be placed at any position within the heteroalkyl radical or at the position at which the alkyl radical is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene," by itself or in combination with other terms, refers to a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene, the heteroatom can be at either or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linking groups, the direction in which the linking group formula is written does not indicate the orientation of the linking group. For example, the formula -C(O)OR'- refers to both -C(O)OR'- and -R'OC(O)-. As described above, heteroalkyl groups as used herein include those groups that are attached to the rest of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -S02R'. Where "heteroalkyl" is mentioned followed by a specific heteroalkyl group such as -NR'R", it is understood that the terms heteroalkyl and -NR'R" are not redundant and are not mutually exclusive. Rather, these specific heteroalkyl groups are cited for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups such as -NR'R".

[0227] The term "cycloalkoxy" refers to a cycloalkyl group as defined above bound to an oxygen atom, such as cyclopropyloxy.

[0228] The term "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by a halo.

[0229] The term "aryl" refers to a monocyclic or bicyclic aromatic group containing only carbon atoms. A "fused analog" of an aryl group refers to an aryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclic group, wherein the point of attachment is on the aryl portion. Examples of aryl groups and fused ring analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrochromenyl, 1,4-benzodioxanyl, and the like.

[0230] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing at least one heteroatom selected from N, O, and S. A "fused analog" of a heteroaryl group refers to a heteroaryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclyl group, wherein the point of attachment is located on the aromatic portion. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, furo(2,3-b)pyridinyl, quinolinyl, indolyl, isoquinolinyl, and the like.

[0231] "Substituted or unsubstituted": the alkyl, aryl and heteroaryl groups are defined as being unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, haloalkyl groups having 1 to 6 carbon atoms, haloalkoxy groups having 1 to 6 carbon atoms, -CN, alkynyl groups having 2 to 6 carbon atoms, alkanoyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, alkyl groups having 2 to 6 carbon atoms, alkynyl groups having 1 to 6 carbon atoms, alkanoyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, alkyl groups having 2 to 6 carbon atoms, alkyl groups having 1 to 6 carbon atoms, alkyl groups having 1 to 6 carbon atoms, alkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aralkyloxy groups having 7-10 carbon atoms, aralkyl groups having 1 to ... an alkenyl group having 1 to 5 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an aminosulfinyl group, an aminosulfonyl group, a hydroxyl group, -SF5, a hydroxyalkyl group having 1 to 4 carbon atoms, a nitro group, an amino group, a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1-4 carbon atoms, an alkanoylamino group having 1 to 4 carbon atoms, an alkanoyl(alkyl)amino group having 1 to 6 carbon atoms, an alkanoylaminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties, an alkanoyl(alkyl)aminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties, an alkylsulfonylamino group having 1 to 4 carbon atoms, a monoalkylaminocarbonyl group or a dialkylaminocarbonyl group having 1 to 6 carbon atoms, a monoalkylaminosulfinyl group or a dialkylaminosulfinyl group having 1 to 6 carbon atoms, a monoalkylaminosulfonyl group or a dialkylaminosulfonyl group having 1 to 6 carbon atoms dialkylaminosulfonyl, aminoalkyl having 1 to 4 carbon atoms, mono- or dialkylamino having 1 to 6 carbon atoms, mono- or dialkylaminoalkyl having 1 to 6 carbon atoms in each alkyl moiety, aralkyl having 7 to 10 carbon atoms, heteroaralkyl having 1 to 4 carbon atoms in the alkyl moiety, heteroarylalkoxy having from 1 to 4 carbon atoms in the alkoxy moiety, and alkylsulfonamide having 1 to 4 carbon atoms.

[0232] As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic) having a single ring or a fused ring (including bridged ring systems and spiro ring systems) with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring. In a fused ring system, one or more rings can be cycloalkyl, aryl or heteroaryl, as long as the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen atom and / or sulfur atom of the heterocyclic group is optionally oxidized. , to provide N-oxide, sulfinyl and sulfonyl moieties. Examples of "heterocyclyl" and its fused analogs include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuryl (2,3-b) pyridinyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolinyl, etc. The term also includes non-aromatic partially unsaturated monocyclic rings, such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through a nitrogen atom.

[0233] As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group substituted with 1 to 5 (e.g., 1 to 3) substituents, the substituents being the same as those defined for substituted cycloalkyl.

[0234] Unless otherwise indicated, the term "halogenated" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C6)alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0235] "Prodrug" refers to a substance that is converted into the parent drug in vivo. In some cases, prodrugs are often used because they are easier to administer than the parent drug. For example, a prodrug may be bioavailable orally while the parent drug cannot. In a pharmaceutical composition, a prodrug may also have a higher solubility than the parent drug. Examples of prodrugs, but not limited to, may be any of the compounds of Formula I administered in the form of an ester (prodrug) to facilitate transcellular transport, where water solubility in the cell membrane is detrimental to migration, and once in the cell where water solubility is beneficial, the ester is subsequently metabolically hydrolyzed to the active substance, carboxylic acid. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, wherein the peptide is metabolized to release the active portion.

[0236] Optical isomers - diastereomers - geometric isomers - tautomers:

[0237] The compounds of formula (I) contain one or more asymmetric centers and can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is intended to encompass all such isomeric forms of the compounds of formula (I).

[0238] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0239] Some of the compounds of the present invention may contain one or more than one ring system and may therefore exist as cis- and trans-isomers. The present invention is intended to include all such cis- and trans-isomers.

[0240] Some compounds described herein may have different sites of attachment to hydrogen atoms, known as tautomers. Examples of such are the ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed within the compounds of the present invention.

[0241] The compounds of the present invention can be separated into diastereomeric pairs of enantiomers, for example by fractional crystallization from a suitable solvent such as methanol or ethyl acetate or a mixture thereof. A pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional methods, for example using an optically active amine or acid as a resolving agent or in a chiral HPLC column.

[0242] Alternatively, any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

[0243] Stable isotope-labeled analogs: One or more protons in the compounds of the present invention may be replaced with deuterium atoms to provide deuterated analogs with improved pharmacological activity. Example

[0244] Preparation of intermediate A1:

[0245] Step 1: (2-chloro-5-methoxypyridin-4-yl)boronic acid (600.00 mg, 3.20 mmol) and methyl 4-bromo-6-methylpyridine-3-carboxylate (810.29 mg, 3.52 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloridopalladium (468.56 mg, 0.64 mmol) and potassium carbonate (1325.58 mg, 9.61 mmol) were added to a solution of 1,4-dioxane (10.00 mL) and water (2.50 mL). The nitrogen atmosphere was replaced several times and stirred at 60 ° C for 1 hour under nitrogen protection, and then stirred at 80 ° C for 12 hours. The reaction was monitored by LCMS, which showed 80% of the product. The reactant was filtered, concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give a white solid (methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (770.00 mg, yield: 82%).

[0246] LCMS(ESI):[M+H] + =293.2.

[0247] Step 2: Methyl (2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (400.00 mg, 1.37 mmol) was dissolved in a solution of tetrahydrofuran (4.00 mL) and water (4.00 mL). Lithium hydroxide (273.30 mg, 6.83 mmol) was added. The reaction mixture was stirred at 20°C for 5 hours. The reaction was monitored by LCMS, which showed 90% of the product. The pH was adjusted to 3 with aqueous citric acid solution, extracted with ethyl acetate (30 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give (2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (360.00 mg, yield: 95%) as a white solid.

[0248] LCMS(ESI):[M+H] + =279.1.

[0249] Preparation of intermediate A2:

[0250] Referring to the synthetic route of intermediate A1, (2-fluoro-6-methoxyphenyl)boronic acid was used to replace (2-chloro-5-methoxypyridin-4-yl)boronic acid to obtain intermediate A2, namely: 4-(2-fluoro-6-methoxyphenyl)-6-methylpyridine-3-carboxylic acid.

[0251] LCMS(ESI):[M+H] + =262.1.

[0252] Preparation of intermediate A3:

[0253] The first step: Benzoyl chloride (2000 mg, 14.23 mmol) was dissolved in acetone (80.0 mL) and added dropwise to a solution of potassium selenocyanate (2050 mg, 14.23 mmol) in acetone (10.00 mL) over a 15-minute period. The reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS, which showed completion. The reaction solution was used directly in the next step without purification.

[0254] LCMS(ESI):[M+H] + =353.1.

[0255] Step 2: 6-Bromo-2-chloropyridin-3-amine (2606 mg, 12.57 mmol) was dissolved in acetone (30 mL) and added to a reaction mixture of benzoyl isoselenocyanate (2200 mg, 10.47 mmol). The reaction was stirred at 60°C for 3 hours. LCMS monitoring indicated a 60% yield. The reaction mixture was filtered, the solid washed with ethyl acetate (10 mL), and dried to afford N-(5-bromo-[1,3]selenazolo[5,4-b]pyridin-2-yl)benzamide (3400 mg, 85% yield) as a yellow solid.

[0256] LCMS(ESI):[M+H] + =382.08 / 384.07.

[0257] Step 3: Add N-(5-bromo-[1,3]selenazolo[5,4-b]pyridin-2-yl)benzamide (3400 mg, 8.92 mmol) to 70% sulfuric acid solution (30.0 mL). The reaction was stirred at 110 ° C for 6 hours. The reaction was monitored by LCMS, which showed 80% product. The reaction was cooled to room temperature and ice water (20 mL) was added to the reaction mixture. The pH was adjusted to 9 with 4N sodium hydroxide aqueous solution, extracted with ethyl acetate (80 mL x 2), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to give 5-bromo-[1.3]selenazolo[5.4-b]pyridin-2-amine (1800 mg, yield: 73%) as a yellow solid.

[0258] LCMS(ESI):[M+H] + =277.94.

[0259] Example 1: 2'-Chloro-5'-methoxy-N-(5-(4-methoxyphenyl)-1,3,4-selenadiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0260] Step 1: 4-Methylbenzenesulfonylhydrazide (1.86 g, 9.99 mmol) and 4-methoxybenzaldehyde (1.50 g, 10.99 mmol) were dissolved in methanol (25.00 mL) and 2 drops of acetic acid were added. The reaction mixture was stirred at 60° C. for 3 hours. The reaction was monitored by LCMS, which showed consumption of the starting material and 90% product. The reaction was directly concentrated to give the crude product (trans)-N'-(4-methoxybenzylidene)-4-methylbenzenesulfonylhydrazide (2.90 g, yield: 85.86%) as a yellow solid.

[0261] LCMS(ESI):[M+H] + =305.19.

[0262] Step 2: Dissolve (trans)-N'-(4-methoxybenzylidene)-4-methylbenzenesulfonylhydrazide (0.61 g, 2.00 mmol) in acetonitrile (20.00 mL). Add N-chlorosuccinimide (0.29 g, 2.20 mmol), potassium selenocyanate (0.58 g, 4.00 mmol), and scandium trifluoromethanesulfonate (0.49 g, 1.00 mmol). Continue stirring the reaction mixture at 20°C for 3 hours. Monitor the reaction by LCMS, which indicates 50% product. The reactant was poured into aqueous sodium bicarbonate solution (30 mL), filtered, extracted with ethyl acetate (50 mL x 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 1 / 1), and purified again by column chromatography (dichloromethane / methanol = 10 / 1) for a second time to give 5-(4-methoxyphenyl)-1,3,4-selenadiazole-2-amine (160,00 mg, yield: 30%) as a yellow solid.

[0263] LCMS(ESI):[M+H] + =256.04.

[0264] Step 3: 4-(2-chloro-5-methoxy(4-pyridinyl))-6-methylpyridine-3-carboxylic acid (75.00 mg, 0.27 mmol) and 5-(4-methoxyphenyl)-1,3,4-selenodiazol-2-amine (75.24 mg, 0.30 mmol) were dissolved in acetonitrile (3.00 mL) and N,N-dimethylformamide (1.00 mL). N-methylimidazole (110.47 mg, 1.35 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (83.06 mg, 0.30 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 3 hours. A large amount of solid precipitated. The reaction was monitored by LCMS, which showed 80% product. The reactant was concentrated, N,N-dimethylformamide (10 mL) and water (15 mL) were added, filtered, washed with water (10 mL), washed with acetonitrile (3.0 mL), and dried to give a white solid 2'-chloro-5'-methoxy-N-(5-(4-methoxyphenyl)-1,3,4-selenadiazole-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (97.57 mg, yield: 70%).

[0265] LCMS(ESI):[M+H] + =516.1.

[0266] 1H NMR(400MHz,DMSO-d6)δppm 13.3(s,1H),8.91(s,1H),8.16(s,1H),7.88-7.86(m,2H),7.55(s,1H), 7.53(s,1H),7.06-7.03(m,2H),3.83(s,3H),3.60(s,3H),2.60(s,3H).

[0267] Example 2: 2'-chloro-N-(5-((4-chlorophenoxy)methyl)-1,3,4-selenadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0268] Step 1: Dissolve hydrazinecarbonylselenoamide (165.11 mg, 1.20 mmol) (synthesis method reference patent: WO2022083687) and 2-(4-chlorophenoxy)acetic acid (186.00 mg, 1.00 mmol) in phosphorus oxychloride (2.00 mL). The reaction was stirred at 80°C for 1 hour. LCMS monitoring indicated 70% product. The reaction solution was cooled to room temperature and added dropwise to methanol (30 mL) at 0°C. Aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL) were then added. The mixture was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford 5-[(4-chlorophenoxy)methyl]-1,3,4-selenadiazol-2-amine (160.00 mg, yield: 56%) as a yellow solid.

[0269] LCMS(ESI):[M+H] + =290.0.

[0270] 1H NMR (400MHz, DMSO-d6) δppm 7.43 (s, 2H), 7.34 (d, J = 8.8, 2H), 7.05 (d, J = 8.8, 2H), 5.24 (s, 2H).

[0271] Step 2: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (40.00 mg, 0.14 mmol) and 5-[(4-chlorophenoxy)methyl]-1,3,4-selenadiazol-2-amine (41.42 mg, 0.14 mmol) were dissolved in acetonitrile (4.00 mL) and N,N-dimethylformamide (1.00 mL). N-Methylimidazole (58.92 mg, 0.72 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (44.30 mg, 0.16 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 16 hours. A large amount of solid precipitated. The reaction was monitored by LCMS, indicating the disappearance of starting material and the presence of approximately 80% product. The reactant was concentrated, N,N-dimethylformamide (1 mL) and water (15 mL) were added, filtered, and the solid was washed with water (10 mL) and acetonitrile (1.0 mL). After drying, 2'-chloro-N-(5-((4-chlorophenoxy)methyl)-1,3,4-selenadiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (46.23 mg, yield: 57%) was obtained as a white solid (light wine red).

[0272] LCMS(ESI):[M+H] + =550.3.

[0273] 1H NMR(400MHz,DMSO-d6)δppm 13.3(s,1H),8.86(s,1H),8.14(s,1H),7.55(s,1H),7.43(s,1H),7.37(dd,J=6 .4,2.4,2H),7.11(dd,J=6.4,2.4,2H),5.46(s,2H),3.55(s,3H),2.60(s,3H).

[0274] Example 3: N-(5-((4-chlorophenoxy)methyl)-1,3,4-selenadiazol-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide

[0275] Referring to the method of Example 2, 4-(2-fluoro-6-methoxyphenyl)-6-methylpyridine-3-carboxylic acid was used to replace (2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid) to obtain Example 3, namely N-(5-((4-chlorophenoxy)methyl)-1,3,4-selenadiazol-2-yl)-4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinamide (52.51 mg, yield: 51%).

[0276] LCMS(ESI):[M+H] + =533.2.

[0277] 1H NMR(400MHz,DMSO-d6)δppm 13.3(s,1H),8.88(s,1H),7.40-7.30(m,4H),7.09-7.07(m,2H),6.90-6.85(m,2H),5.43(s,2H),3.53(s,3H),2.56(s,3H).

[0278] Example 4: 2'-chloro-N-(5-(4-cyanophenyl)-[1,3]selenazolo[5,4-b]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0279] Step 1: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (140 mg, 0.50 mmol), 5-bromo-[1.3]selenazolo[5.4-b]pyridin-2-amine (139 mg, 0.50 mol) were dissolved in acetonitrile (6.0 mL) and N,N-dimethylformamide (2.0 mL). N-methylimidazole (206 mg, 2.51 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (155 mg, 0.55 mmol) were added. The reaction mixture was stirred at 20 ° C for 16 hours. A large amount of solid precipitated. The reaction was monitored by LCMS, which showed 50% product. The reactant was concentrated, N,N-dimethylformamide (5 mL) and water (15 mL) were added, filtered, washed with water (10.0 mL) and acetonitrile (2.0 mL), and dried to give N-(5-bromo-[1,3]selenazolo[5,4-b]pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (120 mg, yield: 44%) as a yellow solid.

[0280] LCMS(ESI):[M+H] + =537.9.

[0281] 1H NMR(400MHz,DMSO-d6)δppm 13.3(s,1H),8.89(s,1H),8.17(s,1H),8.04(d,J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),7.59(s,1H),7.47(s,1H),3.61(s,3H),2.61(s,3H).

[0282] Step 2: To N-(5-bromo-[1,3]selenazolo[5,4-b]pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (40 mg, 0.07 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (20 mg, 0.09 mmol), water (1.0 mL), and 1,4-dioxane (3.0 mL) was added potassium carbonate (30 mg, 0.22 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (11 mg, 0.01 mmol). The reaction mixture was stirred at 80°C for 16 hours. The reaction was monitored by LCMS, which indicated 50% product. The reaction mixture was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 50% to 100%) and preparative HPLC (C18, 0.5% formic acid-water / acetonitrile, 44 to 54%) to give 2'-chloro-N-(5-(4-cyanophenyl)-[1,3]selenazolo[5,4-b]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (6.14 mg, 14%) as a white solid after lyophilization.

[0283] LCMS(ESI):[M+H] + =561.1.

[0284] 1H NMR(400MHz,DMSO-d6)δppm 13.3(s,1H),8.98(s,1H),8.33-8.31(m,2H),8.16-8.08(m,3H),7.94-7.92(m,2H),7.50(s,1H),7.35(s,1H),3.63(s,3H),2.58(s,3H).

[0285] Example 5: 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-[1,3]selenazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide

[0286] Referring to the method of Example 4, 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid was replaced with 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid to give a white solid 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-[1,3]selenazolo[5,4-b]pyridin-2-yl)-6-methylnicotinamide (20.02 mg, yield: 24%).

[0287] LCMS(ESI):[M+H] + =551.2.

[0288] 1H NMR(400MHz,DMSO-d6)δppm 13.3(s,1H),8.85(s,1H),8.34-8.31(m,2H),7.96-7.94(m,2H),7.91-7. 86(m,4H),7.39(s,1H),7.17(d,J=8.8Hz,1H),3.59(s,3H),2.59(s,3H).

[0289] Example 6: 2'-Chloro-5'-methoxy-6-methyl-N-(5-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-selenadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0290] Step 1: Dissolve 3-hydroxytetrahydrofuran (500 mg, 5.67 mmol) in N,N-dimethylformamide (5.0 mL) and cool to 0°C under nitrogen. Then add sodium hydride (491 mg, 7.38 mmol, 60% by mass). Stir the reaction mixture at 0°C for 1 hour. Add 2-bromoacetonitrile (816 mg, 6.81 mmol), which turns dark. Stir for an additional 3 hours. Monitor the reaction by LCMS and TLC, revealing a small amount of product. The reaction mixture is poured into ice water and extracted with ethyl acetate (100 mL x 2). Concentrate and analyze by column chromatography (eluting with 30%-60% ethyl acetate / petroleum ether for 20 minutes). TLC (petroleum ether:ethyl acetate = 1:1) reveals an Rf = 0.3. Iodine shows a pale yellow color. Concentration yields 2-(tetrahydrofuran-3-yl)oxy)acetonitrile (56 mg, 8% yield) as a yellow oil.

[0291] 1H NMR (400MHz, DMSO-d6) δppm4.36-4.34(m,1H),4.26(s,2H),3.92-3.82(m,4H),2.09-2.04(m,2H).

[0292] Step 2: Add hydrazinecarbonylselenoamide (390 mg, 2.82 mmol) and 2-(tetrahydrofuran-3-yl)oxy)acetonitrile (460 mg, 2.35 mmol) to a solution of trifluoroacetic acid (3.00 mL). The reactants were stirred at 80 ° C for 1 hour. The reaction was monitored by LCMS, which showed 30% of the product. The reaction mixture was concentrated to give a crude product. The crude product was eluted by column chromatography (methanol / dichloromethane = 5% to 10%) for 15 to 20 minutes, concentrated to give a crude product, and then further purified by TLC (methanol / dichloromethane = 1 / 10) to give a yellow solid product 5-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-selenadiazole-2-amine (65 mg, yield: 11%).

[0293] LCMS(ESI):[M+H] + =250.03.

[0294] Step 3: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (55 mg, 0.20 mmol) and 5-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-selenadiazol-2-amine (49 mg, 0.20 mmol) were dissolved in acetonitrile (4.00 mL). N-methylimidazole (81.01 mg, 0.99 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (60.91 mg, 0.22 mmol) were added. The reaction mixture was stirred at 20°C for 3 hours. The reaction was monitored by LCMS, which showed 80% product. The reaction was concentrated and purified by flash chromatography using 0-60% ethyl acetate / petroleum ether over 20 minutes to obtain the product with 80% purity. The product was further purified by HPLC (0.5% aqueous formic acid / acetonitrile, 30% to 50%) and freeze-dried to give 2'-chloro-5'-methoxy-6-methyl-N-(5-(((tetrahydrofuran-3-yl)oxy)methyl)-1,3,4-selenadiazole-2-yl)-[4,4'-bipyridine]-3-carboxamide (25.43 mg, yield: 25%) as a white solid.

[0295] LCMS(ESI):[M+H] + =510.2.

[0296] 1H NMR(400MHz,DMSO-d6)δppm 13.22(s,1H),8.90(s,1H),8.14(s,1H),7.49(s,1H),7.36(s,1H),4.75(s,2H),4 .32-4.30(m,1H),3.75-3.65(m,4H),3.64(s,3H),2.50(s,3H),1.97-1.93(m,2H).

[0297] Example 7: 2'-Chloro-5'-methoxy-6-methyl-N-(5-(pyrrolidine-1-carbonyl)-1,3,4-selenadiazol-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0298] Step 1: 4-Methylbenzenesulfonylhydrazide (5.00 g, 26.85 mmol) was dissolved in methanol (50.00 ml), and a 50% toluene solution (11.0 ml) of ethyl glyoxylate (5.48 g, 26.85 mmol) and acetic acid (2 drops) were added. The reaction mixture was stirred at 60° C. for 3 hours. The reaction was monitored by LCMS, which showed that the starting material was consumed and only 5% of the product was obtained. The reaction solution was concentrated and purified by column chromatography (petroleum ether / ethyl acetate = 40% to 60%, elution time 20 minutes) to obtain ethyl (trans)-2-(2-toluenesulfonylhydrazide) acetate (0.63 g, yield: 9%) as a colorless oil.

[0299] LCMS(ESI):[M+H] + =271.15.

[0300] Step 2: Ethyl (trans)-2-(2-toluenesulfonylhydrazide) acetate (300 mg, 1.11 mmol) was dissolved in acetonitrile (6.00 mL). N-chlorosuccinimide (163 mg, 1.22 mmol), potassium selenocyanate (320 mg, 2.22 mmol), and scandium trifluoromethanesulfonate (273 mg, 0.55 mmol) were added. The reaction mixture was stirred at 20°C for 3 hours. The reaction was monitored by LCMS, which indicated 50% product. The reactant was poured into aqueous sodium bicarbonate solution (30 mL), filtered, and extracted twice with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 30% to 50%). The mixture was purified for a second time by column chromatography (methanol / dichloromethane = 5% to 10%) to give 5-amino-1,3,4-selenazole-2-carboxylic acid ethyl ester (160 mg, yield: 30%) as a yellow solid.

[0301] LCMS(ESI):[M+H] +=222.03.

[0302] Step 3: 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (30 mg, 0.11 mmol), 5-amino-1,3,4-selenazole-2-carboxylic acid ethyl ester (26 mg, 0.12 mmol) were dissolved in a solution of acetonitrile (4.00 mL) and N,N-dimethylformamide (1.00 mL), and N-methylimidazole (44 mg, 0.54 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. A large amount of solid precipitated. The reaction was monitored by LCMS (methanol), and LCMS showed 80% of the product. The reactant was concentrated, N,N-dimethylformamide (1 mL) and water (15 mL) were added, filtered, the solid was washed with water (10 mL) and acetonitrile (1.0 mL), and dried to give a white solid 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-formamido)-1,3,4-selenadiazole-2-carboxylic acid ethyl ester (25.71 mg, yield: 47%).

[0303] LCMS(ESI):[M+H] + =482.1.

[0304] 1H NMR(400MHz,DMSO-d6)δppm 13.82(s,1H),8.89(s,1H),8.14(s,1H),7.58(s,1H),7.47(s,1H),4.39-4.37(m,2H),3.54(s,3H),2.61(s,3H),1.33(t,J=7.2Hz,3H).

[0305] Step 4: Ethyl 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-1,3,4-selenadiazole-2-carboxylate (130 mg, 0.27 mmol) was dissolved in a mixture of methanol (4.0 mL), tetrahydrofuran (4.00 mL), and water (1.00 mL). Lithium hydroxide (54 mg, 1.35 mmol) was added. The reaction mixture was stirred at 20°C for 5 hours. The reaction was monitored by LCMS, which showed 90% product. The pH was adjusted to 3 with aqueous citric acid solution, and the mixture was extracted twice with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford 5-(2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamido)-1,3,4-selenadiazole-2-carboxylic acid (95 mg, yield: 83%) as a white solid.

[0306] LCMS(ESI):[M+H] + =454.03.

[0307] Step 5: 5-(2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide)-1,3,4-selenadiazole-2-carboxylic acid (60 mg, 0.13 mmol) was dissolved in acetonitrile (3.00 mL) and N,N-dimethylformamide (1.00 mL). N-methylimidazole (65 mg, 0.80 mol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (41 mg, 0.15 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 10 minutes, followed by the addition of pyrrolidine (28.28 mg, 0.40 mmol). The reaction mixture was stirred at 20°C for 3 hours. The reaction was monitored by LCMS, which indicated 80% product. The reaction mixture was concentrated and purified by flash chromatography using 0-60% ethyl acetate / petroleum ether over 20 minutes to obtain the product with 80% purity. The product was further purified by HPLC (0.5% aqueous formic acid / acetonitrile, 30% to 50%) and freeze-dried to give a white solid 2'-chloro-5'-methoxy-6-methyl-N-(5-(pyrrolidine-1-carbonyl)-1,3,4-selenadiazole-2-yl)-[4,4'-bipyridine]-3-carboxamide (43.05 mg, yield: 64%).

[0308] LCMS(ESI):[M+H] + =507.1.

[0309] 1H NMR(400MHz,DMSO-d6)δppm 13.22(s,1H),8.95(s,1H),8.12(s,1H),7.46(s,1H),7.53(s,1H),3.94-3. 90(m,2H),3.55(s,3H),3.49-3.47(m,2H),2.51(s,3H),1.92-1.83(m,4H).

[0310] Example 8: (S)-2'-chloro-N-(5-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-1,3,4-selenadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0311] Referring to the method of Example 7, pyrrolidine was replaced with (S)-pyrrolidin-2-ylmethanol to carry out amine acid condensation to obtain (S)-2'-chloro-N-(5-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)-1,3,4-selenadiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide.

[0312] LCMS(ESI):[M+H] + =537.2.

[0313] 1H NMR(400MHz,DMSO-d6)δppm 13.22(s,1H),8.95(s,1H),8.12(s,1H),7.46(s,1H),7.33(s,1H),4.85-4.79(m,1H),4.16-4. 13(m,1H),3.99-3.92(m,1H),3.55(s,3H),3.55-3.52(m,3H),2.51(s,3H),1.92-1.83(m,4H).

[0314] Example 9: (4-(5-chloro-2-ethynylphenyl)-N-(5-((4-chlorophenoxy)methyl)-1,3,4-selenadiazol-2-yl)-6-methylnicotinamide

[0315] Referring to the method of Example 2, 4-(5-chloro-2-ethynylphenyl)-6-methylnicotinic acid was used to replace (2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid to obtain 4-(5-chloro-2-ethynylphenyl)-N-(5-((4-chlorophenoxy)methyl)-1,3,4-selenadiazol-2-yl)-6-methylnicotinamide

[0316] LCMS(ESI):[M+H] + =543.1.

[0317] 1 H NMR(400MHz,DMSO-d6)δppm 13.26(s,1H),8.96(s,1H),7.53-7.36(m,4H),7.35-7.34(m,2H),7.11-7.07(m,2H),5.44(s,2H),4.01(s,1H),2.59(s,3H).

[0318] Example 10: 2'-Chloro-N-(5-(cyclopropylethynyl)-1,3,4-selenadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0319] Step 1: Hydrazinecarbonylselenoamide (3000 mg, 21.73 mmol) was suspended in formic acid (3.00 mL) and 25% aqueous sulfuric acid solution (6.00 mL) was carefully added. The reaction mixture was stirred at 100 ° C for 3 hours. The reaction was monitored by LCMS, showing 50% product. The reaction was cooled. 8 ml of water was added and the reaction mixture was basified to pH = 9.0 with saturated aqueous sodium carbonate solution. It was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product 5-(oxo-3-methoxymethyl)-1,3,4-selenadiazole-2-amine (440 mg, yield: 14%) as a yellow solid.

[0320] LCMS (ESI): [M-55+H]+=149.95.

[0321] 1H NMR (400MHz, DMSO-d6) δppm 9.22 (s, 1H), 8.13 (s, 1H), 7.32 (s, 2H).

[0322] Step 2: 5-Bromo-1,3,4-selenadiazol-2-amine (340 mg, 2.30 mmol) was dissolved in tetrahydrofuran (4.00 mL). Triethylamine (697 mg, 6.89 mmol), di-tert-butyl dicarbonate (551 mg, 2.53 mmol), and 4-dimethylaminopyridine (28 mg, 0.23 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. LCMS monitoring indicated 70% product. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column using a mobile phase (30% to 50% ethyl acetate / petroleum ether). Concentration afforded tert-butyl (1,3,4-selenadiazol-2-yl)carbamate (270 mg, 47% yield) as a white solid.

[0323] LCMS (ESI): [M-55+H]+=194.01.

[0324] Step 3: Dissolve tert-butyl (1,3,4-selenadiazole-2-yl)carbamate (270 mg, 1.09 mmol) in methanol (5.00 mL), add sodium bicarbonate (274 mg, 3.26 mmol), and liquid bromine (226 mg, 1.41 mmol) dissolved in 1 ml of methanol and added dropwise to the reaction solution. The reactants were stirred at 25 ° C for 3 hours. The reaction was monitored by LCMS, showing 60% product. The reaction solution was concentrated and purified by silica gel column with mobile phase (30% ethyl acetate / petroleum ether, elution for 10 minutes) to obtain a yellow solid (tert-butyl 5-bromo-1,3,4-selenadiazole-2-yl)carbamate (260 mg, yield: 73%).

[0325] LCMS(ESI):[M-Boc+H]+=227.93,271.90.

[0326] Step 4: tert-Butyl (5-bromo-1,3,4-selenadiazol-2-yl)carbamate (200 mg, 0.61 mmol), cyclopropylacetylene (40 mg, 0.61 mmol), triethylamine (186 mg, 1.84 mmol), cuprous iodide (5.8 mg, 0.03 mmol), and bistriphenylphosphine palladium dichloride (21 mg, 0.03 mol) were added to a solution of tetrahydrofuran (3.00 mL). The mixture was then degassed three times with nitrogen under reduced pressure and stirred at 60°C for 3 hours. LCMS monitoring of the reaction revealed the disappearance of the starting material and 70% product. The mixture was concentrated and purified on a silica gel column using a mobile phase of 30%-35% ethyl acetate / petroleum ether to afford tert-Butyl (5-(cyclopropylethynyl)-1,3,4-selenadiazol-2-yl)carbamate (100 mg, 52% yield) as a yellow solid.

[0327] LCMS (ESI): [M+H]+=314.09.

[0328] Step 5: Dissolve tert-butyl (5-(cyclopropylethynyl)-1,3,4-selenadiazole-2-yl)carbamate (120 mg, 0.38 mmol) in dichloromethane (2.00 mL) and add trifluoroacetic acid (1.00 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS, which showed 70% of the product. The reaction solution was concentrated under reduced pressure to remove dichloromethane and most of the trifluoroacetic acid, and aqueous sodium carbonate (20 ml) and dichloromethane (50 ml) were added. The product was extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 5-(cyclopropylethynyl)-1,3,4-selenadiazole-2-amine (70 mg, yield: 86%) as a yellow solid.

[0329] LCMS (ESI): [M+H]+ = 214.03.

[0330] Step 6: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (50 mg, 0.18 mmol) was dissolved in acetonitrile (5.00 mL). N-methylimidazole (73 mg, 0.90 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (55 mg, 0.20 mmol), and 5-(cyclopropylethynyl)-1,3,4-selenodiazol-2-amine (38 mg, 0.18 mmol) were added. The reaction mixture was stirred at 20°C for 3 hours. The reaction was monitored by LCMS, which indicated 80% product. The reaction was concentrated and purified by flash chromatography using 50%-60% ethyl acetate / petroleum ether for 15 minutes to obtain the product with a purity of 75%. The product was dissolved in 3 ml of N,N-dimethylformamide and further purified by HPLC (0.5% aqueous ammonia solution / acetonitrile, 50% to 60%). After freeze-drying, a white solid 2'-chloro-N-(5-(cyclopropylethynyl)-1,3,4-selenadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (26.83 mg, yield: 31%) was obtained.

[0331] LCMS (ESI): [M+H]+=474.1.

[0332] 1H NMR(400MHz,DMSO-d6)δppm 13.58(s,1H),8.86(s,1H),8.14(s,1H),7.55(s,1H),7.44(s,1H),3.55(s, 3H),2.59(s,3H),1.70-1.66(m,1H),0.99-0.88(m,2H),0.87-0.85(m,2H).

[0333] Example 11: 2-(2-chloro-5-methoxypyridin-4-yl)-4-cyano-N-(5-(cyclopropylethynyl)-1,3,4-selenadiazol-2-yl)benzamide

[0334] Reference Example 10: Replace 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid with 2-(2-chloro-5-methoxypyridin-4-yl)-4-cyanobenzoic acid to obtain a white solid 2-(2-chloro-5-methoxypyridin-4-yl)-4-cyano-N-(5-(cyclopropylethynyl)-1,3,4-selenadiazole-2-yl)benzamide.

[0335] LCMS (ESI): [M+H]+=484.1.

[0336] 1H NMR(400MHz,DMSO-d6)δppm 13.63(s,1H),8.11-8.09(m,2H),8.04(s,1H),7.99(d,J=8.0Hz,1H),7.59(s ,1H),3.53(s,3H),1.69-1.66(m,1H),1.00-0.98(m,2H),0.87-0.85(m,2H).

[0337] Example 12: 2'-chloro-N-(6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0338] Step 1: Benzoyl chloride (15.0 g, 106.71 mmol) was dissolved in 4-methyl-2-pentanone (100 mL) and added dropwise to a solution of potassium selenocyanate (15.4 g, 106.71 mmol) in 4-methyl-2-pentanone (300 mL) over a period of 15 to 30 minutes. The reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS, which indicated completion. The reaction solution was used directly in the next step without purification.

[0339] Step 2: 2-Amino-3,5-dibromopyrazine (13.49 g, 53.35 mmol) and cesium carbonate (57.95 g, 177.85 mmol) were added to the reaction mixture from the previous step and stirred at 110°C for 16 hours. LCMS monitoring indicated a 20% yield. The reaction mixture was poured into water (250 mL) and ethyl acetate (500 mL). The insoluble material was filtered off and extracted with ethyl acetate (300 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 50% to 70%) to afford N-(6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)benzamide (1.20 g, yield: 9%) as a yellow solid.

[0340] LCMS (ESI): [M+H]+=383.0.

[0341] Step 3: Add N-(6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)benzamide (1200 mg, 3.14 mmol) to 70% sulfuric acid solution (10.0 mL). The reaction was stirred at 90°C for 3 hours. The reaction was monitored by LCMS, which showed 80% product. The reaction was cooled to room temperature and ice water (20 mL) was added to the reaction mixture. The pH was adjusted to 9 with 4N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain 6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-amine (540.00 mg, yield: 62%) as a yellow solid.

[0342] LCMS (ESI): [M+H]+=278.9.

[0343] Step 4: Dissolve 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (200 mg, 0.72 mmol) and 6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-amine (248 mg, 1.08 mmol) in acetonitrile (6.0 mL) and N,N-dimethylformamide (2.0 mL). Add N-methylimidazole (295 mg, 3.59 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (242 mg, 0.86 mmol). The reaction mixture is stirred at 25°C for 16 hours. The reaction is monitored by LCMS, which shows 50% product and 20% starting material remaining. The reaction solution was concentrated and then mixed with 200-300 mesh silica gel and purified by column chromatography (5%-7% methanol / dichloromethane as mobile phase, elution for 15-20 minutes) to obtain a yellow solid N-(6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (150 mg, yield: 39%).

[0344] LCMS (ESI): [M+H]+=539.0.

[0345] 1H NMR (400MHz, DMSO-d6) δppm 13.30(s,1H),8.90(s,1H),8.77(s,1H),8.18(s,1H),7.62(s,1H),7.50(s,1H),3.62(s,3H),2.64(s,3H).

[0346] Step 5: Dissolve N-(6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (80 mg, 0.15 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolato)benzonitrile (34 mg, 0.15 mol) in water (1.0 mL) and 1,4-dioxane (5.0 mL). Add potassium carbonate (62 mg, 0.45 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (22 mg, 0.03 mmol). The reaction mixture was stirred at 90°C for 16 hours. The reaction was monitored by LCMS, which indicated 50% product. The reaction mixture was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 50% to 100%) and preparative HPLC (C18, mobile phase acetonitrile / 0.5% formic acid aqueous solution, 44-54% gradient elution) to give 2'-chloro-N-(6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (25.36 mg, yield: 13%) as a white solid after lyophilization.

[0347] LCMS (ESI): [M+H]+=562.1.

[0348] 1H NMR(400MHz,DMSO-d6)δppm 13.79(s,1H),9.39(s,1H),8.99(s,1H),8.46(d,J=8.4Hz,2H),8.26(s,1H) ,8.09(d,J=8.4Hz,2H),7.69(s,1H),7.57(s,1H),3.71(s,3H),2.70(s,3H).

[0349] Example 13: 4-(5-chloro-2-ethynylphenyl)-N-(6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide

[0350] Step 1: Dissolve 6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-amine (340 mg, 1.22 mmol) in tetrahydrofuran (4.0 mL). Add 4-dimethylaminepyridine (75 mg, 0.61 mmol), triethylamine (371 mg, 3.67 mmol), and di-tert-butyl dicarbonate (320 mg, 1.47 mmol). The reaction mixture was stirred at room temperature for 3 hours. LCMS monitoring of the reaction indicated 70% product. The reaction solution was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 50% to 60%) to obtain tert-butyl (6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)carbamate (280 mg, yield: 61%) as a yellow solid.

[0351] LCMS(ESI):[M-100+H]+=278.91.

[0352] Step 2: Dissolve tert-butyl (6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)carbamate (280 mg, 0.74 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolato)benzonitrile (187 mg, 0.81 mmol) in water (2.0 mL) and 1,4-dioxane (8.0 mL). Add potassium carbonate (540 mg, 3.91 mol) and 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (108 mg, 0.15 mmol). The reaction mixture was purged with nitrogen under reduced pressure three to five times and stirred at 100°C under nitrogen for 16 hours. LCMS monitoring indicated 70% product. The residue was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 80% to 90%) to give tert-butyl ((6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)carbamate (220 mg, yield: 74%) as a yellow solid.

[0353] LCMS (ESI): [M+H]+=402.18.

[0354] 1H NMR (400MHz, DMSO-d6) δppm 12.60 (s, 1H), 9.25 (s, 1H), 8.36 (d, J = 8.8Hz, 2H), 8.00 (d, J = 8.8Hz, 2H), 1.55 (s, 9H).

[0355] Step 3: Dissolve tert-butyl (6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)carbamate (220 mg, 0.55 mmol) in dichloromethane (2.0 mL) and add trifluoroacetic acid (1.0 mL). The reaction was stirred at room temperature for 3 hours. The reaction was monitored by LCMS, which showed 80% product. The reaction solution was concentrated at low temperature and then added with dichloromethane (30 mL) and saturated sodium bicarbonate aqueous solution (30 mL). The mixture was extracted twice with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give an orange-yellow crude product 4-(2-amino-[1,3]selenazolo[4,5-b]pyrazin-6-yl)benzonitrile (130 mg, yield: 79%).

[0356] LCMS (ESI): [M+H]+=299.94.

[0357] Step 4: Dissolve 4-(5-chloro-2-ethynylphenyl)-6-methylnicotinic acid (50 mg, 0.18 mmol) and 4-(2-amino-[1,3]selenazolo[4,5-b]pyrazin-6-yl)benzonitrile (55 mg, 0.18 mmol) in acetonitrile (3.0 mL) and N,N-dimethylformamide (0.5 mL). Add N-methylimidazole (76 mg, 0.92 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (62 mg, 0.22 mmol). The reaction mixture is stirred at 25°C for 18 hours. The reaction is monitored by LCMS, which shows 50% product and 20% starting material remaining. The reaction solution was concentrated and then mixed with 200-300 mesh silica gel and purified by column chromatography (5%-7% methanol / dichloromethane as mobile phase, elution for 15-20 minutes). After concentration, it was dissolved in a mixture of N,N-dimethylformamide and tetrahydrofuran (3.0 ml), purified by HPLC, and lyophilized to give 4-(5-chloro-2-ethynylphenyl)-N-(6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (29.05 mg, yield: 29%) as a yellow solid.

[0358] LCMS (ESI): [M+H]+=555.1.

[0359] 1H NMR(400MHz,DMSO-d6)δppm 13.72(s,1H),9.30(s,1H),9.02(s,1H),8.37(d,J=8.4Hz,2H),8.00(d, J=8.4Hz,2H),7.57-7.52(m,3H),7.41(s,1H),4.08(s,1H),2.62(s,3H).

[0360] Example 14: 2'-chloro-N-(5-((4-cyanobenzyl)oxy)-1,3,4-selenadiazol-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0361] Step 1: Dissolve tert-butyl (5-bromo-1,3,4-selenadiazol-2-yl)carbamate (210 mg, 0.64 mmol) in dichloromethane (3.0 mL) and add trifluoroacetic acid (1.0 mL). The reaction was stirred at room temperature for 2 hours. The reaction was monitored by LCMS, which showed 80% product. The reaction solution was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid. Then, aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL) were added and extracted with ethyl acetate (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 5-bromo-1,3,4-selenadiazol-2-amine as a yellow solid (130 mg, yield: 89%).

[0362] LCMS (ESI): [M+H]+=227.96.

[0363] Step 2: 4-(Hydroxymethyl)benzonitrile (187 mg, 1.41 mmol) was dissolved in tetrahydrofuran (5.0 mL) and cooled to -10°C under nitrogen. 60% sodium hydride (68 mg, 1.69 mmol) was then added. The reaction mixture was stirred at 0°C for 15 minutes. A solution of 5-bromo-1,3,4-selenadiazol-2-amine (160 mg, 0.71 mmol) in tetrahydrofuran was added to the reaction mixture. The reaction mixture was stirred at 0°C for an additional 3 hours. The reaction was monitored by LCMS, which indicated 30% 4-(hydroxymethyl)benzonitrile and 60% product. The reactant was poured into water and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 80% to 90%) to give the product 4-((5-amino-1,3,4-selenadiazol-2-yl)oxy)methyl)benzonitrile (70 mg, yield: 36%) as a yellow solid.

[0364] LCMS (ESI): [M+H]+=281.17.

[0365] 1H NMR (400MHz, DMSO-d6) δppm 7.87 (d, J = 8.4Hz, 2H), 7.64 (d, J = 8.4Hz, 2H), 6.86 (s, 2H), 5.43 (s, 2H).

[0366] Step 3: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (30 mg, 0.11 mmol) and 4-((5-amino-1,3,4-selenadiazol-2-yl)oxy)methyl)benzonitrile (30 mg, 0.11 mmol) were dissolved in acetonitrile (4.00 mL) and N,N-dimethylformamide (1.0 mL). Methylimidazole (44 mg, 0.54 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 16 hours. A large amount of solid precipitated. The reaction was monitored by LCMS, indicating the disappearance of starting material and the presence of approximately 80% product. The reactant was concentrated, N,N-dimethylformamide (1.0 mL) and water (5.0 mL) were added, filtered, and the solid was washed with water (2.0 mL) and acetonitrile (1.0 mL). After drying, a white solid 2'-chloro-N-(5-((4-cyanobenzyl)oxy)-1,3,4-selenadiazole-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (26.44 mg, yield: 45%) was obtained.

[0367] LCMS (ESI): [M+H]+=541.2.

[0368] 1H NMR(400MHz,DMSO-d6)δppm 13.07(s,1H),8.84(s,1H),8.16(s,1H),7.89(d,J=8.0Hz,2H),7.69(d,J=8 .4Hz,2H),7.53(s,1H),7.42(s,1H),5.57(s,2H),3.55(s,3H),2.60(s,3H).

[0369] Example 15: 4-(5-chloro-2-ethynylphenyl)-N-(5-((4-cyanobenzyl)oxy)-1,3,4-selenadiazol-2-yl)-6-methylnicotinamide

[0370] 4-(5-Chloro-2-ethynylphenyl)-6-methylnicotinic acid (30 mg, 0.11 mmol) and 4-((5-amino-1,3,4-selenadiazol-2-yl)oxy)methyl)benzonitrile (30 mg, 0.11 mmol) were dissolved in acetonitrile (4.00 mL) and N,N-dimethylformamide (1.0 mL). Methylimidazole (44 mg, 0.54 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 16 hours. A large amount of solid precipitated. The reaction was monitored by LCMS, indicating the disappearance of the starting material and the presence of approximately 80% product. The reaction was concentrated, N,N-dimethylformamide (1.0 mL) and water (5.0 mL) were added, and the mixture was filtered. The solid was washed with water (2.0 mL) and acetonitrile (1.0 mL) and dried to give 4-(5-chloro-2-ethynylphenyl)-N-(5-((4-cyanobenzyl)oxy)-1,3,4-selenadiazol-2-yl)-6-methylnicotinamide (26.88 mg, yield: 46%) as a white solid.

[0371] LCMS (ESI): [M+H]+=534.1.

[0372] 1H NMR(400MHz,DMSO-d6)δppm 13.10(s,1H),8.98(s,1H),7.94(d,J=10.0Hz,2H),7.73(d,J=12.0Hz,2H ),7.59-7.48(m,3H),7.40(s,1H),5.61(s,2H),4.07(s,1H),2.64(s,3H).

[0373] Example 16: (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0374] Step 1: Dissolve (S)-(1,4-dioxan-2-yl)methanol (62 mg, 0.53 mmol) in tetrahydrofuran (5.0 mL) and cool to 0°C under nitrogen. Then add 60% sodium hydride (25 mg, 0.63 mmol). The reaction mixture is stirred at 0°C for 15 minutes. 5-Bromo-1,3,4-selenadiazol-2-amine (30 mg, 0.22 mmol) is added. The reaction mixture is stirred at 0°C for an additional hour. The reaction is monitored for completion by TLC. Water (0.1 mL) is added to the reaction system to quench the reaction, which is then concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 40% to 50%) to afford (R)-5-((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-amine (30 mg, yield: 43%) as a white solid.

[0375] LCMS (ESI): [M+H]+ = 266.12.

[0376] Step 2: 2'-Chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (30 mg, 0.11 mmol) and (R)-5-((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazole-2-amine (28 mg, 0.11 mmol) were dissolved in acetonitrile (5.0 mL) at room temperature, and methylimidazole (44 mg, 0.54 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol) were added respectively. The mixture was stirred at room temperature for 18 hours. A large amount of solid precipitated. The reaction was monitored by LCMS, which indicated the disappearance of starting material and approximately 80% product. The solid was filtered, washed with water (1.0 mL) and acetonitrile (1.0 mL), and dried to afford (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (34.78 mg, 61% yield) as a white solid.

[0377] LCMS (ESI): [M+H]+=526.2.

[0378] 1H NMR(400MHz,DMSO-d6)δppm 13.04(s,1H),8.86(s,1H),8.15(s,1H),7.50(s,1H),7.38(s,1H),4.37-4.35(m,2H),3.92-3.89(m,1H) ,3.80-3.75(m,2H),3.67-3.59(m,2H),3.61(s,3H),3.52-3.46(m,1H),3.40-3.33(m,1H),2.58(s,3H).

[0379] Example 17: (R)-N-(5-(((1,4-dioxane-2-yl)methoxy)-1,3,4-selenadiazol-2-yl)-5'-methoxy-2'-, 6-dimethyl-[4,4'-bipyridine]-3-carboxamide

[0380] 5'-Methoxy-2'-,6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (30 mg, 0.11 mmol) (preparation method reference: WO2022118210) and (R)-5-((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-amine (30 mg, 0.11 mmol) were dissolved in acetonitrile (2.00 mL) and N,N-dimethylformamide (0.2 mL). Methylimidazole (44 mg, 0.54 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 16 hours. A large amount of solid precipitated. The reaction was monitored by LCMS, indicating the disappearance of the starting material and the presence of approximately 70% product. The reaction solution was directly filtered, and the solid was washed with water (1.0 mL) and acetonitrile (1.0 mL). After drying, a white solid 4-(5-chloro-2-ethynylphenyl)-N-(5-((4-cyanobenzyl)oxy)-1,3,4-selenadiazol-2-yl)-6-methylnicotinamide (26.88 mg, yield: 46%) was obtained.

[0381] LCMS (ESI): [M+H]+=506.2.

[0382] 1H NMR(400MHz,DMSO-d6)δppm 13.03(s,1H),8.77(s,1H),8.17(s,1H),7.35(d,1H),7.25(s,1H),4.38(d,J=8.0Hz,2H),3.92-3.90(m,1H),3.8 1-3.75(m,2H),3.67-3.59(m,2H),3.57(s,3H),3.52-3.47(m,1H),3.40-3.35(m,1H),2.58(s,3H),2.47(s,3H).

[0383] Example 18: (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-yl)-5'-ethynyl-2'-, 6-dimethyl-[4,4'-bipyridine]-3-carboxamide

[0384] 5'-Ethynyl-2'-,6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (30 mg, 0.11 mmol) (prepared by reference to patent: WO2023202623) and (R)-5-((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-amine (31 mg, 0.12 mmol) were dissolved in acetonitrile (2.00 mL) and N,N-dimethylformamide (0.2 mL). Methylimidazole (48 mg, 0.59 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (40 mg, 0.14 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 16 hours. A large amount of solid precipitated. The reaction was monitored by LCMS, indicating the disappearance of the starting material and the presence of approximately 70% product. The reaction solution was directly filtered, and the solid was washed with water (1.0 mL) and acetonitrile (1.0 mL). After drying, a white solid (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazole-2-yl)-5'-ethynyl-2'-, 6-dimethyl-[4,4'-bipyridine]-3-carboxamide (23.69 mg, yield: 40%) was obtained.

[0385] LCMS (ESI): [M+H]+=500.2.

[0386] 1H NMR(400MHz,DMSO-d6)δppm 13.10(s,1H),8.99(s,1H),8.55(s,1H),7.34(s,1H),7.28(s,1H),4.38(d,J=8.0Hz,2H),4.08(s,1H),3.92-3.9 0(m,1H),3.81-3.75(m,2H),3.67-3.59(m,2H),3.52-3.47(m,1H),3.40-3.35(m,1H),2.59(s,3H),2.53(s,3H).

[0387] Example 19: N-(6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0388] 2'-(Difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (50 mg, 0.18 mmol) (prepared by reference to patent: WO2022259204) and 4-(2-amino-1,3-selenazolo[4,5-e]pyrazin-6-yl)benzonitrile (51 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (3.0 mL) at room temperature. Methylimidazole (70 mg, 0.85 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (57 mg, 0.20 mmol) were added, respectively. The mixture was stirred at room temperature for 16 hours. LCMS indicated 40% product and 30% starting material remained. The mixture was poured into water and extracted with ethyl acetate (60 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (methanol / dichloromethane=7% to 10%) to give a product purity (85%). The product was further purified by HPLC to give N-(6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (34.78 mg, yield: 35%) as a yellow solid.

[0389] LCMS (ESI): [M+H]+=578.2.

[0390] 1H NMR(400MHz,DMSO-d6)δppm 13.75(s,1H),9.31(s,1H),8.93(s,1H),8.48(s,1H),8.38(d,J=8.8Hz,2H),8.01(d,J= 8.4Hz,2H),7.76(s,1H),7.49(s,1H),7.01(t,J=55.2Hz,1H),3.72(s,3H),2.63(s,3H).

[0391] Example 20: N-(5-(cyclopropylethynyl)-1,3,4-selenadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0392] 2'-(Difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (60 mg, 0.20 mmol) was dissolved in acetonitrile (4.00 mL). N-methylimidazole (84 mg, 1.02 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (69 mg, 0.24 mmol), and 5-(cyclopropylethynyl)-1,3,4-selenodiazol-2-amine (43 mg, 0.20 mmol) were added. The reaction mixture was stirred at 20°C for 18 hours. The reaction was monitored by LCMS, which indicated 80% product. The reaction solution was filtered, and the solid was washed with acetonitrile (0.5 mL) and water (0.5 mL). The solid was further purified by HPLC (0.5% ammonia solution / acetonitrile, 50% to 60%) and freeze-dried to give a white solid N-(5-(cyclopropylethynyl)-1,3,4-selenadiazole-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (43.85 mg, yield: 43%).

[0393] LCMS (ESI): [M+H]+=490.2.

[0394] 1H NMR(400MHz,DMSO-d6)δppm 13.58(s,1H),8.86(s,1H),8.43(s,1H),7.71(s,1H),7.46(s,1H),6.98(t,J=55.2Hz,1 H),3.63(s,3H),2.61(s,3H),1.70-1.66(m,1H),0.99-0.88(m,2H),0.87-0.85(m,2H).

[0395] Example 21: N-(5-(cyclopropylethynyl)-1,3,4-selenadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxamide

[0396] 2'-(Difluoromethyl)-5'-methoxy-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxylic acid (80 mg, 0.21 mmol) (preparation method reference patent: WO2023050007) was dissolved in acetonitrile (3.0 mL), and N-methylimidazole (52 mg, 0.63 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (118 mg, 0.42 mmol), and 5-(cyclopropylethynyl)-1,3,4-selenodiazole-2-amine (40 mg, 0.19 mmol) were added separately. The reaction mixture was stirred at 20°C for 3 hours. The reaction was monitored by LCMS, which showed 65% product. The reaction was concentrated to give a crude product, which was purified by reverse phase column (mobile phase: A: 0.5% formic acid in water, B: acetonitrile; B from 5% to 95% in 20 min), and the fractions containing the product were combined and freeze-dried to give the product as a yellow solid, which was then slurried by (2 mL of acetonitrile), filtered and dried to give a white solid N-(5-(cyclopropylethynyl)-1,3,4-selenadiazole-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxamide (30.78 mg, yield: 25%).

[0397] LCMS (ESI): [M+H]+=375.2.

[0398] 1H NMR(400MHz,DMSO-d6)δppm 13.63(s,1H),8.90(s,1H),8.47(s,1H),8.20(s,1H),7.65(s,1H),7.01(t,J=55.0Hz,1H),4.32( s,2H),4.09-4.02(m,4H),3.65(s,3H),1.72-1.65(m,1H),1.02-0.97(m,2H),0.90-0.83(m,2H).

[0399] 19FNMR(400MHz,DMSO-d6)δppm-113.49(s,2F).

[0400] Example 22: 2'-Chloro-5'-methoxy-N-(5-methoxy-1,3,4-selenadiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0401] Reference Example 16: A white solid 2'-chloro-5'-methoxy-N-(5-methoxy-1,3,4-selenadiazole-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide was obtained

[0402] LCMS (ESI): [M+H]+=440.2.

[0403] 1 H NMR (400MHz, DMSO-d6) δppm 13.07(s,1H),8.84(s,1H),8.16(s,5H),7.53(s,1H),7.41(s,1H),4.06(s,3H),3.62(s,3H),2.59(s,3H).

[0404] Example 23: (2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carbonyl)imino)-5-methoxy-1,3,4-selenazol-3(2H)-yl)methyl dihydrogen phosphate (TD-APRN-B-12-26-PD)

[0405] Step 1: Dissolve 2'-chloro-5'-methoxy-N-(5-methoxy-1,3,4-selenazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (200 mg, 0.46 mmol) in N,N-dimethylformamide (2.0 mL). Add potassium iodide (151 mg, 0.91 mmol) and potassium carbonate (377 mg, 2.74 mmol), respectively. Add di-tert-butyl chloromethylphosphate (353 mg, 1.37 mmol) dropwise over 10 minutes. Stir the mixture at 25°C for 24 hours. The reaction mixture was poured into water (30 mL), extracted twice with ethyl acetate (30 mL), washed with brine (30 mL), dried, and concentrated to give di-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carbonyl)imino)-5-methoxy-1,3,4-selenazol-3(2H)-yl)methyl) phosphate (220 mg, yield: 72%) as a pale yellow solid.

[0406] LCMS (ESI): [M+H]+=662.3.

[0407] Step 2: Di-tert-butyl ((2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carbonyl)imino)-5-methoxy-1,3,4-selenidazole-3(2H)-yl)methyl) phosphate (220 mg, 0.33 mmol) was added to a water (2.0 mL) solution, and formic acid (1.5 mL) was added, and the mixture was stirred at 35°C for 4 hours. The mixture was concentrated and purified by preparative high-performance liquid chromatography (A: 5% aqueous FA solution, B: MeCN, B / A, 45% to 50%), and lyophilized to obtain a yellow solid (2-((2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carbonyl)imino)-5-methoxy-1,3,4-selenidazole-3(2H)-yl)methyl dihydrogen phosphate (144.64 mg, yield: 75%).

[0408] LCMS (ESI): [M+H]+=550.1.

[0409] 1H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.15(s,1H),7.44(s,1H),7.31(s,1H),5.85(d,J=8.8Hz,2H),4.06(s,3H),3.62(s,3H),2.58(s,3H).

[0410] Example 24: (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0411] 2'-(Difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (30 mg, 0.10 mmol), N-methylimidazole (42 mg, 0.51 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (34 mg, 0.12 mmol) were dissolved in acetonitrile (3.0 mL) and stirred at room temperature for 10 minutes. (R)-5-((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-amine (30 mg, 0.11 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours. The reaction suspension was directly filtered, washed with water (1.5 mL) and acetonitrile (1.5 mL) and dried under reduced pressure to give a white solid (R)-N-(5-((1,4-dioxane-2-yl)methoxy)-1,3,4-selenadiazole-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (32.22 mg, yield: 58%).

[0412] LCMS (ESI): [M+H]+=542.2.

[0413] 1H NMR(400MHz,DMSO-d6)δppm 13.07(s,1H),8.84(s,1H),8.45(s,1H),7.68(s,1H),7.42(s,1H),6.98(t,J=55.0Hz,1H),4.41-4.33(m,2H),3.90- 3.88(m,1H),3.78-3.73(m,2H),3.69(s,3H),3.68-3.58(m,2H),3.49-3.41(m,1H),3.37-3.32(m,1H),2.60(s,3H).

[0414] Example 25: (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxamide

[0415] 2'-(Difluoromethyl)-5'-methoxy-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxylic acid (36 mg, 0.09 mmol), N-methylimidazole (39 mg, 0.47 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (32 mg, 0.11 mmol) were dissolved in acetonitrile (3.0 mL) and stirred at room temperature for 10 minutes. (R)-5-((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazol-2-amine (28 mg, 0.10 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours. The reaction suspension was directly filtered, washed with water (2 mL) and acetonitrile (2 mL) and dried under reduced pressure to give a white solid (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-selenadiazole-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxamide (21.13 mg, yield: 35%).

[0416] LCMS (ESI): [M+H]+=627.0.

[0417] 1H NMR(400MHz,DMSO-d6)δppm 13.16(s,1H),8.87(s,1H),8.48(s,1H),8.17(s,1H),7.63(s,1H),7.00(t,J=55.0Hz,1H),4.40-4.35(m,2H),4.31(s,2H),4.08-4. 02(m,4H),3.94-3.87(m,1H),3.78-3.72(m,2H),3.71(s,3H),3.63-3.57(m,2H),3.53-3.45(m,1H),3.38(dd,J=11.4,10.0Hz,1H).

[0418] Example 26: 2'-(Difluoromethyl)-5'-methoxy-N-(5-methoxy-1,3,4-selenadiazol-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0419] 2'-(Difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (25 mg, 0.08 mmol) and 5-methoxy-1,3,4-selenadiazol-2-amine (15 mg, 0.08 mmol) were dissolved in acetonitrile (1.0 mL). N-methylimidazole (35 mg, 0.42 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (26 mg, 0.09 mmol) were added. The reaction mixture was stirred at 20°C for 3 hours. The reaction was monitored by LCMS, which showed 70% product. The reaction suspension was directly filtered, washed with water (0.5 mL) and acetonitrile (0.5 mL) and dried under reduced pressure to give 2'-(difluoromethyl)-5'-methoxy-N-(5-methoxy-1,3,4-selenadiazole-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (15.51 mg, yield: 39.5%) as a white solid.

[0420] LCMS (ESI): [M+H]+=456.1.

[0421] 1H NMR(400MHz,DMSO-d6)δppm 13.07(s,1H),8.84(s,1H),8.45(s,1H),7.68(s,1H),7.42(s,1H),6.98(t,J=55.2Hz,1H),4.05(s,3H),3.69(s,3H),2.60(s,3H).

[0422] Example 27: 2'-(Difluoromethyl)-5'-methoxy-N-(5-methoxy-1,3,4-selenadiazol-2-yl)-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxamide

[0423] 2'-(Difluoromethyl)-5'-methoxy-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxylic acid (25 mg, 0.08 mmol) and 5-methoxy-1,3,4-selenadiazol-2-amine (12 mg, 0.08 mmol) were dissolved in acetonitrile (1.0 mL), and N-methylimidazole (27 mg, 0.42 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (20 mg, 0.09 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 3 hours. The reaction suspension was directly filtered, washed with water (0.5 mL) and acetonitrile (0.5 mL), and dried under reduced pressure to obtain 2'-(difluoromethyl)-5'-methoxy-N-(5-methoxy-1,3,4-selenadiazol-2-yl)-6-(3-oxomorpholinyl)-[4,4'-bipyridine]-3-carboxamide (21.84 mg, yield: 58%) as a white solid. LCMS (ESI): [M+H]+ = 639.3.

[0424] 1H NMR(400MHz,DMSO-d6)δppm 13.15(s,1H),8.88(s,1H),8.48(s,1H),8.16(s,1H),7.62(s,1H),6.99(t,J=55.2Hz,1H),4.31(s,2H),4.08-4.04(m,7H),3.71(s,3H).

[0425] Example 28: 5'-ethynyl-N-(5-methoxy-1,3,4-selenadiazol-2-yl)-2'-6-dimethyl-[4,4'-bipyridine]-3-carboxamide

[0426] 5'-Ethynyl-2'-,6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (20 mg, 0.08 mmol) and 5-methoxy-1,3,4-selenadiazol-2-amine (14 mg, 0.08 mmol) were dissolved in acetonitrile (1.0 mL). N-Methylimidazole (32 mg, 0.40 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (24 mg, 0.09 mmol) were added, respectively. The reaction mixture was stirred at 20°C for 3 hours. The reaction suspension was directly filtered, washed with water (0.5 mL) and acetonitrile (0.5 mL) and dried under reduced pressure to give a yellow solid 5'-ethynyl-N-(5-methoxy-1,3,4-selenadiazole-2-yl)-2'-6-dimethyl-[4,4'-bipyridine]-3-carboxamide (16.70 mg, yield: 50%).

[0427] LCMS (ESI): [M+H]+=414.1.

[0428] 1H NMR(400MHz,DMSO-d6)δppm 13.22(s,1H),9.00(s,1H),8.54(s,1H),7.32(s,1H),7.23(s,1H),4.07(s,1H),4.04(s,3H),2.60(s,3H),2.53(s,3H).

[0429] Example 29: 2'-Chloro-N-(6-(1,4-dimethyl-1H-pyrazol-5-yl)-[1,3]selenazolo[4,5-c]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0430] Step 1: Dilute benzoyl chloride (0.80 g, 5.69 mmol) in acetone (50.0 mL) and add dropwise to a solution of potassium selenocyanate (0.82 g, 5.69 mmol) in acetone (40.0 mL). Stir at 25°C for 2 hours. The reaction mixture is used directly in the next step.

[0431] Step 2: 4,6-Dibromopyridin-3-amine (0.54 g, 2.58 mmol) was added to a solution of benzoyl isoselenocyanate (0.65 g, 2.58 mmol) in acetone (45.0 mL). The reaction was stirred at 60°C for 2 hours. The reaction mixture was filtered and the residue was dried to afford N-(6-bromo-[1,3]selenazolo[4,5-c]pyridin-2-yl)benzamide (0.80 g, 81%) as a brown solid.

[0432] LCMS (ESI): [M+H]+=382.0

[0433] Step 3: Dissolve N-(6-bromo-[1,3]selenazolo[4,5-c]pyridin-2-yl)benzamide (800 mg, 2.10 mmol) in 60% sulfuric acid (10.0 mL, 60% purity) and stir at 110°C for 2 hours. The reaction mixture was adjusted to pH 10 with aqueous sodium hydroxide solution, filtered, and the filter residue was dried to obtain 6-bromo-[1,3]selenazolo[4,5-c]pyridin-2-amine (235 mg, 40% yield) as a yellow solid.

[0434] LCMS (ESI): [M+H]+=278.0

[0435] 1H NMR(400MHz,DMSO-d6)δppm 8.24(s,1H),8.00(s,1H),7.97(br s,2H)

[0436] Step 4: 6-Bromo-[1,3]selenazolo[4,5-c]pyridin-2-amine (220 mg, 0.79 mmol) was dissolved in N,N-dimethylformamide (5.00 mL), followed by the addition of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (243 mg, 0.87 mmol) and N,N-diisopropylethylamine (308 mg, 2.38 mmol). The reaction was stirred at 25°C for 15 minutes. 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (453 mg, 1.19 mmol) was then added, and the reaction was allowed to proceed at 25°C for 16 hours. The reaction mixture was extracted with ethyl acetate / tetrahydrofuran (V / V=1 / 1, 20 mL*3). The organic phase was dehydrated with anhydrous magnesium sulfate and concentrated, and then purified by flash column chromatography (silica gel, 0-55% gradient of tetrahydrofuran / industrial hexane) to give a yellow solid N-(6-bromo-[1,3]selenazolo[4,5-c]pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (180 mg, 30% yield).

[0437] LCMS (ESI): [M+H]+=537.9

[0438] Step 5: N-(6-Bromo-[1,3]selenazolo[4,5-c]pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (99.1 mg, 0.45 mmol) was dissolved in N,N-dimethylformamide (6.00 mL) and purified water (1.50 mL). 1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (243 mg, 0.87 mmol), potassium carbonate (154 mg, 1.12 mmol), and Pd118 (24.2 mg, 0.04 mmol) were then added. The atmosphere was purged with nitrogen three times, and the reaction was stirred at 90°C for 4 hours. After filtering the reaction solution, preparative HPLC (C18, 4.00%-44.00% gradient of water (0.05% ammonia + 10 mM ammonium bicarbonate) / acetonitrile) was used to obtain an off-white solid 2'-chloro-N-(6-(1,4-dimethyl-1H-pyrazol-5-yl)-[1,3]selenazolo[4,5-c]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (20.90 mg, 10% yield). LCMS (ESI): [M+H]+=554.0

[0439] 1H NMR(400MHz,DMSO-d6)δppm 13.38(br s,1H),9.10(br s,1H),8.89(s,1H),8.29(s,1H),8.17(s,1H),7.60(s,1H),7.48(s,1H),7.35(s,1H),3.90(s,3H),3.60(s,3H),2.61(s,3H),2.11(s,3H)

[0440] Example 30: 2'-Chloro-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-[1,3]selenazolo[4,5-c]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0441] N-(6-Bromo-[1,3]selenazolo[4,5-c]pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (100 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (6.00 mL) and purified water (1.50 mL). 1,4-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (276 mg, 0.74 mmol), potassium carbonate (77.1 mg, 0.56 mmol), and PD118 (12.1 mg, 0.02 mmol) were then added. After nitrogen substitution three times, the reaction mixture was stirred at 90°C for 4 hours. After filtering the reaction solution, preparative HPLC (C18, 0.00%-38.00% gradient of water (0.05% ammonia water + 10 mM ammonium bicarbonate) / acetonitrile) was used to give a white solid 2'-chloro-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-[1,3]selenazolo[4,5-c]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (24.6 mg, 24% yield).

[0442] LCMS (ESI): [M+H]+=555.0

[0443] 1H NMR(400MHz,DMSO-d6)δppm 13.43(br s,1H),9.12(br s,1H),8.90(s,1H),8.42(s,1H),8.16(s,1H),7.60(s,1H),7.48(s,1H),4.15(s,3H),3.59(s,3H),2.61(s,3H),2.40(s,3H)

[0444] Example 31: 2'-Chloro-5'-methoxy-6-methyl-N-(6-(2-oxo-piperidin-1-yl)-[1,3]selenazolo[4,5-c]pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0445] N-(6-Bromo-[1,3]selenazolo[4,5-c]pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (60.0 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (5.00 mL), followed by the addition of piperidin-2-one (13.2 mg, 0.13 mmol), cesium carbonate (109 mg, 0.33 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (12.9 mg, 0.02 mmol), and tris(dibenzylideneacetone)dipalladium (10.2 mg, 0.01 mmol). The atmosphere was purged with nitrogen three times, and the reaction was stirred at 90°C for 4 hours. After filtering the reaction solution, preparative HPLC (C18, 0.00%-36.00% gradient of water (0.05% ammonia water + 10 mM ammonium bicarbonate) / acetonitrile) was used to give a white solid 2'-chloro-5'-methoxy-6-methyl-N-(6-(2-oxo-piperidin-1-yl)-[1,3]selenazolo[4,5-c]pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide (14.66 mg, 24% yield).

[0446] LCMS (ESI): [M+H]+=557.0

[0447] 1H NMR(400MHz,DMSO-d6)δppm 13.25(br s,1H),8.87(s,1H),8.83(s,1H),8.24(s,1H),8.16(s,1H),7.59(s,1H),7.47(s,1H), 3.85(t,J=5.6Hz,2H),3.59(s,3H),2.61(s,3H),2.49-2.45(m,2H),1.94-1.80(m,4H)

[0448] Example 32: 2'-Chloro-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-fluoro-[1,3]selenazolo[4,5-c]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0449] Step 1: Dissolve 5-fluoropyridin-3-amine (10.0 g, 89.2 mmol) in N,N-dimethylformamide (100 mL). Add N-bromosuccinimide (17.4 g, 98.1 mmol) portionwise at 0°C. The mixture is then heated to 25°C and stirred for 2 hours. Extract with ethyl acetate (300 mL x 3). The organic phase is dehydrated with anhydrous magnesium sulfate, concentrated, and purified by flash column chromatography (silica gel, 0-31% ethyl acetate / technical hexane gradient) to afford 6-bromo-5-fluoropyridin-3-amine (18.50 g, crude) as a yellow oil.

[0450] LCMS (ESI): [M+H]+=191.1

[0451] Step 2: 6-Bromo-5-fluoropyridin-3-amine (18.5 g, 67.8 mmol) was added to BOC anhydride (29.6 g, 135 mmol), and the reaction was stirred at 80°C for 16 hours. Purification by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / technical hexane) gave tert-butyl (6-bromo-5-fluoropyridin-3-yl)aminomethyl ester (17.5 g, 89%) as a colorless oil.

[0452] LCMS (ESI): [M+H]+=293.1

[0453] 1H NMR (400MHz, CDCl3-d6) δppm 8.03 (d, J=2.4Hz, 1H), 7.98 (br d, J=8.0Hz, 1H), 7.06 (br s, 1H), 1.50 (s, 9H)

[0454] Step 3: Dissolve tert-butyl (6-bromo-5-fluoropyridin-3-yl) aminomethyl ester (17.5 g, 60.1 mmol) in tetrahydrofuran (90.0 mL), then add lithium diisopropylamide (90.2 mL, 90.2 mmol) dropwise under nitrogen protection at 0°C, and then stir at 0°C for 0.5 hours. Dilute iodine in tetrahydrofuran (5.00 mL) and then add dropwise to the above reaction system at -70°C and stir at -70°C. The reaction mixture was carefully added to water (150 mL) and then extracted with ethyl acetate (100 mL x 3). The organic phase was dehydrated with anhydrous magnesium sulfate, concentrated, and purified by flash column chromatography (silica gel, 0-20% gradient of ethyl acetate / industrial hexane) to obtain tert-butyl (6-bromo-5-fluoro-4-iodopyridin-3-yl)aminomethyl ester (12.50 g, 50%) as a yellow solid. LCMS (ESI): [M+H]+ = 417.0

[0455] Step 4: Dissolve 6-tert-butyl (6-bromo-5-fluoro-4-iodopyridin-3-yl)aminomethyl ester (12.5 g, 29.9 mmol) in a mixture of dichloromethane (100 mL) and trifluoroacetic acid (25.0 mL). Stir the reaction at 25°C for 2 hours. Quench the reaction with saturated sodium bicarbonate (500 mL). Extract with ethyl acetate (300 mL x 3). The organic phase is then concentrated with anhydrous magnesium sulfate to yield 6-bromo-5-fluoro-4-iodopyridin-3-amine (7.50 g, 79%) as a yellow solid.

[0456] LCMS (ESI): [M+H]+=317.0

[0457] Step 5: Add 6-bromo-5-fluoro-4-iodopyridin-3-amine (2.00 g, 6.31 mmol) to a solution of benzoyl isoselenylcyanide (1.33 g, 6.31 mmol) in acetone (65.0 mL), and then stir at 60 ° C for 2 hours. The reaction solution was filtered and the residue was washed with ethyl acetate to obtain a yellow solid N-(6-bromo-7-fluoro-[1,3]selenazolo[4,5-c]pyridin-2-yl)benzamide (2.50 g, 99%).

[0458] LCMS (ESI): [M+H]+=400.0

[0459] Step 6: Add N-(6-bromo-7-fluoro-[1,3]selenazolo[4,5-c]pyridin-2-yl)benzamide (2.50 g, 6.26 mmol) to a sulfuric acid (30.0 mL, 60%) solution and stir at 110°C for 2 hours. The reaction solution was quenched by adding ice, and the pH was adjusted to alkaline with aqueous NaOH solution. Then, the reaction solution was extracted with ethyl acetate / tetrahydrofuran = 1 / 1 (50 mL * 3). The organic phase was dehydrated and concentrated to obtain 6-bromo-7-fluoro-[1,3]selenazolo[4,5-c]pyridin-2-amine (0.70 g, 38%) as a yellow solid.

[0460] LCMS (ESI): [M+H]+=296.0

[0461] Step 7: Dissolve 6-bromo-7-fluoro-[1,3]selenazolo[4,5-c]pyridin-2-amine (400 mg, 1.36 mmol) in tetrahydrofuran (5.00 mL), then add 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (453 mg, 1.63 mmol), N-methylimidazole (334 mg, 4.07 mmol), and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (570 mg, 2.03 mmol). Stir the reaction at 60°C for 16 hours. The reaction solution was added to water (30.0 mL) to quench, and then extracted with ethyl acetate / tetrahydrofuran = 1 / 1 (20 mL*3). The organic phase was dehydrated and concentrated, and then purified by flash column chromatography (silica gel, 0-45% gradient of tetrahydrofuran / industrial hexane) to give a yellow solid N-(6-bromo-7-fluoro-[1,3]selenazolo[4,5-c]pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (280 mg, 38%).

[0462] LCMS (ESI): [M+H]+=558.1

[0463] Step 8: Dissolve N-(6-bromo-7-fluoro-[1,3]selenazolo[4,5-c]pyridin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (100 mg, 0.19 mmol) in N,N-dimethylformamide (4.00 mL) and water (1.00 mL). Then, add 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (267 mg, 0.72 mmol), potassium carbonate (74.6 mg, 0.54 mmol), and PD118 (11.7 mg, 0.02 mmol). The atmosphere is purged with nitrogen three times. The reaction mixture is stirred at 90°C for 16 hours. The reaction solution was filtered and purified by preparative HPLC (C18, 2.00%-42.00% gradient of water (0.05% ammonia + 10 mM ammonium bicarbonate) / acetonitrile) to give an off-white solid 2'-chloro-N-(6-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-7-fluoro-[1,3]selenazolo[4,5-c]pyridin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (5.70 mg, 6%).

[0464] LCMS (ESI): [M+H]+=573.0

[0465] 1H NMR(400MHz,DMSO-d6)δppm 13.82(s,1H),8.98(br s,2H),8.15(s,1H),7.55(br s,1H),7.41(br s,1H),4.01(s,3H),3.59(s,3H),2.60(s,3H),2.25(s,3H)

[0466] Example 33: 2'-Chloro-N-(5-((2-hydroxy-2-methylpropyl)amino)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0467] Step 1: Add cuprous iodide (11.85 g, 60.98 mmol) to a solution of 2,4-dichloropyrimidin-5-amine (10.00 g, 60.98 mmol) and potassium selenocyanate (19.33 g, 134.15 mmol) in 1-methyl-2-pyrrolidone (200.00 mL, 0.00 mmol) at 20°C. After addition, stir at 135°C under a nitrogen atmosphere for 24 hours. Dilute the reaction mixture with 700 mL of water and extract with ethyl acetate:tetrahydrofuran (1:1) (2000 mL x 2). Wash the combined organic layers with 2000 mL of brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure to obtain a residue. Slurry the mixture with acetonitrile (100 mL) at 25°C for 30 minutes to yield 5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-amine (9.00 g, 60%) as a gray solid.

[0468] LCMS (ESI): [M+H]+=234.9

[0469] 1 H NMR(400MHz,DMSO-d6)δppm 8.46(br s,1H),8.32(br s,2H)

[0470] Step 2: Add 5-chloro-1,3-selenoazo[5,4-d]pyrimidine-2-ethylamine (1.50 g, 6.10 mmol) and 4-(2-chloro-5-methoxy(4-pyridyl))-6-methylpyridine-3-carboxylic acid (0.72 g, 2.57 mmol) to tetrahydrofuran (30.00 mL). Then add N,N-diisopropylethylamine (0.85 g, 6.43 mmol) and 2-chloro-1-methylpyridine (salt) iodide (0.82 g, 3.21 mmol). The mixture was stirred at 65 ° C under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (100 mL*2). The combined organic layers were washed with 300 mL of brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a residue. Silica gel column chromatography Purified; 40g Silica gel flash column, eluent 0-50% tetrahydrofuran / petroleum ether gradient 60 mL / min) to give 2'-chloro-N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (1.40 g, 46%) as a yellow solid.

[0471] LCMS (ESI): [M+H]+=494.9

[0472] Step 3: Add 2'-chloro-N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (100.00 mg, 0.20 mmol) and 1-amino-2-methylpropane-2-ol (36.07 mg, 0.40 mmol) to a solution of 2-methylbutane-2-ol (2.00 mL). Then, add triethylamine (61.43 mg, 0.61 mmol). The mixture is stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution is directly isolated and purified. Pre-HPLC (column: F-Welch xextreme C1840*200mm 7um; mobile phase: [A: H2O (0.225% FA); B: ACN); B%: 10.00%-50.00%, 19.00 min; flow rate: 60.00 ml / min) yielded the compound 2'-chloro-N-(5-((2-hydroxy-2-methylpropyl)amino)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (46.42 mg, 42%) as a yellow solid. LCMS (ESI): [M+H]+ = 547.9

[0473] 1H NMR(400MHz,DMSO-d6)δppm 13.00(br s,1H),8.83(s,1H),8.61(s,1H),8.18(s,1H),7.58(s,1H),7.46(s,1H),6.94(br t,J=5.2Hz,1H),4.54(s,1H),3.63(s,3H),3.35(br s,2H),2.60(s,3H),1.12(s,6H)

[0474] Example 34: 2'-Chloro-5'-methoxy-6-methyl-N-(5-(2-oxo-piperidin-1-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0475] 2'-Chloro-N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (100.00 mg, 0.20 mmol), piperidin-2-one (40.12 mg, 0.40 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.42 mg, 0.04 mmol), and cesium carbonate (197.78 mg, 0.61 mmol) were added to a dioxane (4.00 mL) solution. Pd2(dba)3 (18.53 mg, 0.02 mmol) was then added. The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The desired product was detected by LCMS (SHPL-XY001-36-P1A). The reaction solution was directly isolated and purified. Pre-HPLC (column: F-Welch xextreme C1840*200mm 7um; mobile phase: [A:H2O(0.225% FA); B:ACN); B%: 14.00%-54.00%, 19.00min; flow rate: 60.00ml / min) was used to obtain 2'-chloro-5'-methoxy-6-methyl-N-(5-(2-oxo-piperidin-1-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide (6.74mg, 6% yield) as a white solid.

[0476] LCMS (ESI): [M+H]+=558.1

[0477] 1H NMR(400MHz,DMSO-d6)δppm 13.66(br s,1H),9.06(s,1H),8.86(s,1H),8.16(s,1H),7.75(s,1H),7.37(s,1H),3.84( t,J=5.8Hz,2H),3.59(s,3H),2.62(s,3H),2.49-2.45(m,2H),1.93-1.79(m,4H)

[0478] Example 35: 2'-Chloro-N-(5-(4-cyanocyclohexatrien-1-en-1-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0479] To a solution of N,N-dimethylformamide (4.00 mL) and water (1.00 mL) were added Pd118 (26.38 mg, 0.04 mmol), 2'-chloro-N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (200.00 mg, 0.40 mmol), potassium carbonate (167.80 mg, 1.21 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexatriene-3-ene-1-carbonitrile (113.21 mg, 0.49 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 4 hours. The reaction mixture was directly isolated and purified. Pre-HPLC (column: F-Welch xmax C1840*200mm 7um, mobile phase: [A:H2O (0.225% FA); B:ACN]; B%: 22.00%-62.00%, 19.00 min; flow rate: 60.00 ml / min) was used to obtain compound 2'-chloro-N-(5-(4-cyanocyclohexatriene-1-en-1-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (6.74 mg, 6%) as a white solid.

[0480] LCMS (ESI): [M+H]+=566.0

[0481] 1H NMR(400MHz,DMSO-d6)δppm 13.46(br s,1H),9.06(s,1H),8.88(s,1H),8.18(s,1H),7.60(s,1H),7.48(s,1H),7.21(br s,1H),3.61(s,3H),3.22-3.14(m,1H),2.78-2.64(m,3H),2.61(s,3H),2.59-2.54(m,1H),2.09-1.94(m,2H)

[0482] Example 36: 2'-Chloro-N-(5-(4-hydroxypiperidin-1-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0483] 2'-Chloro-N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (100.00 mg, 0.20 mmol) and piperidin-4-ol (40.93 mg, 0.40 mmol) were added to a solution of 2-methylbutan-2-ol (2.00 mL). Triethylamine (61.43 mg, 0.61 mmol) was then added. The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was then directly isolated and purified. Pre-HPLC (chromatographic column: F-Welch xmax C1840*200mm 7um; mobile phase: [A: H2O (0.05% NH3H2O ​​+ 10mM NH4HCO3); B: ACN]; B%: 0.00% ~ 36.00%, 20.00min; flow rate: 60.00ml / min) was used to obtain compound 2'-chloro-N-(5-(4-hydroxypiperidin-1-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (50.62mg, 44%) as a yellow solid.

[0484] LCMS (ESI): [M+H]+=560.0

[0485] 1H NMR(400MHz,DMSO-d6)δppm 12.99(br,1H),8.83(s,1H),8.65(s,1H),8.17(s,1H),7.56(s,1H),7.45(s,1H),4.73(d,J=4.2Hz,1H),4.34-4. 23(m,2H),3.79-3.68(m,1H),3.62(s,3H),3.32-3.26(m,2H),2.59(s,3H),1.84-1.74(m,2H),1.39-1.29(m,2H)

[0486] Example 37: 2'-Chloro-5'-methoxy-6-methyl-N-(5-(methylthio)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0487] 2'-Chloro-N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (200.00 mg, 0.40 mmol) and (C-methylthiocarbamidyl)azane sulfate (450.59 mg, 1.62 mmol) were added to dimethyl sulfoxide (4.00 mL), followed by cesium carbonate (527.42 mg, 1.62 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was directly isolated and purified. Pre-HPLC (column: F-Welch xmax C1840*200mm 7um, mobile phase: [A:H2O (0.225% FA); B:ACN]; B%: 26.00%-66.00%, 19.00 min; flow rate: 60.00 ml / min) was used to obtain compound 2'-chloro-5'-methoxy-6-methyl-N-(5-(methylthio)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-[4,4'-bipyridine]-3-carboxamide (11.54 mg, 6%) as a white solid.

[0488] LCMS (ESI): [M+H]+=507.0

[0489] 1H NMR(400MHz,DMSO-d6)δppm 13.40(br s,1H),8.95(s,1H),8.86(s,1H),8.17(s,1H),7.60(s,1H),7.48(s,1H),3.61(s,3H),2.59(d,J=9.6Hz,6H)

[0490] Example 38: 2'-(Difluoromethyl)-N-(5-((2-hydroxy-2-methylpropyl)amino)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0491] Step 1: Add 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (330.00 mg, 1.12 mmol) and 5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-amine (340.46 mg, 1.46 mmol) to tetrahydrofuran (5.00 mL). Then, add N,N-diisopropylethylamine (434.81 mg, 3.36 mmol) and 2-chloro-1-methylpyridinium iodide (429.76 mg, 1.68 mmol). The reaction mixture is stirred at 80°C for 16 hours. The mixture is poured into water (25 mL). The aqueous phase is extracted with ethyl acetate (25 mL x 2). The combined organic layers are washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. N-(5-Chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (600.00 mg, 73%) was obtained as a brown solid.

[0492] LCMS (ESI): [M+H]+=511.2

[0493] Step 2: Add N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (200.00 mg, 0.31 mmol), 1-amino-2-methylpropane-2-ol (83.93 mg, 0.94 mmol) and triethylamine (127.04 mg, 1.26 mmol) to 2-methylbutane-2-ol (0.50 mL) and stir at 100 ° C under nitrogen atmosphere for 16 hours. The reaction solution was diluted with dimethyl sulfoxide (2 ml) and filtered. The filtrate was purified by preparative HPLC (C 18 Purification was performed using a 5-mercaptoethanol column; mobile phase: [A: water (0.225% formic acid); B: acetonitrile]; B%: 10.00% to 50.00%, 20.00 min; flow rate: 60.00 ml / min. 2'-(Difluoromethyl)-N-(5-((2-hydroxy-2-methylpropyl)amino)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (14.69 mg, 8%) was obtained as an orange solid.

[0494] LCMS (ESI): [M+H]+=564.1

[0495] 1 H NMR(400MHz,DMSO-d6)δppm 13.01(br s,1H),8.82(s,1H),8.61(s,1H),8.46(s,1H),7.72(s,1H),7.46(s,1H),7.16-6.82(m,2H),4.52(s,1H),3.70(s,3H),3.34(br s,2H),2.61(s,3H),1.12(s,6H)

[0496] Example 39: 2'-(Difluoromethyl)-N-(5-(4-hydroxypiperidin-1-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0497] N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (150.00 mg, 0.24 mmol), piperidin-4-ol (23.81 mg, 0.24 mmol) and triethylamine (95.28 mg, 0.94 mmol) were added to 2-methylbutan-2-ol (0.50 mL), and the reaction solution was stirred at 100 ° C under nitrogen atmosphere for 16 hours. The reaction solution was diluted with dimethyl sulfoxide (2 mL) and filtered. The filtrate was subjected to preparative HPLC (C 18 Purification was performed using a column; mobile phase: [A: water (0.225% formic acid); B: acetonitrile); B%: 12.00%-52.00%, 20.00 min; flow rate: 60.00 ml / min]. 2'-(Difluoromethyl)-N-(5-(4-hydroxypiperidin-1-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (44.28 mg, 33%) was obtained as a yellow solid.

[0498] LCMS (ESI): [M+H]+=576.1

[0499] 1H NMR(400MHz,DMSO-d6)δppm 13.01(br s,1H),8.83(s,1H),8.65(s,1H),8.46(s,1H),7.72(s,1H),7.45(s,1H),6.99(t,J=54.8Hz,1H),4.73(d,J=4.0Hz,1H),4.35-4 .18(m,2H),3.70(s,4H),3.31-3.24(m,2H),2.61(s,3H),2.54(s,1H),2.56-2.53(m,1H),1.85-1.73(m,2H),1.41-1.29(m,2H)

[0500] Example 40: 2'-Chloro-N-(5-(6-cyano-2-azaspiro[3.3]heptane-2-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0501] 2'-Chloro-N-(5-chloro-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (150.00 mg, 0.30 mmol) and 2-azaspiro[3.3]heptane-6-carbonitrile trifluoroacetate (74.16 mg, 0.61 mmol) were added to 2-methylbutan-2-ol (2.00 mL, 0.00 mmol), followed by Et3N (122.85 mg, 1.21 mmol). The mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction solution was directly isolated and purified. High performance liquid chromatography (chromatographic column: F-Welch xmax C1840*200mm 7um, mobile phase: [A:H2O(0.225%FA); B:ACN]; B%: 16.00%-56.00%, 19.00min; flow rate: 60.00ml / min) was used to obtain compound 2'-chloro-N-(5-(6-cyano-2-azaspiro[3.3]heptane-2-yl)-[1,3]selenazolo[5,4-d]pyrimidin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (37.50mg, 21%) as a yellow solid.

[0502] LCMS (ESI): [M+H]+=580.9

[0503] 1H NMR(400MHz,DMSO-d6)δppm 13.06(s,1H),8.83(s,1H),8.69(s,1H),8.18(s,1H),7.58(s,1H),7.47(s,1 H),4.10(d,J=13.2Hz,4H),3.62(s,3H),3.34-3.26(m,1H),2.66-2.53(m,7H)

[0504] Example 41: 2'-Chloro-N-(6-(4-cyanocyclohexatrien-1-en-1-yl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0505] Step 1: Dissolve 6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-amine (1.20 g, 4.32 mmol) and 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridyl]-3-carboxylic acid (1.44 g, 5.18 mmol) in tetrahydrofuran (5.00 mL). Add N,N-diisopropylethylamine (1.67 g, 12.95 mmol) and 2-chloro-1-methylpyridinium iodide (1.65 g, 6.48 mmol). Stir the reaction mixture at 20°C for 2 hours. Pour the reaction mixture into water (25 mL). Extract the aqueous phase with ethyl acetate (25 mL x 2). Wash the combined organic phases with brine (50 mL), dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. The crude product is purified by column chromatography (hexane / ethyl acetate = 1 / 0 to 3 / 1). N-(6-Bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (1.80 g, 62% yield) was obtained as a yellow solid.

[0506] LCMS (ESI): [M+H]+=539.2

[0507] 1H NMR (400MHz, DMSO-d6) δppm 13.87-13.52(m,1H),8.94(s,1H),8.66(s,1H),8.16(s,1H),7.56(s,1H),7.42(s,1H),3.61(s,3H),2.60(s,3H)

[0508] Step 2: Dissolve N-(6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (0.15 g, 0.28 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexatriene-3-carbonitrile (0.06 g, 0.28 mmol), potassium carbonate (0.12 g, 0.84 mmol), and 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (0.02 g, 0.03 mmol) in a mixed solvent of N,N-dimethylformamide (2 mL) and water (0.4 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 90°C under a nitrogen atmosphere for 1 hour. The reaction solution was filtered. The filtrate was purified by preparative HPLC (C18 [A: water (0.05% ammonia + 10 mM ammonium bicarbonate); B: acetonitrile]; B%: 2.00% to 42.00%, 20.00 min; flow rate: 60.00 ml / min). The purified fraction was lyophilized to afford 2'-chloro-N-(6-(4-cyanocyclohexatrien-1-en-1-yl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (0.08 g, 48% yield) as a yellow solid.

[0509] LCMS (ESI): [M+H]+=566.0

[0510] 1H NMR(400MHz,DMSO-d6)δppm 13.58(br s,1H),8.90(s,1H),8.81(s,1H),8.17(s,1H),7.60(s,1H),7.47(s,1H),6.79(br s,1H),3.62(s,2H),3.69-3.56(m,1H),3.33(s,13H),3.24-3.12(m,1H),2.75-2.58(m,6H),2.57-2.52(m,1H),2.13-1.89(m,2H)

[0511] Example 42: 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide

[0512] Step 1: Dissolve 6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-amine (0.30 g, 1.08 mmol) and 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinic acid (0.20 g, 0.72 mmol) in tetrahydrofuran (5.00 mL). Add N,N-diisopropylethylamine (0.37 g, 2.88 mmol) and 2-chloro-1-methylpyridinium iodide (0.28 g, 1.08 mmol). Stir the reaction mixture at 80°C for 16 hours. Pour the reaction mixture into water (50 mL). Extract the aqueous phase with ethyl acetate / tetrahydrofuran (50 mL x 2) at a ratio of 1:1. Wash the combined organic layers with brine (150 mL), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. The crude product was purified by column chromatography (silica, hexane / tetrahydrofuran = 1 / 0 to 1 / 1) to give N-(6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide (0.16 g, 41%) as a yellow solid.

[0513] LCMS (ESI): [M+H]+=537.9

[0514] Step 2: N-(6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide (126.00 mg, 0.23 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (53.69 mg, 0.23 mmol), potassium carbonate (97.17 mg, 0.70 mmol) and 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (38.18 mg, 0.06 mmol) were added to N,N-dimethylformamide (2.50 mL) and water (0.50 mL), and the atmosphere was replaced with nitrogen three times. The reaction solution was stirred at 100 ° C under nitrogen atmosphere for 1 hour. The reaction solution was diluted with dimethyl sulfoxide (2 ml) and filtered. The filtrate was purified by preparative HPLC (C 18 Purification was performed using a column; mobile phase: [A: water (0.225% formic acid); B: acetonitrile); B%: 38.00%-78.00%, 20.00 min; flow rate: 60.00 ml / min]. 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (52.32 mg, 40%) was obtained as a yellow solid.

[0515] LCMS (ESI): [M+H]+=561.1

[0516] 1H NMR(400MHz,DMSO-d6)δppm 13.58(br s,1H),9.32(s,1H),8.80(s,1H),8.38(d,J=8.8Hz,2H),8.02(d,J=8.4Hz,2H), 7.56-7.40(m,3H),7.02(d,J=8.8Hz,1H),3.51(s,3H),2.60(s,3H),2.07(s,1H)

[0517] Example 43: 2'-Chloro-N-(6-(difluoromethoxy)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0518] Step 1: Dissolve N-(6-bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (400 mg, 0.74 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (63.0 mg, 0.15 mmol), and potassium hydroxide (166 mg, 2.97 mmol) in N,N-dimethylacetamide (6.00 mL) and purified water (1.00 mL). Add tris(dibenzylideneacetone)dipalladium (68.0 mg, 0.07 mmol). Stir at 100°C under nitrogen for 16 hours. After the reaction solution was filtered, the crude product was purified by preparative HPLC (C18, 0%-40% gradient of water (0.1% trifluoroacetic acid) / acetonitrile) to give 2'-chloro-N-(6-hydroxy-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (80.0 mg, 20.0%) as a yellow solid.

[0519] LCMS(ESI):[M+H] + =477.0

[0520] Step 2: Dissolve 2'-chloro-N-(6-hydroxy-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (80.0 mg, 0.17 mmol) and cesium carbonate (164 mg, 0.50 mmol) in N,N-dimethylacetamide (2.00 mL), and add 2-chloro-2,2-difluoroacetic acid sodium salt (51.2 mg, 0.34 mmol). Stir at 80°C under nitrogen atmosphere for 4 hours. After the reaction solution was filtered, the crude product was purified by preparative HPLC (C18, 26%-66% gradient of water (0.225% formic acid) / acetonitrile) to give 2'-chloro-N-(6-(difluoromethoxy)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (1.12 mg, 1%) and 2'-chloro-N-(6-(difluoromethoxy)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (1.95 mg, 2.00%) as a yellow solid.

[0521] LCMS(ESI):[M+H] + =526.8

[0522] 1 H NMR(400MHz,DMSO-d6)δppm 13.63(br s,1H),8.89(s,1H),8.52(s,1H),8.18(s,1H),7.96-7.55(m,2H),7.50(s,1H),3.62(s,3H),2.62(s,3H)

[0523] Example 44: 2'-Chloro-5'-methoxy-6-methyl-N-(6-((trifluoromethyl)thio)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide

[0524] N-(6-Bromo-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (200.00 mg, 0.37 mmol) and trifluoromethylthio(2,2-bipyridine)copper(I) (238.23 mg, 0.74 mmol) were added to N-methylpyrrolidone (4.00 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 100°C under a nitrogen atmosphere for 16 hours. LCMS (SHPL-JF001-34-P1B) analysis showed that 57% of the target compound was produced. The reaction solution was diluted with dimethyl sulfoxide (4 ml). Purification by reverse phase high performance liquid chromatography (C 18 Column; Mobile phase: [A: Water (0.05% ammonia + 10 mM sodium bicarbonate); B: Acetonitrile); B%: 10.00%-50.00%, 20.00 min; Flow rate: 60.00 ml / min. 2'-Chloro-5'-methoxy-6-methyl-N-(6-((trifluoromethyl)thio)-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide (17.2 mg, 8%) was obtained as a yellow solid. LCMS (ESI): [M+H]+ = 561.1

[0525] 1 H NMR(400MHz,DMSO-d6)δppm 13.90(br s,1H,9.06-8.77(m,2H),8.17(s,1H),7.61(s,1H),7.48(s,1H),3.62(s,3H),2.61(s,3H)

[0526] Example 45: 2'-Chloro-5'-methoxy-N-(6-methoxy-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0527] Reference Example 43: 2'-chloro-5'-methoxy-N-(6-methoxy-[1,3]selenazolo[4,5-b]pyrazin-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide can be obtained

[0528] LCMS (ESI): [M+H]+=491.3.

[0529] 1 H NMR (400MHz, DMSO) δ8.87(s,1H),8.27(s,1H),8.17(s,1H),7.60(s,1H),7.48(s,1H),3.98(s,3H),3.62(s,3H),2.61(s,3H).

[0530] Using the above synthesis method and different raw materials, the following target compounds can be obtained:

[0531] Practical Example 1: POLQ enzyme activity inhibition experiment

[0532] Compounds were serially diluted in DMSO using a 384PP Plate. Using an Echo, 0.1 μL of compound was transferred to a 384-well plate (Optiplate-384) to ensure a final DMSO content of 1% (in duplicate). 5 μL of POLQ-N (M1-N899) enzyme solution was added to each well of the 384-well plate and incubated at 25°C for 10 minutes. Wells containing DMSO and enzyme served as high controls, while wells containing the same amount of DMSO and assay buffer served as low controls. 5 μL of a mixed ssDNA and ATP solution was added to each well and incubated at 25°C for 60 minutes (final concentrations: 40 mM Hepes (pH 7.5), 20 mM MgCl2, 0.01% BSA, 1 mM DTT, 1 nM POLQ-N, 50 nM ssDNA, 50 μM ATP). 5 μL of ADP-Glo ​​Reagent solution was added to each well and incubated for a further 40 minutes. Add 10 μL of ADP-Glo ​​Detection solution to each well and incubate for another 40 minutes. Luminescence signals were read on a BMG (PHERAstar FSX) microplate reader. Percent inhibition in compound-treated wells was normalized between the high and low control groups (% inhibition = (Ave high control - compound treatment) / (Ave high control - Ave low control) * 100). Four-parameter IC values ​​were then fitted using XLfit 5.5.0. 50 Curve and analysis, IC 50 It is the concentration of compound corresponding to 50% inhibition on the curve.

[0533] Effect Example 2: Experiment on the inhibition of tumor cell proliferation by compounds

[0534] POLQ cell activity assay. Collect cells and resuspend them in RPMI1640 (SH30809.01, Hyclone) cell culture medium containing 10% FBS (#76294-180, Avantar). Use a cell counter to determine the cell density. Pipette an appropriate amount of cell suspension from the centrifuge tube to prepare 125 cells / 100 μL of DLD-1 cell line and 500 cells / 100 μL of DLD-1BRCA2 (- / -) cell line. Spread 100 μL of cell suspension in each well of a 96-well plate (3603, Corning) and incubate overnight in an incubator. Add the diluted test compound solution to the well plate. Replace fresh culture medium and re-treat the compound on the fourth and seventh days of incubation, for a total incubation time of 10 days. After the incubation is completed, remove the cell culture plate and equilibrate to room temperature. 60 μL of CellCounting-lite (DD1101-03, Vazyme) was added to each well and incubated at room temperature for 30 minutes. The plate was read using a 96-well microplate reader in Luminescence mode (PHERAstar FSX, BMG). Data were analyzed, curve-fitted, and reported using the dose-response one-site 205 model of IDBS XLfit.

[0535] Table 2 IC50 of the example compounds on the inhibition of tumor cell growth

[0536] Biological Test 3:

[0537] 3.1: Pharmacokinetic testing in rats

[0538] Experimental animals: Male SD rats, about 250 g, 6-8 weeks old, 6 rats per compound, purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0539] Experimental design: On the day of the experiment, 6 SD rats / compound were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration. Note: Intravenous and oral administration solvent: 5% DMSO / 40% PEG 400 / 55% H2O

[0540] (DMSO: dimethyl sulfoxide: PEG400: polyethylene glycol 400: H2O: water for injection)

[0541] Before and after administration, 0.20 mL of blood was collected from the jugular vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 4000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from the intravenous and oral gavage groups at 5 (for the intravenous injection group), 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS. Note: The actual administration was that of Example 23, but the AUC and T1 / 2 measurements were those of Example 22.

[0542] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in rats.

[0543] 3.2: Pharmacokinetic testing in mice

[0544] Experimental animals: Male CD1 mice, about 25 g, 6-8 weeks old, 6 mice / compound, purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0545] Experimental design: On the day of the experiment, 6 CD1 mice / compound were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration. Note: Intravenous and oral administration solvent: 5% DMSO / 40% PEG 400 / 55% H2O

[0546] (DMSO: dimethyl sulfoxide: PEG400: polyethylene glycol 400: H2O: water for injection)

[0547] Before and after administration, 0.030 mL of blood was collected via the jugular vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 4000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from the intravenous and oral gavage groups at 5 (for the intravenous injection group), 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0548] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in mice.

[0549] 3.3: Pharmacokinetic testing in beagle dogs

[0550] Test animals: Male beagle dogs, 6-13 kg, aged 8 months to 3 years, 6 per compound, purchased from Mars Biotechnology Co., Ltd.

[0551] Test method: On the test day, 6 beagle dogs were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration. Note: Intravenous and oral administration solvent: 5% DMSO / 65% PEG400 / 30% Water;

[0552] Before and after administration, 0.6 mL of blood was collected from the four extremity veins. The blood was placed in EDTAK2 centrifuge tubes and centrifuged at 2000g at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at the following time points: 5 (for the intravenous injection group), 15, 30 minutes, and 1, 2, 4, 6, 8, 24, 48, and 72 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0553] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in beagle dogs.

[0554] 3.4: Monkey Pharmacokinetics Test

[0555] Experimental animals: Male cynomolgus monkeys, weighing approximately 2-6 kg and aged 3-5 years, 6 per compound, purchased from Ankai Yibo (Zhanjiang) Biotechnology Co., Ltd. or Ankai Yibo (Zhaoqing) Biotechnology Co., Ltd.

[0556] Test method: On the day of the test, 6 cynomolgus monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration. Note: Intravenous and oral administration solvent: 5% DMSO / 65% PEG400 / 30% Water;

[0557] Before and after administration, 0.6 mL of blood was collected from the four extremity veins. The blood was placed in EDTAK2 centrifuge tubes and centrifuged at 2000g at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at the following time points: 5 (for the intravenous injection group), 15, 30 minutes, and 1, 2, 4, 6, 8, 24, 48, and 72 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0558] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in cynomolgus monkeys.

[0559] 3.5: hERG K+ channel inhibition assay

[0560] Experimental platform: electrophysiology manual patch clamp system

[0561] Cell line: Human embryonic kidney (HEK293) cell line stably expressing hERG potassium channel

[0562] Experimental Methods: A slide seeded with cells was placed in a cell recording chamber. A glass electrode filled with intracellular solution was inserted into the amplifier headstage. After connecting to a patch clamp amplifier (EPC10), the inlet resistance was measured, which should be 2-5 MΩ. Single cells were selected for whole-cell recording under a microscope, and a high-resistance seal of >1000 MΩ was formed between the recording cell and the glass electrode. After the seal was established, the amplifier sampling frequency was set to 20 kHz, the filter frequency to 10 kHz, and the clamping voltage to -90 mV. The hERG tail current was evoked by repeated Ikr(hERG) stimulation with a 10-second interstimulus interval: the clamping voltage was switched from -90 mV to -80 mV for 500 ms to measure the leak current. A 4.8-second depolarizing voltage was applied to depolarize the membrane potential from -80 mV to +30 mV. A 5.2-second repolarizing voltage was then applied to reduce the membrane potential to -50 mV to eliminate channel inactivation, thereby eliciting the hERG tail current. The peak value of the tail current is the hERG current. After starting the current recording, perfuse the blank extracellular solution and continue recording for 120 seconds. After the current stabilizes, the test compound is perfused in order from low to high concentration. After each dose concentration perfusion, wait until the current stabilizes again before perfusing the next concentration (≥3 minutes). Each compound needs to be tested on at least 2 cells (n≥2).

[0563] Data analysis: Data were output by PatchMaster software.

[0564] After perfusing the blank solvent or compound gradient solution, the average of the five consecutive current values ​​obtained was calculated and used as the "tail current size blank" and "tail current size compound" respectively.

[0565] The current suppression percentage is calculated using the following formula.

[0566] The standard deviation of the two sets of data is less than 15 (SD<15)

[0567] The dose-effect curve was fitted using Graphpad Prism 8.0 software and the IC50 value was calculated. The fitting formula is as follows:

[0568] X is the Log value of the test compound concentration, Y is the percentage inhibition rate at the corresponding concentration, Top is the inhibition rate at the end point of the fitting curve, Bottom is the inhibition rate at the starting point of the fitting curve, and Hill is the slope of the curve.

[0569] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no obvious hERG inhibitory activity or weak inhibitory activity.

[0570] 3.6: PPB (UC) trial design

[0571] 1. Experimental Design

[0572] 1) Preparation of a buffer solution containing 100 mM sodium phosphate and 150 mM NaCl

[0573] Prepare an alkaline solution with ultrapure water containing 14.2 g / L sodium dihydrogen phosphate and 8.77 g / L sodium chloride. This alkaline solution can be stored at 4°C for 7 days. Prepare an acidic solution with ultrapure water containing 12.0 g / L sodium dihydrogen phosphate and 8.77 g / L sodium chloride. This acidic solution can be stored at 4°C for 7 days. Titrate the alkaline solution with the acidic solution to a pH of 7.4. This buffer can be stored at 4°C for 7 days. Test the buffer pH on the day of the experiment and adjust the pH if it is outside the range of 7.4 ± 0.1.

[0574] 2) Preparation of plasma

[0575] Frozen plasma was quickly thawed in a 37°C water bath.

[0576] The plasma was centrifuged at 3,220 g for 10 minutes at room temperature to remove clots. The supernatant was collected into a new centrifuge tube and the plasma pH was measured and recorded. The plasma was diluted with PBS (pH 7.4) 9 times the volume of the plasma to obtain 10% plasma. The plasma was pre-incubated in a 37°C water bath for 5 minutes.

[0577] Note: a) Only use plasma that has been thawed no more than twice. b) Only use plasma with a pH of 7 to 8.

[0578] 3) Preparation of stock solution and working solution

[0579] Prepare 10mM DMSO stock solutions of the test substance and control drug, ketoconazole. Dilute 10μL of the 10mM stock solution with 90μL of DMSO to obtain a 1mM working solution. Take 3μL of the working solution and add 2997μL of plasma to a final concentration of 1μM (0.1% DMSO) in plasma. Vortex thoroughly.

[0580] 4) Preparation of T0 samples

[0581] 50 μL of plasma sample was transferred to 50 μL of blank phosphate buffered saline, and then 400 μL of acetonitrile containing internal standards (200 nM labetalol, 200 nM imipramine, and 2 μM ketoprofen) was added to precipitate the protein. The protein-precipitated sample was vortexed for 5 minutes and then centrifuged at 16,000 g for 15 minutes at room temperature. The supernatant was diluted with ultrapure water for LC-MS / MS analysis.

[0582] 5) Preparation of T0.5 and T3.5 samples

[0583] 50 μL of plasma samples were transferred to 0.6 mL tubes and incubated in a 37°C, 5% CO2 incubator for 0.5 h and 3.5 h, respectively. After incubation, the samples were processed in the same manner as T0.

[0584] 6) Ultracentrifugation step

[0585] Transfer 1 ml of plasma sample to a new ultracentrifuge tube and incubate the tube at 37°C in a 5% CO2 incubator for 30 minutes. After incubation, centrifuge the tube at 800,000 g for 3 hours at 37°C. After centrifugation, remove 50 μL of the ultracentrifuge tube as the post-ultracentrifugation sample. Add 50 μL of blank plasma and 400 μL of acetonitrile containing internal standards (200 nM labetalol, 200 nM imipramine, and 2 μM ketoprofen) to precipitate proteins and release compounds. The protein-precipitated sample is vortexed for 5 minutes and then centrifuged at 16,000 g for 15 minutes at room temperature. The supernatant is diluted with ultrapure water for LC-MS / MS analysis.

[0586] 2. Data Analysis

[0587] All calculations were performed using Microsoft Excel.

[0588] Determine the peak area of ​​the test substance on the buffer side and the plasma side. The formula for calculating the plasma protein binding rate of the test substance and the reference drug is as follows: Binding rate Fu 100％ =(1-100% plasma free rate Fu 100％ *100) Note: D is the plasma dilution factor. In this study, D is 10.

[0589] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good PPB binding rates.

[0590] 3.7: Liver microsome stability test

[0591] The purpose of this study was to investigate the in vitro metabolic stability of the test substance in liver microsomes of mice, rats, dogs, monkeys and humans.

[0592] Test substances were incubated with mouse, rat, dog, monkey, and human liver microsomes (0.5 mg / mL) in phosphate buffer (100 mM, pH 7.4) at 37°C with or without the cofactor NADPH (1 mM). The incubation system was maintained at a test substance concentration of 1 μM. Samples were collected at 0.5, 5, 15, 30, and 60 minutes, and the reaction was terminated with ice-cold acetonitrile containing an internal standard. Verapamil was used as a positive control. Samples were analyzed by UPLC-MS / MS to determine the ratio of the test substance peak area to the internal standard, and the half-life (t½), residual percentage, intrinsic clearance (in vitro CLint), scaled-up clearance (Scale-up CLint), predicted hepatic clearance (Predicted hepatic CLint), and hepatic uptake (E) were calculated.

[0593] Metabolic Stability of Test Compounds in Pooled Human and Male Mouse Liver Microsomes

[0594] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good metabolic stability in liver microsomes.

[0595] 3.8: CYP450 enzyme inhibition testing

[0596] Experimental process:

[0597] 1) Transfer 1 μL of 2 mM test compound or positive control compound (see Table 1 for control compound information) to the culture plate. The final concentration of the test compound or positive control compound is 10 μM. A DMSO blank vehicle control is also included. Test samples should be prepared in duplicate.

[0598] Positive inhibitor information

[0599] 2) The stock solution was placed in a culture plate with the following substrate concentrations.

[0600] Preparation of incubation system

[0601] Substrate information

[0602] 3) Preheat the culture plate in a 37°C water bath for 5 min, add 20 μL of 10 mM NADPH solution to initiate the reaction at a final concentration of 1 mM, and carry out the reaction at 37°C.

[0603] 4) After incubation for the appropriate time, add 2 volumes of quencher (200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen) to each well. Centrifuge the sample at 3,220 g for 40 minutes to precipitate the protein. Then, transfer 100 μL of the supernatant to each well of a new 96-well plate containing an appropriate volume of ultrapure water for LC-MS / MS analysis.

[0604] Data Analysis:

[0605] All data calculations were performed using Microsoft Excel. Peak areas were determined using extracted ion chromatograms.

[0606] The percentage of residual enzyme activity was calculated using the following formula: Residual activity percentage (%) = metabolite peak area ratio test substance / inhibitor / metabolite peak area ratio blank control × 100%

[0607] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on any subtype of CYP enzymes.

[0608] 3.9: CYP450 enzyme induction test

[0609] Purpose: The purpose of this study was to evaluate the induction of CYP1A2, CYP2B6, and CYP3A4 in vitro using frozen human hepatocytes as a test system.

[0610] Hepatocyte viability assay in CYP induction assay

[0611] After 72 hours of compound action, the cell culture plate was taken out from the incubator and the cell morphology was observed under a microscope.

[0612] CellTiter-Fluor TM Melt the cell viability assay reagents in a 37°C water bath. Mix the GF-AFC substrate and assay buffer at a ratio of 1:1000 (GF-AFC substrate:Assay buffer) to create a 2× reaction solution. Dilute the solution halfway with an equal volume of PBS to create a 1× reaction solution. Remove the cell culture plate from the incubator. Aspirate the medium from each well and wash twice with PBS. Add 100 μL of the 1× CellTiter reaction solution to each well. A well without cells serves as a background control. Incubate the cell culture plate in a 37°C, 5% CO2 incubator for 30 minutes.

[0613] Remove the culture plate, cool it to room temperature, and transfer 80 μL of 1× CellTiter™ reaction solution to a new black flat-bottom 96-well plate. Measure the fluorescence of each well using an Infinite200PRO microplate reader under the conditions of 400 nm excitation and 505 nm emission.

[0614] Enzyme activity level detection

[0615] Prepare 1000× DMSO working solutions of the labeled substrates for CYP1A2 and CYP3A4, and 100× pure water working solutions of the labeled substrate for CYP2B6. Preheat incubation medium to 37°C and dilute the substrate working solutions to the following concentrations in incubation medium. The final DMSO concentration in the system should be ≤ 0.1%.

[0616] After the cell viability assay, remove the remaining CellTiter reaction solution, wash the cells twice with PBS, add 125 μL of prewarmed incubation medium, and preincubate for 10 minutes at 37°C in a 5% CO2 incubator. Then, remove the incubation medium and add 125 μL of substrate-containing medium. Incubate for the time indicated for each enzyme in a 5% CO2 incubator at 37°C. After the incubation period, transfer 100 μL of medium to each well of a 96-well plate and add 400 μL of quencher. Vortex for 10 minutes and centrifuge at 3000 g at 4°C for 30 minutes. Transfer a volume of the supernatant to a new 96-well plate and add an equal volume of water to mix before analysis by LC-MS / MS.

[0617] Dilute the labeled metabolites in incubation medium to the following standard curve concentrations.

[0618] A standard curve was prepared in a 96-well plate by adding 1 μL of 100× DMSO metabolite solution to 99 μL of culture medium, followed by the addition of 400 μL of quencher. The mixture was vortexed for 10 minutes and centrifuged at 3220 g at 4°C for 30 minutes. A volume of the supernatant was transferred to a new 96-well plate and then mixed with an equal volume of purified water before analysis by LC-MS / MS.

[0619] The induction effects of the test and control compounds on each enzyme need to be tested in three different donor cells, and each sample should be incubated in triplicate.

[0620] mRNA level detection

[0621] After removing samples for enzyme activity assay, mRNA was extracted and measured using the FlysisAmp Cells-to-Ct 2-Step Probe kit. Remove any remaining culture medium, wash the cells twice with PBS, and place the cell plate on ice. Add 50 μL of the lysis buffer provided in the kit to each well, pipette up and down five times to mix thoroughly, and incubate the cells at room temperature for 5 minutes. Then, add 5 μL of the stop buffer to each well, pipette up and down five times to mix thoroughly, and incubate at room temperature for 2 minutes.

[0622] Prepare the reverse transcription mix according to the table below and add 42 μL of the reverse transcription mix to each well of a 96-well PCR plate.

[0623] Add 8 μL of the lysed sample from the previous step to each well of a 96-well PCR plate containing 42 μL of reverse transcription mix, bringing the total volume per well to 50 μL. Mix gently and centrifuge to remove any bubbles.

[0624] Perform reverse transcription in a QPCR instrument using the protocol below.

[0625] 1) Prepare the Real-Time PCR reaction mixture according to the table below.

[0626] 2) Add the reaction mixture to a 96-well PCR plate, 17 μL per well. Add 3 μL of reverse-transcribed cDNA sample to each well, bringing the total reaction volume to 20 μL. Mix gently and centrifuge to remove bubbles. Perform real-time PCR on a QPCR instrument. The real-time PCR protocol is shown in the table below.

[0627] Data Analysis

[0628] All data calculations were performed using Microsoft Excel.

[0629] Cell viability

[0630] CellTiter-Fluor TM The cell viability assay kit is used to detect intracellular protease activity.

[0631] The cell viability percentage was calculated using the following formula:

[0632] Cell viability percentage (%) = (I sample – I background value) / (I solvent – ​​I background value) × 100

[0633] Where: Isample is the fluorescence intensity value in the test well;

[0634] I Vehicle is the mean fluorescence intensity value of vehicle-treated cells;

[0635] The background value is the average fluorescence intensity of the medium without cells.

[0636] Cell viability was expressed as the percentage of the average cell viability at each concentration. Compounds with an average cell viability greater than 70% were considered non-cytotoxic.

[0637] Enzyme activity

[0638] CYP enzyme activity is expressed in pmol / min / million cells, pmol represents the amount of metabolite produced during incubation, and the number of cells per well is calculated based on the cell seeding density. The seeding density is 0.55 × 106 cells / mL, and the number of cells per well is 55,000. The calculation is done using the following formula:

[0639] Where: Conc. Product is the concentration of the incubation product per well (pmol / mL)

[0640] VIncubation solution is the volume of incubation solution containing specific substrate in each well (125 μL)

[0641] T is the incubation time for hepatocytes to metabolize CYP-specific substrates (30 minutes)

[0642] Conc. Hepatocytes are seeded at a density of 0.55 × 106 cells / mL per well.

[0643] VHepatocytes is the volume of hepatocytes per well (100 μL).

[0644] The induction fold of enzyme activity was calculated using the following formula:

[0645] The percentage of positive control was calculated using the following formula:

[0646] mRNA levels

[0647] For mRNA level determination, the Ct value is the cycle number at which the fluorescence signal crosses a threshold. The average Ct value of the vehicle control group is used to determine the uninduced mRNA level.

[0648] The mRNA induction fold was determined by the following equation: ΔCt = Ct ACTB -Ct 目的基因 ΔΔCt=ΔCt 受试物 / 对照化合物 -ΔCt 溶媒 Induction factor = 2 ΔΔCt

[0649] The percentage of positive control was calculated using the following formula:

[0650] The PCR amplification efficiency is determined by the following equation:

[0651] E = 10-1 / slope – 1

[0652] The slope was determined by the Log value of the Ct value of the standard curve.

[0653] Amplification efficiency range: 0.9–1.1.

[0654] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no obvious inducing effect on any subtype of CYP enzymes.

[0655] 3.10: Apparent Solubility Test

[0656] The purpose of this study was to determine the apparent solubility of the test substance under specific incubation conditions.

[0657] Dispense 30 μL of 10 mM analyte into the corresponding position of a 96-well plate. Add 970 μL of buffer to the corresponding vial in the sample plate. Place a stir bar in each vial and cap with a Teflon / silicone stopper. Place the sample plate in an Eppendorf Thermomixer Comfort and shake at 1100 rpm at 25°C for 2 hours. After 2 hours, remove the stoppers, remove the stir bars with a magnet, and transfer the samples from the sample plate to a filter plate. Filter the samples using a vacuum pump to generate negative pressure. Transfer 5 μL of the filtrate to a new sample plate, then add 5 μL of DMSO and 490 μL of ACN.H2O (acetonitrile:water = 1:1, including internal standard). Mix thoroughly and transfer 200 μL to a new 96-well plate for LC-MS / MS analysis. The dilution factor may need to be adjusted depending on the solubility of the analyte or the strength of its LC-MS / MS response.

[0658] To prepare the standard solution: Transfer 15 μL from the 10 mM DMSO stock solution plate to an empty plate and add 485 μL of DMSO to make a 300 μM standard solution. Transfer 5 μL from the 300 μM standard solution plate to another empty plate and add 5 μL of buffer and 490 μL of ACN.H2O (acetonitrile:water = 1:1, including the internal standard) to a final concentration of 3 μM. Transfer 200 μL of this diluent to a new 96-well plate for LC-MS / MS analysis. The concentration of the standard sample may be adjusted based on the LC-MS signal response.

[0659] Finally, the sample concentration was determined based on the LC-MS data of the standards and test samples.

[0660] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good solubility under specific incubation conditions.

[0661] 3.11: Caco2 permeability test

[0662] Remove the Caco-2 Transwell plate from the incubator. Rinse the cell monolayer twice with buffer and incubate at 37°C for 30 minutes. To measure the rate of compound transport from the apical to the basolateral side, add 125 μL of test compound (containing 3% BSA) and control drug solution to each well of the insert (apical side). Add 235 μL of HBSS (10 mM HEPES, pH 7.4, containing 3% BSA) buffer to each well of the test compound receiving plate (basolateral side), and add 235 μL of HBSS (10 mM HEPES, pH 7.4) buffer to each well of the control drug receiving plate (basolateral side). Transfer 50 μL of sample from the apical solution to 200 μL of acetonitrile containing internal standards (200 nM labetalol, 500 nM tolxanthin, and 2 μM ketoprofen) as the 0-minute apical administration sample for measurement.

[0663] To measure the transport rate of compounds from the basolateral to the apical side, 285 μL of test compound (containing 3% BSA) and control drug solution were added to each well of the receiver plate (basolateral side). 75 μL of HBSS (10 mM HEPES, pH 7.4, containing 3% BSA) buffer was added to each well of the test compound solution insert (apical side). 75 μL of HBSS (10 mM HEPES, pH 7.4) buffer was added to each well of the control drug solution insert (apical side). A 50 μL sample was transferred from the basolateral solution and added to 200 μL of acetonitrile containing internal standards (200 nM labetalol, 500 nM tolxanthin, and 2 μM ketoprofen) as the 0-minute basolateral administration sample for detection.

[0664] Incubate in a 37°C CO2 incubator for 2 hours.

[0665] After the transport experiment, 50 μL of sample was transferred from the dosing port (apical port for Ap→Bl direction, basolateral port for Bl→Ap direction) to 200 μL of acetonitrile containing internal standards (200 nM labetalol, 500 nM tolxanthinamide, and 2 μM ketoprofen). From the receiving port (basolateral port for Ap→Bl direction, apical port for Bl→Ap direction), 50 μL of sample was transferred from the receiving port (200 nM labetalol, 500 nM tolxanthinamide, and 2 μM ketoprofen). The mixture was vortexed at 1000 rpm for 10 minutes. The quenched samples at each time point were centrifuged at 3220 g for 30 minutes. 100 μL of the supernatant from each sample was transferred to a 96-well plate, and 100 μL of purified water was added to the corresponding well. The sample analysis plate was vortexed at 1000 rpm for 2 minutes before LC / MS / MS analysis. All incubations were performed in duplicate.

[0666] After the two-hour transport experiment, fluorescence values ​​were measured. A 10mM Lucifer Yellow stock solution was prepared with water and diluted to 100μM with transport buffer. 100μL of Lucifer Yellow solution was added to the top of the Transwell chamber and 300μL of transport buffer was added to the base. The cells were incubated at 37°C in a CO2 incubator for 30 minutes. 80μL of solution was directly removed from the top and base (using the basolateral wells) and transferred to a new 96-well plate. Cell fluorescence values ​​(to detect membrane integrity) were measured using a microplate reader with an excitation wavelength of 485nM and an emission wavelength of 530nM.

[0667] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Caco2 permeability.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, in, L is selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m -、-(CR a R a ) m -S-, -NR a -(CR a R b ) m -、-(CR a R b ) m -NR a - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-, m is 0, 1, 2, 3, 4, 5, or 6; X is selected from C or N; Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace; Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace; Ring B is selected from a 5-10 membered heteroaryl group containing at least one Se atom, wherein the ring B optionally contains 1, 2, 3, or 4 N atoms, and the ring B is optionally surrounded by 0, 1, 2, 3, or 4 R yx replace; Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring; Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a Rb, -SF5, -SF3, -C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO) Ra 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace; R 1 Selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace; Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace; R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace; or R a and R b Together with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace; Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)R a’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl; in, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The ring B has the following structure: or Wherein, @ indicates the site connected to the amide bond; * indicates the site connected to L; Wherein, Y is selected from CR Y or N; Where M is selected from CR M or N; Where X1 represents R X1 or N; X2 represents R X2 or N; X3 represents R X3 or N; X4 is selected from R X4 or N; Among them, R M , R Y 、R X1 、R X2 、R X3 、R X4 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R yx replace.

3. A compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, in, M is selected from CR M or N; Y is selected from CR Y or N; L is selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m -、-(CR a R a ) m -S-, -NR a -(CR a R b ) m -、-(CR a R b ) m -NR a - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-, m is 0, 1, 2, 3, 4, 5, or 6; X is selected from C or N; X1 represents R X1 or N; X2 represents R X2 or N; X3 represents R X3 or N; X4 is selected from R X4 or N; R M 、R Y 、R X1 、R X2 、R X3 、R X4 are each independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R yx replace; Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace; Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace; Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring; Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a Rb, -SF5, -SF3, -C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO) Ra 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace; R 1 Selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace; Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR(CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C14 aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace; R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace; or R a and R b Together with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace; Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)R a’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl; in, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Has the following structure: Among them, Cy, ring A, M, X, X1, X2, X3, L, R 1 As defined in claim 3.

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Has any of the following structures: Among them, Cy, ring A, M, X, L, R 1 Having as defined in claim 3; wherein G represents CH, C(Cl), C(F), C(CH 3 ), or N.

6. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Has the following structure: Among them, Cy, ring A, M, X, L, R 1 As defined in claim 3.

7. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein Has the following structure: Among them, Cy, ring A, M, X, L, R 1 As defined in claim 3.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein: Ring A represents the following groups: phenyl or 5-6 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O and S, and the ring A can be arbitrarily replaced by 0, 1, 2 or 3 groups selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein: Ring A represents phenyl or pyridyl, and the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein: Ring A represents the following group: Wherein, Cy has the definition as claimed in claim 1; Where W1 represents CR W1 or N, W2 means CR W2 or N, W3 means CR W3 or N, W4 means CR W4 or N; R W1 、R W2 、R W3 、R W4 Each independently represents hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3; Alternatively, the bond between W1 and W2 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following: Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3; Alternatively, the bond between W2 and W3 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following: Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(O)R a 、-S(=O)(=NH)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3; Alternatively, the bond between W1 and W4 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following: Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein ring A represents the following group: in, R W1 、R W2 、R W3 、R W4 , Cy has the definition as claimed in claim 10.

12. The compound according to any one of claims 10 to 11 or a pharmaceutically acceptable salt thereof, wherein: R W1 represents hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

13. The compound according to any one of claims 10 to 12 or a pharmaceutically acceptable salt thereof, wherein: R W1 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

14. The compound according to any one of claims 10 to 11 or a pharmaceutically acceptable salt thereof, wherein: R W2 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

15. The compound according to any one of claims 10 to 11 or a pharmaceutically acceptable salt thereof, wherein: R W3 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein ring A represents the following group: Further, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein ring A represents the following group: Further, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

17. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein: Cy represents a 3-18 membered monocycloalkyl, a 3-18 membered spirocycloalkyl, a 3-18 membered bridged cycloalkyl, a 3-18 membered fused cycloalkyl, a 3-18 membered monoheterocycloalkyl, a 3-18 membered spiroheterocycloalkyl, a 3-18 membered bridged heterocycloalkyl, a 3-18 membered fused heterocycloalkyl, a 6-14 membered aryl or a 3-18 membered heteroaryl, wherein Cy is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C 6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

18. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein: Cy represents phenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, 2-oxo-1,2-dihydropyridinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl, and the Cy is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

19. The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein: Cy represents any of the following groups: and Cy is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

20. The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein: L represents -CH2O-, -C(CH3)O-, -OCH2-, CH2S-, -C(CH3)S-, -SCH2-, 21. The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a C1-C6 alkyl group, a 3-18-membered monocycloalkyl group, a 3-18-membered spirocycloalkyl group, a 3-18-membered bridged cycloalkyl group, a 3-18-membered fused cycloalkyl group, a 3-18-membered monoheterocycloalkyl group, a 3-18-membered spiroheterocycloalkyl group, a 3-18-membered bridged heterocycloalkyl group, a 3-18-membered fused heterocycloalkyl group, a 6-14-membered aryl group or a 3-18-membered heteroaryl group, wherein R 1 Can be arbitrarily selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

22. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a C1-C6 alkyl group, wherein R 1 It may be arbitrarily substituted with 0, 1, 2, or 3 OH groups, halogen, -COOH, or -P(=O)(OH)2.

23. The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a 6-14 membered aryl group, preferably a phenyl group, and said R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

24. The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a 3-18 membered heteroaryl group, preferably a pyridyl group, and said R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

25. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a 3-18 membered spirocycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

26. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a 3-18 membered bridged cycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

27. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a 3-18 membered fused cycloalkyl group, and said R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

28. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a 3-18 membered monoheterocyclic alkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

29. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a 3-18 membered spiroheterocycloalkyl group, and said R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

30. The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein: R 1 represents a 3-18 membered bridged heterocyclic alkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

31. The compound according to any one of claims 2 to 30, or a pharmaceutically acceptable salt thereof, wherein: X1 represents CR X1 , where R X1 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

32. The compound according to any one of claims 2 to 31 or a pharmaceutically acceptable salt thereof, wherein X1 represents N.

33. The compound according to any one of claims 2 to 32, or a pharmaceutically acceptable salt thereof, wherein: X2 represents CR X2 , where R X2 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

34. The compound according to any one of claims 2 to 33 or a pharmaceutically acceptable salt thereof, wherein: X2 represents N.

35. The compound according to any one of claims 2 to 34, or a pharmaceutically acceptable salt thereof, wherein: X3 means CR X3 , where R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

36. The compound according to any one of claims 2 to 35, or a pharmaceutically acceptable salt thereof, wherein: X3 represents N.

37. The compound according to any one of claims 2 to 36, or a pharmaceutically acceptable salt thereof, wherein: X4 means CR X4 , where R X4 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a hydroxy C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, a C3-C6 cycloalkyloxy group, a C3-C6 cycloalkylthio group, or -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

38. The compound according to any one of claims 2 to 37, or a pharmaceutically acceptable salt thereof, wherein: X4 represents N.

39. A compound or a pharmaceutically acceptable salt thereof having the following formula (III): in, L1 and L2 are each independently selected from -(CR a R b ) m -、-O-(CR a R b ) m -、-(CR a R b ) m -O-、-S-(CR a R b ) m -、-(CR a R a ) m -S-、-NRL-(CR L R L’ ) m -、-(CR L R L’ ) m -NR L - or C3-C 10 Cycloalkylene, C2-C4 alkenyl, C2-C4 alkynyl, -C(=O)NR a -、-NR a C(=O)-, m is 0, 1, 2, 3, 4, 5, or 6; X is selected from C or N; Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 1a replace; Every R 1a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 1b replace; Cy represents 0, 1, 2, or 3 R 2a a substituted 3-18-membered saturated or unsaturated monocyclic ring, a 3-18-membered saturated or unsaturated spirocyclic ring, a 3-18-membered saturated or unsaturated bridged ring, a 3-18-membered saturated or unsaturated condensed ring, a 3-18-membered saturated or unsaturated monoheterocyclic ring, a 3-18-membered saturated or unsaturated spiroheterocyclic ring, a 3-18-membered saturated or unsaturated bridged heterocyclic ring, or a 3-18-membered saturated or unsaturated condensed ring; Every R 2a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR a (CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 2b replace; R 1 、R 2 Each independently selected from C1-C 10 Alkyl, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group, wherein the C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl or 4-12 membered heterocyclic group is optionally substituted with 0, 1, 2, 3, 4 R 3a replace; Every R 3a independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a R b 、-SF5、-SF3、-C(=O)NR a R b 、-P(=O)R a R b 、-S(=O)2NR a R b 、-S(=O)2R a 、-S(=O)(=NH)R a 、-NR a (CO)R a 、-NR(CO)NR a R b 、-NR a S(=O)2R a 、-NR a (CO)2R a 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl, the C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 Aryl is optionally substituted with 0, 1, 2, 3, or 4 R 3b replace; R a and R b independently selected from hydrogen, deuterium, C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl, the C3-C 10 Cycloalkyl, C1-C 10 Alkylcarbonyl, 4-8 membered heterocyclic group or C1-C 10 Alkyl group optionally 0, 1, 2, 3, 4 R 4b replace; or R a and R b Together with the atoms connected thereto, they form a saturated, partially saturated or unsaturated 4-membered, 5-membered, 6-membered or 7-membered ring, which may optionally contain 0, 1 or 2 heteroatoms selected from O, S and N; and further, the ring may optionally be substituted by 0, 1 or 2 R 5b replace; Every R yx 、R 1b 、R 2b 、R 3b 、R 4b 、R 5b independently selected from H, deuterium, halogen, hydroxyl, cyano, nitro, =O, -NR a’ R b’ 、-SF5、-SF3、-C(=O)NR a’ R b’ 、-P(=O)R a’ R b’ 、-S(=O)2NR a’ R b’ 、-S(=O)2R a’ 、-S(=O)(=NH)R a’ 、-NR a’ (CO)R a’ 、-NR a’ (CO)NR a’ R b’ 、-NR a’ S(=O)2R a’ 、-NR a’ (CO)2R a’ 、C1-C 10 Alkyl, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl, C1-C 10 Alkoxy, C1-C 10 Alkylthio, C3-C 10 Cycloalkyloxy, C3-C 10 Cycloalkylthio, C2-C 10 Alkenyl, C2-C 10 Alkynyl, 4-12 membered heterocyclic group, 5-10 membered heteroaryl, C6-C 14 aryl; Among them, R a’ and R b’ independently selected from hydrogen, deuterium, C1-C 10 Alkyl or C3-C 10 Cycloalkyl.

40. The compound according to any one of claims 39 or a pharmaceutically acceptable salt thereof, wherein Ring A represents the following groups: phenyl or 5-6 membered heteroaryl, wherein the heteroaryl contains 1, 2 or 3 heteroatoms selected from N, O and S, and the ring A can be arbitrarily replaced by 0, 1, 2 or 3 groups selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

41. The compound according to any one of claims 39-40 or a pharmaceutically acceptable salt thereof, wherein: Ring A represents phenyl or pyridyl, and the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(O)R a 、-S(=O)(=NH)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

42. The compound according to any one of claims 39 to 41 or a pharmaceutically acceptable salt thereof, wherein: Ring A represents the following group: wherein Cy is as defined in claim 39; Where W1 represents CR W1 or N, W2 means CR W2 or N, W3 means CR W3 or N, W4 means CR W4 or N; R W1 、R W2 、R W3 、R W4 Each independently represents hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3; Alternatively, the bond between W1 and W2 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following: Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3; Alternatively, the bond between W2 and W3 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following: Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3; Alternatively, the bond between W1 and W4 may be fused to a 5-6 membered saturated or unsaturated ring; and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, and S; further, the ring may be optionally substituted with 0, 1, 2, or 3 substituents selected from the following: Hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

43. The compound according to any one of claims 39 to 42, or a pharmaceutically acceptable salt thereof, wherein Ring A represents the following group: in, R W1 、R W2 、R W3 、R W4 , Cy has the definition as claimed in claim 42.

44. The compound according to any one of claims 42-43 or a pharmaceutically acceptable salt thereof, wherein R W1 represents hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

45. The compound according to any one of claims 42 to 44, or a pharmaceutically acceptable salt thereof, wherein: R W1 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

46. ​​The compound according to any one of claims 42 to 45, or a pharmaceutically acceptable salt thereof, wherein: R W2 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

47. The compound according to any one of claims 42 to 46, or a pharmaceutically acceptable salt thereof, wherein: R W3 represents hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, or halogen.

48. The compound according to any one of claims 39 to 40 or a pharmaceutically acceptable salt thereof, wherein ring A represents the following group: Further, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

49. The compound according to any one of claims 39 or a pharmaceutically acceptable salt thereof, wherein Ring A represents the following group: Further, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

50. The compound according to any one of claims 39 to 49 or a pharmaceutically acceptable salt thereof, wherein: Cy represents a 3-18 membered monocycloalkyl, a 3-18 membered spirocycloalkyl, a 3-18 membered bridged cycloalkyl, a 3-18 membered fused cycloalkyl, a 3-18 membered monoheterocycloalkyl, a 3-18 membered spiroheterocycloalkyl, a 3-18 membered bridged heterocycloalkyl, a 3-18 membered fused heterocycloalkyl, a 6-14 membered aryl or a 3-18 membered heteroaryl, wherein Cy is substituted by 0, 1, 2 or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C 6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

51. The compound according to any one of claims 39 to 49 or a pharmaceutically acceptable salt thereof, wherein: Cy represents phenyl, pyridyl, piperidyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, tetrahydropyranyl, 3,6-dihydro-2H-pyranyl, 2-oxo-1,2-dihydropyridinyl, thiomorpholinyl or 1,1-dioxothiomorpholinyl, and the Cy is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

52. The compound according to any one of claims 39 to 51 or a pharmaceutically acceptable salt thereof, wherein: Cy represents any of the following groups: and Cy is substituted by 0, 1, 2, or 3 substituents selected from the group consisting of hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3.

53. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein L1 represents -CH2O-, -C(CH3)O-, -OCH2-, CH2S-, -C(CH3)S-, -SCH2-, 54. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein L2 represents -CH2O-, -C(CH3)O-, -OCH2-, CH2S-, -C(CH3)S-, -SCH2-, 55. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a C1-C6 alkyl group, a 3-18-membered monocycloalkyl group, a 3-18-membered spirocycloalkyl group, a 3-18-membered bridged cycloalkyl group, a 3-18-membered fused cycloalkyl group, a 3-18-membered monoheterocycloalkyl group, a 3-18-membered spiroheterocycloalkyl group, a 3-18-membered bridged heterocycloalkyl group, a 3-18-membered fused heterocycloalkyl group, a 6-14-membered aryl group or a 3-18-membered heteroaryl group, wherein R 1 Can be arbitrarily selected from deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3 substituents.

56. The compound according to any one of claims 39 or 55, or a pharmaceutically acceptable salt thereof, wherein: R 1 、R 2 Each independently represents a C1-C6 alkyl group, and the R 1 It may be arbitrarily substituted with 0, 1, 2, or 3 OH groups, halogen, -COOH, or -P(=O)(OH)2.

57. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a 6-14 membered aryl group, preferably a phenyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

58. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a 3-18 membered heteroaryl group, preferably a pyridyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

59. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a 3-18 membered spirocycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

60. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a 3-18 membered bridged cycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

61. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a 3-18 membered fused cycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

62. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a 3-18 membered monoheterocyclic alkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

63. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a 3-18 membered spiro heterocycloalkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

64. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 Each independently represents a 3-18 membered bridged heterocyclic alkyl group, and the R 1 It can be arbitrarily selected from hydrogen, deuterium, oxo, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 alkylthio, deuterated C1-C6 alkyl, deuterated C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, hydroxy C2-C6 alkenyl, hydroxy C2-C6 alkynyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkylthio, -S(O)2R a 、-S(=O)(=NH)R a 、-S(O)R a 、-CN、-OC(O)R a 、-C(O)R a 、-C(O)OR a 、-OCONR a R b , halogen, -C(O)NR a R b 、-OSO3R a 、-NR a R b , -SF5, -SF3, wherein R a 、R b Each independently represents hydrogen or a C1-C6 alkyl group.

65. A compound or a pharmaceutically acceptable salt thereof having the following structure:

66. A pharmaceutical composition comprising the compound according to any one of claims 1 to 65 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

67. Use of the compound according to any one of claims 1 to 65 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 66, in the preparation of a medicament for treating diseases mediated by the POLQ target.

68. The use according to claim 67, characterized in that The POLQ target-mediated related disease is a tumor. Preferably, the tumor is liver cancer, breast cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer or head and neck cancer.

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