Compound for regulating and controlling TEAD activity and preparation method and application thereof

Abstract

The present application relates to compounds of formula (I), stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or solvates thereof, or prodrugs thereof, pharmaceutical compositions comprising them, and their use in inhibiting TEAD activity, having a function of regulating TEAD activity.

Description

A compound for regulating TEAD activity, preparation method thereof and use thereof Technical Field

[0001] The present application relates to a compound for regulating TEAD activity, a preparation method thereof, and uses thereof, and specifically to a compound for regulating TEAD activity that can be used as a drug, and a pharmacologically acceptable salt thereof, a composition containing the compound or its salt, and a preparation method thereof, and uses thereof for preparing drugs, belonging to the field of medicinal chemistry. Background Art

[0002] The Hippo signaling pathway, a highly conserved signaling pathway consisting of a series of kinase cascades, is involved in regulating physiological processes such as cell proliferation, cell differentiation, stemness, extracellular matrix deposition, damage repair, and organ development. It is a key pathway for cancer biogenesis and tumor maintenance. In many cancer indications, the Hippo signaling pathway is affected by the loss of function of proteins encoded by genes such as NF2, leading to overactivation of downstream transcriptional coactivators, including YAP (Yes Associated Protein) and TAZ (Transcriptional coactivator with PDZ-binding motif). YAP comprises multiple domains and a specific amino acid sequence, including a TEAD (Transcriptional Enhanced Associate Domains) binding region, two WW domains, a proline-rich N-terminal domain, a C-terminal PDZ-binding motif, an SH3 binding motif, a coiled-coil domain, and a transcriptional activation domain. TAZ is homologous to YAP and has similar domain structures and functions to YAP, but lacks the proline-rich domain and the second WW domain. Overactivated YAP / TAZ translocates to the cell nucleus, where it binds to several nuclear transcription factors, including TEADs, to form a transcription complex, promoting the abnormal expression of several downstream target genes, including CTGF (Connective tissue growth factor), Cyr61 (Mysteine ​​rich angiogenic inducer 61), and AXL (AXL receptor tyrosine kinase), thereby causing physiological and pathological processes in the body.

[0003] TEADs / TEAD (transcription enhancer-associated domain) are the most important transcription factors of YAP and TAZ, and are also the final effectors of the Hippo signaling pathway. The human TEAD family of transcription factors includes four members: TEAD1 / 2 / 3 / 4. All TEADs subtypes have a DNA-binding TEA domain at the N-terminus and a YAP / TAZ-binding domain at the C-terminus. The DNA-binding domain and YAP / TAZ-binding domain are highly conserved in mammals, but there are significant differences in the linker connecting the TEA domain and the transactivation domain. The overall homology of the four TEADs subtypes ranges from 61% to 73%. The function of TEADs is mediated by its interaction with nuclear coactivators, and YAP is the main nuclear coactivator that interacts with TEADs.

[0004] Studies have shown that after Hippo pathway dysregulation, YAP / TAZ overactivation is commonly overexpressed in cancer cells, including lung, liver, pancreatic, and breast cancers. In cancer stem cells of various solid tumors, YAP / TAZ can promote their survival and are closely associated with tumor cell metastasis and drug resistance, contributing to the development and progression of various tumors. During chemotherapy, antimicrotubule drugs, antimetabolites, and DNA-damaging agents can affect the Hippo signaling pathway, leading to YAP / TAZ activation and transcription, thereby conferring drug resistance. Excessive YAP / TAZ activation leads to elevated expression of various drug transporters, which can transport drugs to the extracellular space, resulting in upregulation of anti-apoptotic proteins such as Bcl-3 and survivin, thereby inhibiting apoptosis. Numerous studies have demonstrated that YAP / TAZ activation, triggered by deregulation of the Hippo pathway, is a primary mechanism of resistance to various targeted drugs. YAP / TAZ activation is not only associated with drug resistance, but studies have also shown that YAP gene amplification is associated with recurrence in colon and pancreatic cancers.

[0005] The activation of YAP / TAZ-TEADs has a significant promoting effect on tumor development. In some cancers, such as malignant mesothelioma, ovarian cancer and bile duct cancer, the YAP / TAZ-TEADs complex is often overactivated or overexpressed, leading to the worsening and development of cancer. This overactivation is usually caused by changes in upstream genes of the Hippo signaling pathway. Especially in patients with malignant mesothelioma, the overactivation of the YAP / TAZ-TEADs complex helps promote tumor cell proliferation, metastasis, epithelial to mesenchymal transition (EMT) and maintenance of tumor stem cells. Existing studies have shown that the downstream proteins CTGF and CYR61 of YAP / TAZ-TEADs can induce tumor cells to develop resistance to chemotherapy drugs such as paclitaxel. YAP / TAZ-TEADs has become an alternative survival pathway for drug-resistant cancer cells.

[0006] Existing studies have shown that the interaction between YAP and TEADs is crucial for initiating transcriptional programs to promote tumorigenesis and proliferation, and TEADs with defects in the DNA binding domain can block tumor formation mediated by mutations in genes upstream of the Hippo signaling pathway. Point mutations at key positions of TEAD, especially mutations associated with the YAP and TEAD binding domains, significantly inhibit the expression and function of YAP-induced genes. Disruption of the YAP / TAZ-TEAD interaction can eliminate the oncogenic properties of YAP / TAZ, and inhibiting the interaction between YAP / TAZ and TEADs can significantly inhibit the proliferation of tumor cells. Therefore, inhibiting the interaction between YAP / TAZ and TEADs has the potential to be anti-tumor and therapeutic, especially for tumors with overactivation or mutations upstream of the Hippo signaling pathway. Inhibition of the interaction between YAP / TAZ and TEADs is a promising new tumor treatment method.

[0007] To target the Hippo oncogenic pathway, the present application provides a TEAD inhibitor that prevents TEAD palmitoylation, selectively binds to TEAD and disrupts its interaction with YAP / TAZ, thereby downregulating YAP-dependent and TAZ-dependent transcription, inhibiting the interaction between YAP and TEAD, inhibiting tumor cell proliferation (such as mesothelioma tumor cells, malignant pleural mesothelioma tumor cells, etc.), inhibiting tumor invasion and metastasis, reducing resistance to targeted drugs or chemotherapy drugs, and reducing tumor immune escape, thereby achieving the effect of treating tumors.

[0008] Additionally, the TEAD inhibitors described herein inhibit YAP / TAZ-dependent cell proliferation in vitro (ie, Hippo pathway-deficient cancer cell lines), but do not inhibit the proliferation of Hippo pathway wild-type cancer cell lines.

[0009] Summary of the Invention

[0010] The present application provides a compound represented by formula (I), its stereoisomers, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates (such as hydrates), or its prodrugs.

[0011] X and Y are each independently selected from CR 0 or N,

[0012] Z is a C1-C6 chain hydrocarbon group,

[0013] W 2 、W 3 Each independently selected from C, CR 2 or N,

[0014] W 1 Does not exist, CR 1 or N, W 4Selected from C or N, W 5 Selected from C=O, CR 3 or N, and when W 1 does not exist or when W 5 When C=O, W 4 For N,

[0015] represents an aromatic ring,

[0016] Ring C is absent, an aromatic ring, an aromatic heterocycle, an unsaturated alicyclic ring or an unsaturated alicyclic heterocycle,

[0017] Ring A is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic ring, an unsaturated alicyclic ring, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle.

[0018] Ring B is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic heterocycle, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle.

[0019] m, n, and o are each independently selected from 0, 1, 2, 3, and 4.

[0020] R A 、R B 、R 0 、R 1 、R 2 、R 3 are each independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,

[0021] Among them, the R 0 、R 1 、R 2 、R 3 、R A 、R B , Ring C is each optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C1-C6 alkyl, and C1-C6 alkoxy,

[0022] The Z is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C1-C6 alkyl, C1-C6 alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl,

[0023] The aromatic heterocycle, unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each independently contain 1 to 4 heteroatoms; the heterocycloalkyl group contains 1 to 2 heteroatoms, and the heteroatoms are independently selected from N, O and S.

[0024] In certain embodiments of the present application, Ring C is absent, an aromatic ring, an aromatic heterocycle, an unsaturated alicyclic ring, or an unsaturated alicyclic heterocycle.

[0025] In certain embodiments of the present application, the ring C is absent or is a 5-10 membered aromatic heterocycle, preferably a 5-6 membered aromatic heterocycle. Preferably, the ring C is absent or is a 5-6 membered aromatic heterocycle containing 1-3 heteroatoms (preferably 1-2 heteroatoms), wherein the heteroatoms are selected from N, O, S (preferably N), and W 2 、W 3 are all selected from C, and the ring C is optionally substituted by one or more independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C1-C6 alkyl, C1-C6 alkoxy (preferably, the ring C is optionally substituted by one or more independently selected from deuterium, tritium, C1-C6 alkyl).

[0026] In certain embodiments of the present application, the ring C does not exist, and W 2 、W 3 Each independently selected from CR 2 or N, the R 2 The definition is the same as above;

[0027] In certain embodiments of the present application, the ring C is a 5-membered aromatic heterocycle (e.g., a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms, preferably an aromatic heterocycle containing 1 to 2 heteroatoms, wherein the heteroatoms are selected from N, O, and S), and W 2 、W 3 are all selected from C, and the ring C is optionally substituted by one or more independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, ═O, C1-C6 alkyl, and C1-C6 alkoxy;

[0028] In certain embodiments of the present application, the ring C is a 3-8 membered unsaturated aliphatic heterocycle (eg, a 3-8 membered unsaturated aliphatic heterocycle containing 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, and S), and W 2 、W 3 are all selected from C, and the ring C is optionally substituted by one or more independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, ═O, C1-C6 alkyl, and C1-C6 alkoxy;

[0029] In certain embodiments of the present application, the ring C is a 3-8 membered unsaturated alicyclic ring (also known as a C3-C8 unsaturated alicyclic ring), and W 2 、W 3 are all selected from C, and the ring C is optionally substituted by one or more independently selected from deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, ═O, C1-C6 alkyl, and C1-C6 alkoxy;

[0030] In certain embodiments of the present application, W 1 Selected from CR 1 , W 2 、W 3 Selected from C or CR 2 , W 4 Selected from C, W 5 Selected from CR 3 , the R 1 、R 2 、R 3 Consistent with the above definition;

[0031] In certain embodiments of the present application, W 1 Selected from CR 1 or N, W 2 、W 3 Select from C or W 2 、W 3 Each independently selected from CR 2 , W 4 Selected from C, W 5 Selected from CR 3 , the R 1 、R 2 、R 3 Consistent with the above definition;

[0032] In certain embodiments of the present application, W 1 CR 1 or N, R 1 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C1-C6 alkyl and C1-C6 haloalkyl (preferably, R 1 is selected from hydrogen, deuterium, tritium and C1-C6 alkyl); W 2 、W 3 are all selected from C or are independently selected from CR 2 , each R 2 independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy (preferably, W 2 、W 3 All selected from C; or W 2 Selected from CR2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, W 3 Selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; more preferably, W 2 、W 3 All selected from C; or W 2 Selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl and C1-C6 alkoxy; W 3 Selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 alkoxy); W 4 C; W 5 CR 3 , R 3 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amino, C1-C6 alkyl, C1-C6 haloalkyl (preferably, R 3 selected from hydrogen, deuterium, tritium, halogen and C1-C6 alkyl);

[0033] In certain embodiments of the present application, W 1 CR 1 , R 1 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C1-C6 alkyl and C1-C6 haloalkyl (preferably, R 1 is selected from hydrogen, deuterium, tritium and C1-C6 alkyl); W 2 、W 3 Each independently selected from CR 2 , each R 2 independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy (preferably, W 2 Selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, W 3 Selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; more preferably, W2 Selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl and C1-C6 alkoxy; W 3 Selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 alkoxy); W 4 C; W 5 CR 3 , R 3 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amino, C1-C6 alkyl, C1-C6 haloalkyl (preferably, R 3 selected from hydrogen, deuterium, tritium, halogen and C1-C6 alkyl);

[0034] In certain embodiments of the present application, Z is selected from Wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, aldehyde, amine, halogen, cyano, ester, carboxyl, amide, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl; or in certain embodiments of the present application, Z is selected from wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, R is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, and the heterocycloalkyl contains 1-2 heteroatoms independently selected from N, O, and S;

[0035] In certain embodiments of the present application, the Z is C1-C6 alkylene (preferably C1-C4 alkylene, C1-C3 alkylene, such as -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH2CH3)-, -CH[CH(CH3)2]-), and the Z is optionally substituted by any one of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, and =O (preferably, the Z is optionally substituted by hydroxyl);

[0036] In certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring (also known as a C6-C 10 aromatic ring), 5-10 membered aromatic heterocyclic ring, 3-14 membered saturated alicyclic ring (also known as C3-C 14 Saturated alicyclic rings), 3-14 membered unsaturated alicyclic rings (also known as C3-C 14unsaturated alicyclic ring), 3-14 membered unsaturated alicyclic heterocyclic ring, 7-14 membered cyclic ring composed of aromatic ring and unsaturated alicyclic ring, 7-14 membered cyclic ring composed of aromatic heterocyclic ring and unsaturated alicyclic ring, 7-14 membered cyclic ring composed of aromatic ring and unsaturated alicyclic heterocyclic ring, 7-14 membered cyclic ring composed of aromatic ring and unsaturated alicyclic heterocyclic ring, 7-14 membered cyclic ring composed of aromatic heterocyclic ring and unsaturated alicyclic heterocyclic ring, the aromatic heterocyclic ring contains 1-4 (preferably 1-3) heteroatoms independently selected from N, O, S, the unsaturated alicyclic heterocyclic ring Contains 1 to 2 heteroatoms independently selected from N, O, and S; preferably, the ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, a 3- to 14-membered saturated alicyclic ring, a 7- to 14-membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7- to 14-membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; more preferably, the ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocycle, and a 7- to 14-membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring.

[0037] In certain embodiments of the present application, the ring A is selected from C6 to C 10 Aromatic ring, 5-10 membered aromatic heterocycle, C5-C 10 Saturated alicyclic, C5~C 10 Unsaturated alicyclic, C6~C 10 Aromatic ring and C5~C 10 Unsaturated alicyclic rings, 5-10 membered aromatic heterocycles and C5-C 10 Unsaturated alicyclic ring; preferably, ring A is selected from C6~C 10 an aromatic ring, a 6-10 membered aromatic heterocyclic ring, a C5-C8 saturated alicyclic ring, or a fused ring consisting of a C6 aromatic ring and a C5-C6 unsaturated alicyclic ring, wherein the aromatic heterocyclic ring contains 1-3 (preferably 1-2) heteroatoms independently selected from N, O, and S. More preferably, Ring A is selected from a benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, or pyrimidine (for example, Ring A is selected from a benzene ring, indane, pyridine, or cyclohexane).

[0038] In certain embodiments of the present application, the ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered (preferably 3-12 membered) saturated alicyclic ring, a 3-14 membered (preferably 3-12 membered) unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring. The aromatic heterocycle contains 1 to 4 heteroatoms independently selected from N, O, and S, and the unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each contain 1 to 2 heteroatoms independently selected from N, O, and S; preferably, the ring B is selected from a 5-10 membered aromatic heterocycle and a 3-12 membered saturated aliphatic heterocycle, the aromatic heterocycle contains 1 to 3 heteroatoms independently selected from N, O, and S, and the unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each contain 1 heteroatom independently selected from N, O, and S.

[0039] In certain embodiments of the present application, the ring B is selected from C6 to C 10 Aromatic ring, 5-10 membered aromatic heterocycle, C3-C 10 Saturated heterocyclic rings, 5-10 membered unsaturated heterocyclic rings, 5-10 membered aromatic heterocyclic rings and C5-C 10 Unsaturated alicyclic ring, C6~C 10 A cyclic ring consisting of an aromatic ring and a 5-10 membered unsaturated alicyclic ring; preferably, ring B is a 5-10 membered aromatic heterocyclic ring or a C4-C8 saturated alicyclic ring, wherein the aromatic heterocyclic ring, the unsaturated alicyclic ring, and the saturated alicyclic ring each contain 1-3 (preferably 1-2) heteroatoms independently selected from N, O, and S. More preferably, ring B is selected from pyridine, pyrazole, pyrazine, pyrimidine, tetrahydropyran, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, piperidine, oxazole, isoxazole, indazole, and azetidine (for example, ring B is selected from pyridine, pyrazole, pyrazine, piperidine, oxazole, isoxazole, indazole, and azetidine).

[0040] Furthermore, in certain embodiments of the present application, the ring A is selected from a benzene ring, cyclohexane, bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1-4 (preferably 1-3) heteroatoms, an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, and an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1-2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S; the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1-4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1-2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1-2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S.

[0041] In certain embodiments of the present application, m, n, and o are each independently selected from 0, 1, or 2.

[0042] In certain embodiments of the present application, R A is selected from deuterium, tritium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 haloalkoxy and C1-C6 haloalkyl; preferably, R A is selected from deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 haloalkyl; more preferably, R A is deuterium, tritium, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy, tribromomethoxy or tribromomethyl.

[0043] In certain embodiments of the present application, R B is selected from deuterium, tritium, hydroxyl, cyano, amine, amide, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 amidoalkyl and C1-C6 haloalkyl; preferably, RB is selected from deuterium, tritium, amine and C1-C6 alkyl; more preferably, R B is deuterium, tritium, methyl, ethyl, propyl or -NH2; R B Optionally substituted with deuterium, tritium, or halogen.

[0044] The present application also provides a compound represented by formula (II), its stereoisomers, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates (such as hydrates), or its prodrugs,

[0045] X and Y are each independently selected from CR 0 or N and not N at the same time, the R 0 is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl,

[0046] W 2 、W 3 are each independently selected from CH or N,

[0047] W 1 Does not exist, CH or N, W 4 Selected from C or N, W 5 is selected from C═O, CH or N, and when W 1 does not exist or when W 5 When C=O, W 4 For N,

[0048] R C Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, q is selected from 0, 1, 2, 3,

[0049] Z is selected from

[0050] Ring A is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic ring, an unsaturated alicyclic ring, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; Ring B is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic heterocycle, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; the aromatic heterocycle, the unsaturated alicyclic heterocycle, and the saturated alicyclic heterocycle each independently contain 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O, and S, wherein R, R A 、R B 、m、n、o、p、*、 Consistent with the above definition.

[0051] In certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered saturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 (preferably 1-3) heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle contains 1-2 heteroatoms independently selected from N, O, and S;

[0052] In certain embodiments of the present application, the ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered (preferably 3-12 membered) saturated alicyclic ring, a 3-14 membered (preferably 3-12 membered) unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle and the saturated alicyclic heterocycle each contain 1-2 heteroatoms independently selected from N, O, and S;

[0053] Furthermore, in certain embodiments of the present application, the ring A is selected from a benzene ring, cyclohexane, bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1-4 (preferably 1-3) heteroatoms, an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, and an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1-2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S; the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1-4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1-2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1-2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S.

[0054] In certain specific embodiments of the present application, the compound represented by formula (II) provided herein, its stereoisomers, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates (e.g., hydrates), or its prodrugs have any of the structures represented by the following formulas (II-a) to (II-g), its stereoisomers, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates (e.g., hydrates), or its prodrugs,

[0055] where R A 、R B 、R C , Ring A, Ring B, m, n, o, q, X, Y, and Z are consistent with the above definitions.

[0056] The present application also provides a compound represented by formula (III), its stereoisomers, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates (such as hydrates), or its prodrugs,

[0057] X and Y are each independently selected from CR 0 or N and not N at the same time, the R 0 is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl,

[0058] W 1 Does not exist, CH or N, W 4 Selected from C or N, W 5 is selected from C═O, CH or N, and when W 1 is not present or when W 5 When C=O, W 4 For N,

[0059] V 1 、V 2 、V 3 are each independently selected from CH, N, NH, O, S, and V 1 、V 2 、V 3 Not CH at the same time,

[0060] R C Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, q is selected from 0, 1, 2, 3,

[0061] Z is selected from

[0062] Ring A is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic ring, an unsaturated alicyclic ring, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; Ring B is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic heterocycle, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring; the aromatic heterocycle, the unsaturated alicyclic heterocycle, and the saturated alicyclic heterocycle each independently contain 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O, and S, wherein R, R A 、R B 、m、n、o、p、*、 Consistent with the above definition.

[0063] In certain embodiments of the present application, the W 1 、W 5 Both CH, W 4 For C.

[0064] In certain embodiments of the present application, the ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered saturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 (preferably 1-3) heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle contains 1-2 heteroatoms independently selected from N, O, and S;

[0065] In certain embodiments of the present application, the ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered (preferably 3-12 membered) saturated alicyclic ring, a 3-14 membered (preferably 3-12 membered) unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocycle and the saturated alicyclic heterocycle each contain 1-2 heteroatoms independently selected from N, O, and S;

[0066] Furthermore, in certain embodiments of the present application, the ring A is selected from a benzene ring, cyclohexane, bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1-4 (preferably 1-3) heteroatoms, an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, and an 8-12 membered paracyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1-2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S; the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1-4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1-2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1-2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S.

[0067] In certain specific embodiments of the present application, the compound represented by formula (III) provided herein, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (e.g., a hydrate), or its prodrug has any one of the structures represented by the following formulas (III-a) to (III-f), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (e.g., a hydrate), or its prodrug,

[0068] where R A 、R B 、R C , Ring A, Ring B, m, n, o, q, X, Y, and Z are consistent with the above definitions.

[0069] The present application also provides a compound represented by formula (IV), its stereoisomers, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates (such as hydrates), or its prodrugs.

[0070] X, Y, Z, W 1 、W 4 、W 5 , Ring A, Ring B, R A 、R B 、m、n、o、 Same as the definitions of the above compounds of formula (I) and formula (III); V 4 and V 5 are each independently CH or N, and V 4 、V 5 Not CH at the same time.

[0071] In certain specific embodiments of the present application, the compound represented by formula (IV) provided herein is selected from the compounds represented by formulas (III-a) to (III-f): Among them, X, Y, Z, W 1 、W 4 、W 5 , Ring A, Ring B, R A 、R B 、m、n、o、 Same as above definition.

[0072] The compounds provided herein are represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain embodiments, the R 0Selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, -COCH3, -COCH2CH3, -CO(CH2)2CH 3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl.

[0073] The compounds provided herein are represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain embodiments, the R A 、R Beach independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2 CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl.

[0074] The present application provides compounds represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or mixtures thereof In certain embodiments, R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, sulfhydryl, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3) 2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy.

[0075] The compounds provided herein are represented by formula (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain embodiments, the R CSelected from deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3 , -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl.

[0076] The present application provides a compound represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), its stereoisomers, its tautomers or its mixture form, or Its pharmaceutically acceptable salt, or its solvate (such as hydrate), or its prodrug, in certain embodiments, the ring A is selected from a benzene ring, cyclohexane, bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1-3 (preferably 1-2) heteroatoms, an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1-2 heteroatoms, wherein the heteroatoms are each independently selected from N, O, and S; in certain embodiments, the ring A is selected from

[0077] The present application provides compounds represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain embodiments, the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1 to 4 heteroatoms, or a 3-10 membered saturated aliphatic heterocycle containing 1 to 2 heteroatoms, wherein the heteroatoms are each independently selected from N, O, or S. In certain embodiments, the ring B is selected from Preferably, the ring B is selected from a 5-10 membered aromatic heterocycle containing 1-3 heteroatoms, a 3-10 membered saturated aliphatic heterocycle containing 1 heteroatom, wherein the heteroatoms are independently selected from N, O, S (for example, the ring B is selected from

[0078] The present application provides compounds represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain embodiments, X and Y are each independently selected from N, CH, CCH3, CCl, CCN, CCF3, and Z is selected from The m, n, o, p, q are each independently selected from 0 or 1, the R is selected from hydrogen, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl), C1-C6 hydroxyalkyl (such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, etc.), the R A is selected from halogen (such as fluorine, chlorine, bromine), C1-C6 haloalkyl (such as trifluoromethyl), C1-C6 haloalkoxy (such as trifluoromethoxy), wherein R Bis selected from halogen (such as fluorine, chlorine, bromine), C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl), amino, cyano, the ring A is selected from benzene ring, cyclohexane, bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1-2 heteroatoms, an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring containing 1-2 heteroatoms, the heteroatoms are each independently selected from N, O, S (such as The ring A is selected from a benzene ring, cyclohexane, bicyclo[1,1,1]pentane, pyridine, indane, etc.), the ring B is selected from a benzene ring, a 5-10 membered aromatic heterocycle containing 1-4 heteroatoms (for example, containing 1, 2, 3 or 4 heteroatoms), and a 3-10 membered saturated aliphatic heterocycle containing 1-2 heteroatoms, and the heteroatoms are each independently selected from N, O, and S (for example, the ring B is selected from pyrazole, isoxazole, oxazole, imidazole, tetrazole, pyridine, pyrazine, tetrahydropyran, morpholine, piperidine, etc.).

[0079] The compounds provided herein are represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs. In certain preferred embodiments, ring B is selected from a 5- to 10-membered aromatic heterocycle containing 1 to 3 heteroatoms (e.g., the ring B is selected from More preferably, the ring B is selected from, for example ), Ring A is selected from a 6- to 10-membered aromatic ring, a 5- to 10-membered aromatic heterocyclic ring, a 3- to 10-membered saturated aliphatic ring, a 7- to 10-membered cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring, and a 7- to 10-membered cyclic ring composed of an aromatic heterocyclic ring and an unsaturated alicyclic ring (for example, Ring A is selected from ).

[0080] In some embodiments of the present application, in the compound represented by formula (I), (II), (III), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (IV), (IV-a), (IV-b) or (IV-c), its stereoisomers, its tautomers or mixtures thereof, or its pharmaceutically acceptable salts, or its solvates (e.g., hydrates), or its prodrugs,

[0081] X and Y are each independently selected from CR 0 or N (preferably X and Y are not N at the same time), R 0 is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, amino and methyl, preferably R 0 selected from hydrogen, deuterium and tritium;

[0082] Z is C1-C6 alkylene (preferably C1-C4 alkylene, C1-C3 alkylene, such as -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH2CH3)-, -CH[CH(CH3)2]-), and is optionally substituted by any one of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano or =O (preferably, Z is optionally substituted by hydroxyl);

[0083] Ring A is selected from C6~C 10 Aromatic ring, 5-10 membered aromatic heterocycle, C5-C 10 Saturated alicyclic, C5~C 10 Unsaturated alicyclic, C6~C 10 Aromatic ring and C5~C 10 Unsaturated alicyclic rings, 6-10 membered aromatic heterocycles and C5-C 10 Unsaturated alicyclic ring (preferably, ring A is selected from C6 to C 10 aromatic ring, 6-10 membered aromatic heterocyclic ring, C5-C8 saturated alicyclic ring, and a C6 aromatic ring and a C5-C6 unsaturated alicyclic ring, more preferably, ring A is selected from benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, and pyrimidine);

[0084] Ring B is selected from C6~C 10 Aromatic ring, 5-10 membered aromatic heterocycle, C3-C 10 Saturated heterocyclic rings, 5-10 membered unsaturated heterocyclic rings, 5-10 membered aromatic heterocyclic rings and C5-C 10 Unsaturated alicyclic ring, C6~C 10a cyclic ring consisting of an aromatic ring and a 5-10 membered unsaturated aliphatic heterocycle (preferably, ring B is a 5-10 membered aromatic heterocycle or a C4-C8 saturated aliphatic heterocycle, more preferably, ring B is a 5-10 membered aromatic heterocycle containing 1-3 heteroatoms selected from N, O, and S; specifically, ring B is selected from pyridine, pyrazole, pyrazine, pyrimidine, tetrahydropyran, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, piperidine, oxazole, isoxazole, pyrimidine, indazole, and azetidine, preferably pyridine, pyrazole, pyrazine, pyrimidine, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, oxazole, isoxazole, pyrimidine, indazole);

[0085] o is 0, 1 or 2 (preferably, o is 0);

[0086] m is 0, 1 or 2 (preferably, m is 0 or 1);

[0087] n is 0, 1 or 2 (preferably, n is 0 or 1);

[0088] R A is selected from deuterium, tritium, hydroxyl, halogen, C1-C6 alkyl, C1-C6 haloalkoxy and C1-C6 haloalkyl (preferably, R A is selected from deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkoxy and C1-C6 haloalkyl; more preferably, R A is deuterium, tritium, fluorine, chlorine, bromine, trifluoromethyl, trichloromethyl, tribromomethyl, trifluoromethoxy, trichloromethoxy or tribromomethoxy);

[0089] R B is selected from deuterium, tritium, hydroxyl, cyano, amine, amide, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 amidoalkyl and C1-C6 haloalkyl (preferably, R B is selected from deuterium, tritium, amine and C1-C6 alkyl; more preferably, R B is hydrogen, deuterium, tritium, methyl, ethyl, propyl or -NH2), R B optionally substituted with deuterium, tritium or halogen;

[0090] The aromatic heterocycle, unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O and S.

[0091] In some embodiments of the present application, in the compound represented by formula (I),

[0092] X and Y are each independently selected from CR 0 or N (preferably X and Y are not N at the same time), R 0 is selected from hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, amino and methyl, preferably R 0selected from hydrogen, deuterium and tritium;

[0093] Z is C1-C6 alkylene (preferably C1-C4 alkylene, C1-C3 alkylene, such as -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH2CH3)-, -CH[CH(CH3)2]-), and is optionally substituted by any one of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano or =O (preferably, Z is optionally substituted by hydroxyl);

[0094] W 2 、W 3 All are C, or W 2 、W 3 Each independently selected from CR 2 , each R 2 independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy (preferably, W 2 Selected from C or CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; W 3 Selected from C or CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; more preferably, W 2 Selected from C or CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl and C1-C6 alkoxy; W 3 Selected from C or CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 alkoxy);

[0095] W 1 CR 1 or N, R 1 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C1-C6 alkyl and C1-C6 haloalkyl (preferably, R 1 selected from hydrogen, deuterium, tritium and C1-C6 alkyl);

[0096] W 4 is C;

[0097] W 5 CR 3 , R 3is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amino, C1-C6 alkyl, C1-C6 haloalkyl (preferably, R 3 selected from hydrogen, deuterium, tritium, halogen and C1-C6 alkyl);

[0098] represents an aromatic ring;

[0099] Ring C is absent, a 5-6 membered aromatic heterocycle, or a 5-6 membered unsaturated aliphatic heterocycle (preferably, ring C is absent or a 5-6 membered aromatic heterocycle; more preferably, ring C is absent, pyrazole, pyrazine, or pyridine), and ring C is optionally substituted with deuterium, tritium, or a C1-C6 alkyl group;

[0100] Ring A is selected from C6~C 10 Aromatic ring, 5-10 membered aromatic heterocycle, C5-C 10 Saturated alicyclic, C5~C 10 Unsaturated alicyclic, C6~C 10 Aromatic ring and C5~C 10 Unsaturated alicyclic rings, 6-10 membered aromatic heterocycles and C5-C 10 Unsaturated alicyclic ring (preferably, ring A is selected from C6 to C 10 aromatic ring, 6-10 membered aromatic heterocyclic ring, C5-C8 saturated alicyclic ring, and a C6 aromatic ring and a C5-C6 unsaturated alicyclic ring, more preferably, ring A is selected from benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, and pyrimidine);

[0101] Ring B is selected from C6~C 10 Aromatic ring, 5-10 membered aromatic heterocycle, C3-C 10 Saturated heterocyclic rings, 5-10 membered unsaturated heterocyclic rings, 5-10 membered aromatic heterocyclic rings and C5-C 10 Unsaturated alicyclic ring, C6~C 10 a cyclic ring consisting of an aromatic ring and a 5-10 membered unsaturated aliphatic heterocycle (preferably, ring B is a 5-10 membered aromatic heterocycle or a C4-C8 saturated aliphatic heterocycle, more preferably, ring B is a 5-10 membered aromatic heterocycle containing 1-3 heteroatoms selected from N, O, and S, specifically, ring B is preferably selected from pyridine, pyrazole, pyrazine, pyrimidine, tetrahydropyran, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, piperidine, oxazole, isoxazole, pyrimidine, indazole, and azetidine);

[0102] o is 0, 1 or 2 (preferably, o is 0);

[0103] m is 0, 1 or 2 (preferably, m is 0 or 1);

[0104] n is 0, 1 or 2 (preferably, n is 0 or 1);

[0105] R Ais selected from deuterium, tritium, hydroxyl, halogen, C1-C6 alkyl and C1-C6 haloalkyl (preferably, R A is selected from deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 haloalkyl; more preferably, R A is deuterium, tritium, fluorine, chlorine, bromine, trifluoromethyl, trichloromethyl or tribromomethyl);

[0106] R B is selected from deuterium, tritium, hydroxyl, cyano, amine, C1-C6 alkyl and C1-C6 haloalkyl (preferably, R B is selected from deuterium, tritium, amine and C1-C6 alkyl; more preferably, R B is deuterium, tritium, methyl, ethyl, propyl or -NH2), R B optionally substituted with deuterium, tritium or halogen;

[0107] The aromatic heterocycle, unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms (preferably 1 to 2 heteroatoms), and the heteroatoms are independently selected from N, O and S.

[0108] In some embodiments of the present application, in the compound represented by formula (I),

[0109] X and Y are each independently selected from CR 0 or N and not both N and R 0 are each independently selected from hydrogen, deuterium and tritium,

[0110] Z is selected from wherein * is connected to ring B, p is 0, 1 or 2, and R is selected from hydrogen, deuterium, tritium, hydroxyl, C1-C6 alkyl and C1-C6 hydroxyalkyl,

[0111] W 2 、W 3 All selected from C or W 2 、W 3 Each independently CR 2 , each R 2 independently selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy,

[0112] W 1 CR 1 or N, R 1 independently selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 haloalkyl,

[0113] W 4 For C,

[0114] W 5 CR 3, R 3 independently selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 haloalkyl,

[0115] represents an aromatic ring,

[0116] Ring C is a 5-6 membered aromatic heterocycle that does not contain or contains 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, and S, and the ring C is optionally substituted by deuterium, tritium, or a C1-C6 alkyl group.

[0117] Ring A is selected from (Preferred ),

[0118] Ring B is selected from (Preferred ),

[0119] m, n, o are each 0, 1 or 2 (preferably, o is 0, m is 0 or 1, and n is 0 or 1),

[0120] R A is selected from deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 haloalkyl,

[0121] R B Selected from deuterium, tritium, amino and C1-C6 alkyl.

[0122] In some specific embodiments of the present application, the present application provides the compounds shown below, their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs,

[0123] Another object of the present application is to provide a pharmaceutical composition comprising at least one of the aforementioned compounds, their stereoisomers, their tautomers or mixtures thereof, or their pharmaceutically acceptable salts, or their solvates, or their prodrugs, and at least one pharmaceutically acceptable excipient.

[0124] Another object of the present application is to provide a kind of aforementioned compound, its stereoisomer, or its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or pharmaceutical composition for the preparation of a drug. Wherein, the drug is a TEAD inhibitor, which can be used to treat diseases associated with increased levels of unwanted TEAD activity. Alternatively, the present application provides a kind of aforementioned compound or its stereoisomer, tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or pharmaceutical composition for use as a drug (preferably a TEAD inhibitor). Alternatively, the present application provides a method for treating or preventing TEAD-related diseases, comprising administering the aforementioned compound or its stereoisomer, tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or pharmaceutical composition to a subject in need. The TEAD-related diseases herein refer to diseases or complications thereof that achieve clinically beneficial therapeutic effects such as alleviation, improvement, cessation of progression, alleviation, or no longer worsening by inhibiting TEAD.

[0125] In certain embodiments, the drug or method is used to treat a disease or condition associated with increased TEAD expression or increased TEAD activity. In certain embodiments, the drug or method is used to treat a disease associated with increased YAP expression or increased TAZ expression. In certain embodiments, the drug or method is used to treat a disease associated with a fusion mutation of YAP or TAZ with another gene. In certain embodiments, the drug or method is used to treat a disease associated with a mutation or inactivation of the Hippo pathway. In certain specific embodiments, the drug or method is used to treat tumor cell proliferative diseases (such as mesothelioma tumor cells, malignant pleural mesothelioma tumor cells and other proliferative diseases), inhibit tumor invasion and metastasis, reduce resistance to targeted drugs or chemotherapy drugs, reduce tumor immune escape, treat polycystic kidney disease or liver fibrosis; in certain specific embodiments, the drug or method is used to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (such as monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic Leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, adverse proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid cancer, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.

[0126] definition

[0127] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular term should not be considered ambiguous or unclear if it is not specifically defined, but should be understood according to its ordinary meaning in the art.

[0128] "Chained hydrocarbon group" refers to an aliphatic group that is connected in a chain and contains only carbon and hydrogen atoms. The hydrocarbon group may be a saturated hydrocarbon group or an unsaturated hydrocarbon group; the chain may be straight-chain or branched. The C1-C6 chained hydrocarbon group used in this application refers to a straight-chain hydrocarbon group or a branched hydrocarbon group composed of 1 to 6 (for example, 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms, including saturated hydrocarbon groups and unsaturated hydrocarbon groups. Common chained hydrocarbon groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, -CH2-, -CHCH3-, -CHCH2CH3-, -CHCH(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, etc.

[0129] "Alkyl" is a saturated aliphatic chain hydrocarbon group, including straight-chain alkyl and branched-chain alkyl, and refers to a group formed by removing a hydrogen atom from a chain alkane molecule. For example, the C1-C6 alkyl group used in this application refers to a straight-chain alkyl or branched-chain alkyl group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the foregoing values). Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, and the like.

[0130] "Alkylene" is a type of saturated aliphatic chain hydrocarbon group, including straight-chain alkylene and branched-chain alkylene, which refers to a group formed by missing two hydrogen atoms in an alkane molecule, wherein the missing hydrogen atoms can be connected to the same carbon atom or to different carbon atoms. The C1-C6 alkylene used in this application refers to a straight-chain alkylene or branched-chain alkylene composed of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the foregoing values) carbon atoms. Typical alkylene groups include, but are not limited to -CH2-, -CH(CH3)-, -CH(CH2CH3)-, -CH[CH(CH3)2]-, -CH2CH2-, -CH(CH3)CH2-, etc.

[0131] "Alkoxy" refers to an -O-alkyl group; as used herein, a C1-C6 alkoxy group refers to a straight-chain or branched alkoxy group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or a range consisting of any two of the foregoing values). Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, n-hexoxy, and the like.

[0132] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0133] "Haloalkyl" refers to an alkyl group in which at least one hydrogen is replaced by a halogen atom. The C1-C6 haloalkyl group used in this application refers to a straight-chain or branched alkyl group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or a range consisting of any two of the foregoing values), and at least one hydrogen on the alkyl group is arbitrarily replaced by a halogen atom. Common haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 1,1-dichloroethyl, 2-chloroethyl, 2,2-dichloroethyl, 1,2-dichloroethyl, 2,2,2-trichloroethyl, and the like.

[0134] "Haloalkoxy" refers to an alkoxy group in which at least one hydrogen is replaced by a halogen atom. The C1-C6 haloalkoxy group used in this application refers to a straight-chain alkoxy or branched alkoxy group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or a range consisting of any two of the foregoing values), and at least one hydrogen on the alkoxy group is arbitrarily replaced by a halogen atom. Common haloalkoxy groups include, but are not limited to, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,2-difluoroethoxy, 2,2,2-trifluoroethoxy, monochloromethoxy, dichloromethoxy, trichloromethoxy, 1-chloroethoxy, 1,1-dichloroethoxy, 2-chloroethoxy, 2,2-dichloroethoxy, 1,2-dichloroethoxy, 2,2,2-trichloroethoxy, and the like.

[0135] "Hydroxyalkyl" refers to an alkyl group in which any one of the hydrogen atoms is replaced by a hydroxyl group. As used herein, C1-C6 hydroxyalkyl refers to a linear or branched alkyl group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or a range consisting of any two of the foregoing values) and in which any one of the hydrogen atoms is replaced by a hydroxyl group. Common hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxyn-propyl, 2-hydroxyn-propyl, 3-hydroxyn-propyl, 2-hydroxyisopropyl, and 4-hydroxyn-butyl.

[0136] "Ring" refers to any cyclic covalently closed structure, including, for example, a carbocycle (e.g., an aromatic ring or an alicyclic ring) or a heterocycle (e.g., an aromatic heterocycle or an alicyclic heterocycle). A carbocycle refers to a ring composed solely of carbon atoms, and a heterocycle refers to a closed structure formed by covalently bonding carbon atoms and heteroatoms. Depending on the number of rings, a "ring" can be a monocyclic, bicyclic, tricyclic, or polycyclic ring. When the ring is bicyclic, tricyclic, or polycyclic, the relationships between the rings may include fused rings, spirocyclic rings, or bridged rings.

[0137] "Heteroatom" refers to any atom other than a carbon atom that can be covalently bonded to a carbon atom. Common heteroatoms include, but are not limited to, O, S, N, P, Si, etc.

[0138] "Member" refers to the number of atoms that make up the ring. Typical 5-membered rings include, but are not limited to, cyclopentane, pyrrole, imidazole, thiazole, furan, and thiophene; typical 6-membered rings include, but are not limited to, cyclohexane, pyridine, pyran, pyrazine, thiopyran, pyridazine, pyrimidine, and benzene.

[0139] "Alicyclic" or "alicyclic group" refers to a saturated or partially unsaturated aliphatic carbocyclic group. A saturated aliphatic carbocyclic ring is referred to as, for example, a saturated alicyclic ring, and may also be referred to as a "cycloalkyl group." A partially unsaturated carbocyclic ring may be referred to as, for example, an unsaturated alicyclic ring. An alicyclic ring may be a monocyclic, spirocyclic, fused, or bridged ring. For example, a 3- to 14-membered alicyclic ring refers to an aliphatic carbocyclic ring group composed of 3-14 backbone carbon atoms.

[0140] "Saturated alicyclic ring" is also called "cycloalkyl", which is an aliphatic cyclic group composed of saturated carbon atoms as the backbone. The 3-14 membered cycloalkyl or 3-14 membered saturated alicyclic ring used in this application refers to a cyclic group composed of 3-14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the aforementioned values) saturated carbon atoms. Typical saturated alicyclic rings include but are not limited to wait.

[0141] "Unsaturated alicyclic ring" is an aliphatic cyclic group composed of saturated carbon atoms and unsaturated carbon atoms as a backbone. The 3-14 membered unsaturated alicyclic ring used in this application refers to a cyclic group composed of 3-14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the aforementioned values) carbon atoms and unsaturated carbon atoms as a backbone structure. Typical unsaturated alicyclic rings include but are not limited to wait.

[0142] "Aliphatic heterocycle" or "aliphatic heterocyclic group" refers to a non-aromatic cyclic group formed by replacing a carbon atom in an alicyclic ring with one or more heteroatoms. Aliphatic heterocycles or aliphatic heterocyclic groups may include saturated aliphatic heterocycles and unsaturated aliphatic heterocycles. For example, a 3- to 14-membered aliphatic heterocyclic group refers to a non-aromatic cyclic group containing one or more heteroatoms and composed of 3-14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or a range consisting of any two of the foregoing) backbone atoms, and may be a saturated aliphatic heterocyclic group or an unsaturated aliphatic heterocyclic group.

[0143] "Saturated heterocyclic ring" is also called "heterocycloalkyl", which means that the carbon atoms constituting the ring backbone of the heterocyclic ring are all saturated. For example, the 3-14 membered saturated heterocyclic ring used in this application refers to a non-aromatic cyclic group formed by 3-14 atoms (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing values) forming the ring backbone, wherein the atoms constituting the ring backbone are composed of saturated carbon atoms and heteroatoms. Typical saturated heterocyclic rings include but are not limited to:

[0144] wait.

[0145] "Unsaturated aliphatic heterocycle" or "unsaturated aliphatic heterocyclic group" refers to a non-aromatic cyclic structure containing some unsaturated carbon atoms as the ring skeleton in the aliphatic heterocycle. For example, in certain embodiments of the present application, "unsaturated aliphatic heterocycle" refers to a non-aromatic cyclic structure containing unsaturated carbon atoms in the skeleton constituting the aliphatic heterocycle. The 3-14 membered unsaturated aliphatic heterocycle used in the present application refers to a non-aromatic cyclic group composed of 3-14 (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing values) skeleton atoms, wherein the atoms constituting the ring skeleton include saturated carbon atoms, unsaturated carbon atoms and heteroatoms. Typical unsaturated aliphatic heterocycles include but are not limited to wait.

[0146] "Aromatic ring" or "aryl" refers to a cyclic structure with aromaticity that has a conjugated planar ring system and is completely composed of unsaturated carbon atoms. Its planar ring has a delocalized π electron system and contains 4n+2 π electrons, where n is an integer. The aromatic ring can be composed of six, eight, ten or more carbon atoms. The aromatic ring can be a monocyclic ring or a polycyclic ring (such as a bicyclic ring or a tricyclic ring). Common aromatic rings include but are not limited to benzene rings, naphthalene rings, phenanthrene rings, anthracene rings, tetraphenyl rings, pyrene rings, pentaphenyl rings, etc. The 6-10 membered aromatic ring or 6-10 membered aryl used in this application refers to an aromatic ring group composed of 6 to 10 (for example, 6, 7, 8, 9, 10 or a range consisting of any two of the foregoing values) skeleton carbon atoms.

[0147] "Aromatic heterocycle" or "heteroaryl" refers to an aromatic cyclic structure formed by replacing a carbon atom in an aromatic ring with one or more heteroatoms. As used herein, a 5- to 10-membered aromatic heterocycle or 5- to 10-membered heteroaryl refers to an aromatic cyclic group containing heteroatoms and composed of 5 to 10 (e.g., 5, 6, 7, 8, 9, 10, or a range consisting of any two of the foregoing) backbone atoms. Typical aromatic heterocycles or heteroaryl groups include, but are not limited to: wait.

[0148] An "aromatic ring" refers to a group with aromatic properties formed by the cyclic backbone and the substituents on the ring. The planar ring has a delocalized π electron system and contains 4n+2 π electrons. An "aromatic ring" can be an aromatic ring or an aromatic heterocycle, or an unsaturated alicyclic ring or an unsaturated alicyclic heterocycle in which a saturated carbon atom is replaced by an =O, =S, =NH, or other substitution, resulting in an aromatic structure. For example, pyridone is an "aromatic ring" group.

[0149] "Cyclic ring" refers to a cyclic structure in which two adjacent ring atoms are shared between the rings. Cyclic rings can be bicyclic, tricyclic or polycyclic.

[0150] In the present application, "a cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring" refers to a cyclic ring structure formed by sharing two adjacent ring atoms between an aromatic ring and an unsaturated alicyclic ring. "A cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring" refers to a cyclic ring structure formed by sharing two adjacent ring atoms between an aromatic ring and an unsaturated alicyclic ring. "A cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring" refers to a cyclic ring structure formed by sharing two adjacent ring atoms between an aromatic heterocycle and an unsaturated alicyclic ring. "A cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring" refers to a cyclic ring structure formed by sharing two adjacent ring atoms between an aromatic heterocycle and an unsaturated alicyclic ring. In the present application, "a cyclic ring composed of a 7-14 membered aromatic ring and an unsaturated alicyclic ring" refers to a cyclic ring structure having 7 to 14 (for example, 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing values) skeletal ring atoms formed by sharing two adjacent ring atoms between an aromatic ring and an unsaturated alicyclic ring. "7- to 14-membered cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring" refers to a cyclic ring structure having 7 to 14 (e.g., 7, 8, 9, 10, 11, 12, 13, 14, or a range consisting of any two of the aforementioned values) skeletal ring atoms formed by the aromatic heterocycle and the unsaturated alicyclic ring sharing two adjacent ring atoms. In the present application, "7- to 14-membered cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring" refers to a cyclic ring structure having 7 to 14 (e.g., 7, 8, 9, 10, 11, 12, 13, 14, or a range consisting of any two of the aforementioned values) skeletal ring atoms formed by the unsaturated alicyclic heterocycle and the aromatic heterocycle sharing two adjacent ring atoms. In this application, "a 7- to 14-membered cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring" refers to a cyclic ring structure having 7 to 14 (e.g., 7, 8, 9, 10, 11, 12, 13, 14, or a range consisting of any two of the aforementioned values) backbone ring atoms formed by the unsaturated alicyclic ring and the aromatic ring sharing two adjacent ring atoms. Common cyclic rings composed of aromatic rings and unsaturated alicyclic rings include but are not limited to Common cyclic rings formed by aromatic rings and unsaturated heterocyclic rings include but are not limited to Common cyclic rings formed by aromatic heterocycles and unsaturated aliphatic heterocycles include but are not limited to:

[0151] "Amine" or "amine" refers to a group having -NR S R T The chemical structure of S 、R T Each is independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl, common "amino" includes but is not limited to -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2.

[0152] "Iminyl" or "imine" refers to a group having ═NR W The chemical structure of W Selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl.

[0153] "Carbonyl" refers to a group having -COR Z The chemical structure of Z Selected from alkyl, cycloalkyl, heterocycloalkyl, common carbonyl groups include but are not limited to -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2.

[0154] "Amide" or "amido" refers to a group having -C(O)NR U R V or -NR U C(O)R V The chemical structure of U 、R V Each is independently selected from hydrogen, deuterium, tritium, alkyl, cycloalkyl, heterocycloalkyl, common amide groups include but are not limited to -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3.

[0155] "Aminoalkyl" refers to an alkyl group in which any hydrogen atom is replaced by an amino group. As used herein, a C1-C6 aminoalkyl group refers to a linear or branched alkyl group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or a range consisting of any two of the foregoing values), wherein any hydrogen atom on the alkyl group is replaced by an amino group. Common aminoalkyl groups include, but are not limited to, -CH2N(CH3)2, -CH2NH2, -CH2NHCH3, -CH2NHCH2CH3, and -CH2N(CH2CH3)2.

[0156] "Acylamidealkyl" refers to an alkyl group in which any hydrogen atom is replaced by an amide group. As used herein, a C1-C6 acylamidealkyl group refers to a linear or branched alkyl group consisting of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or a range consisting of any two of the foregoing values), wherein any hydrogen atom is replaced by an amide group. Common acylamidealkyl groups include, but are not limited to, -CH2NHCOCH3 and -CH2CONH2.

[0157] "Ester group" refers to a group having the formula -C(O)OR a or -OC(O)R b The chemical structure of a 、R b Selected from alkyl, cycloalkyl, heterocycloalkyl, common ester groups include but are not limited to -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2.

[0158] " substitution " refers to that one or more hydrogen atoms in the group are replaced by the substituent of corresponding number independently of one another. It goes without saying that substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution when not paying too much effort. For example, amino or hydroxyl with free hydrogen may be unstable when combined with the carbon atom with unsaturated (such as olefinic) key. Separately and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, alkylthio, aryloxy, nitro, acyl, halogen, haloalkyl, amino etc.

[0159] "Inhibitor" refers to a substance that reduces enzyme activity.

[0160] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted" includes both substituted and unsubstituted, and "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0161] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0162] "Pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0163] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0164] "Tautomers" or "tautomeric forms" refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, where the proton can migrate between two ring nitrogens. Valence tautomers include interconversions via reorganization of some of the bonding electrons. Non-limiting examples of tautomers include, but are not limited to,

[0165] "Stereoisomers" refer to isomers with the same molecular formula and functional groups, which are produced by different spatial arrangements of atoms or functional groups in the molecule. They include cis-trans isomers and chiral isomers, among which chiral isomers include enantiomers and diastereomers.

[0166] "Enantiomers" refer to compounds with the same molecular formula and functional groups, which exhibit isomerism due to different spatial configurations of atoms or functional groups. At the same time, the compounds form non-superimposable stereoisomers that are mirror images of each other.

[0167] "Diastereoisomers" refer to compounds with the same molecular formula and functional groups, which are stereoisomers caused by different spatial configurations of atoms. At the same time, the compounds are not stereoisomers that are in a mirror-image relationship with each other.

[0168] In this application, a straight covalent bond "—" in a compound structure may indicate that the bond is in the same plane as the paper. In this application, when stereoisomers exist for the atoms connected by a straight covalent bond, the straight covalent bond indicates that the arrangement of the atoms connected by the straight covalent bond may include being in the same plane as the paper, facing outward from the paper, facing inward from the paper, or a mixture of these arrangements.

[0169] Unless otherwise indicated, the terms "comprise, comprise, and comprising" or their equivalents (contain, contains, containing, include, includes, including) used herein are open-ended expressions and mean that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0170] Unless otherwise indicated, all numbers used herein expressing amounts of ingredients, measurements, or reaction conditions are to be understood as modified in all instances by the term "about." When used in conjunction with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0171] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0172] Obviously, based on the above content of this application, in accordance with the common technical knowledge and means in this field, without departing from the above basic technical ideas of this application, various other forms of modifications, replacements or changes can be made.

[0173] The abbreviations in this application have the following meanings: DETAILED DESCRIPTION

[0174] Synthesis method

[0175] The present application also provides a method for synthesizing the above-mentioned compounds. The method for synthesizing the above-mentioned compounds is mainly based on the preparation methods reported in chemical literature or is synthesized using commercially available chemical reagents as starting materials.

[0176] Method 1

[0177] Step 1) The compound represented by formula (ia) is subjected to a condensation reaction with the compound represented by formula (id) under the action of a condensing agent (e.g., diethyl azodicarboxylate) to obtain a compound represented by formula (ib); Step 2) The compound represented by formula (ib) is borated under the action of a boration agent (e.g., pinacol diboron) to obtain a compound represented by formula (ic); Step 3) The compound represented by formula (ic) is subjected to a coupling reaction with the compound represented by formula (ie) to obtain a compound represented by formula (I).

[0178] Method 2

[0179] Step 1) The compound represented by formula (ie) in method 1 is treated with a boration reagent (e.g., pinacol diboron) to obtain a compound represented by formula (ii-e); Step 2) The compound represented by formula (ii-e) is subjected to a coupling reaction with the compound represented by formula (ib) obtained in method 1 to obtain a compound represented by formula (I).

[0180] Method 3

[0181] Step 1) The compound represented by formula (iii-a) is treated with p-toluenesulfonylhydrazine to obtain a compound represented by formula (iii-b); Step 2) The compound represented by formula (iii-b) is coupled under metal catalysis to obtain a compound represented by formula (iii-c); Step 3) The compound represented by formula (iii-c) is coupled with the compound represented by formula (ii-e) in method 2 to obtain a compound represented by formula (I).

[0182] In methods 1 to 3, the X, Y, Z, ring A, ring B, ring C, W 1 、W 2 、W 3 、W 4 、W 5 、m、n、o、p、R A 、R B 、 Consistent with the above definition; L is selected from O, NH, NCH3, etc.; R' is selected from hydrogen, deuterium, tritium, nitro, cyano, C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl), C1-C6 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy). When the compound represented by formula (I) has an amino protecting group or a hydroxy protecting group (e.g., tert-butyloxycarbonyl, tert-butylcarbonyl, tert-butyldimethylsilyl, trimethylsilylethoxymethyl, etc.), the protecting group can be further removed under the action of a strong acid such as trifluoroacetic acid or hydrochloric acid.

[0183] In the present application, the compound represented by formula (ie) can be a commercially available product or can be prepared by a person skilled in the art using a preparation method disclosed in the prior art. For example, ie can be prepared by the following methods i-e1, i-e2, i-e3, i-e4, etc.

[0184] Method i-e1

[0185] The compound represented by formula (i-1) undergoes substitution reaction with the compound represented by formula (i-2) to obtain the compound represented by formula (ie), wherein ring A, ring C, and W 1 、W 2 、W 3、W 4 、W 5 、m、o、R A 、 Consistent with the above definition; L "is selected from F, Cl or I; L 'is selected from -OH, -NH2, -NHCH3, and when L' is -OH, L is O, when L' is -NH2, L is -NH-, when L' is -NHCH3, L is -NCH3-.

[0186] Method i-e2

[0187] The compound represented by formula (i-3) undergoes substitution reaction with the compound represented by formula (i-4) to obtain the compound represented by formula (ie), wherein ring C, W 1 、W 2 、W 3 、W 4 、W 5 ,m,R A 、 Consistent with the above definition; Ring A is selected from an aromatic ring, an aromatic heterocycle (e.g., a benzene ring, a 5-10 membered aromatic heterocycle containing 1-3 heteroatoms, specifically a benzene ring, pyridine, pyrimidine, pyrazine, thiophene, imidazole, pyrazole, etc.); L" is selected from F, Cl or I; L' is selected from -OH, -NH2, -NHCH3, and when L' is -OH, L is O, when L' is -NH2, L is -NH-, and when L' is -NHCH3, L is -NCH3-.

[0188] Method i-e3

[0189] The compound represented by formula (i-5) and the compound represented by formula (i-6) undergo condensation reaction under the action of a condensing agent (such as DIAD, DEAD) to obtain a compound represented by formula (ie), wherein ring C, W 1 、W 2 、W 3 、W 4 、W 5 、m、o、R A 、 Consistent with the above definition; Ring A is selected from a saturated alicyclic ring, an unsaturated alicyclic ring, an unsaturated alicyclic heterocyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a cyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring (for example, cyclohexane, an 8-12 membered cyclic ring consisting of a benzene ring and an unsaturated alicyclic ring, specifically cyclohexane, cyclopentane, indane ring, etc.).

[0190] Method i-e4

[0191] The compound represented by formula (i-7) undergoes a coupling reaction with the compound represented by formula (i-6) to obtain the compound represented by formula (ie), wherein ring A, ring C, and W 1 、W 2 、W 3 、W 4 、W 5 、m、o、R A 、 Consistent with the above definition.

[0192] The following examples illustrate the synthesis methods of the compounds and intermediates of this application. The following examples are merely examples of this application and should not be construed as limiting the scope of this application. Unless otherwise specified, the raw materials and reagents involved in this application can be obtained through commercial channels, and the specific source of the channel does not affect the implementation of the technical solution of this application.

[0193] Preparation Example 1: Preparation of 3-bromo-5-(4-trifluoromethyl)phenoxypyridine

[0194] 5-Bromopyridin-3-ol (1.05 g) was dissolved in NMP (5 mL), followed by the addition of 1-fluoro-4-trifluoromethylbenzene (1 g) and potassium carbonate (1.26 g). The reaction system was heated to 150°C and stirred for 4 hours using a microwave. After LC-MS showed that the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =318.0.

[0195] Preparation Example 2: Preparation of 2-bromo-1-methyl-4-(4-trifluoromethyl)phenoxybenzene

[0196] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =331.0.

[0197] Preparation Example 3: Preparation of 1-bromo-2-chloro-3-(4-trifluoromethyl)phenoxybenzene

[0198] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =350.9.

[0199] Preparation Example 4: Preparation of 2-bromo-4-(4-trifluoromethyl)phenoxypyridine

[0200] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e1. MS (ESI) m / z (M+H) + =318.0.

[0201] Preparation Example 5: Preparation of 1-bromo-2-methyl-3-(4-trifluoromethyl)phenoxybenzene

[0202] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =331.0.

[0203] Preparation Example 6: Preparation of 1-chloro-2-bromo-4-(4-trifluoromethyl)phenoxybenzene

[0204] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =350.9.

[0205] Preparation Example 7: Preparation of 4-bromo-2-(4-trifluoromethyl)phenoxypyridine

[0206] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e1. MS (ESI) m / z (M+H) + =318.0.

[0207] Preparation Example 8: Preparation of 4-bromo-1-methyl-2-(4-trifluoromethyl)phenoxybenzene

[0208] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =331.0.

[0209] Preparation Example 9: Preparation of 4-bromo-1-chloro-2-(4-trifluoromethyl)phenoxybenzene

[0210] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =350.9.

[0211] Preparation Example 10: Preparation of 3-bromo-N-methyl-N-(4-trifluoromethyl)phenylamine

[0212] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =330.0.

[0213] Preparation Example 11: Preparation of 2-bromo-1-methoxy-4-(4-trifluoromethyl)phenoxybenzene

[0214] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =347.0.

[0215] Preparation Example 12: Preparation of 1-bromo-2-methoxy-3-(4-trifluoromethyl)phenoxybenzene

[0216] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =347.0.

[0217] Preparation Example 13: Preparation of 1-bromo-3-methoxy-5-(4-trifluoromethyl)phenoxybenzene

[0218] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =347.0.

[0219] Preparation Example 14: Preparation of 4-bromo-1-methoxy-2-(4-trifluoromethyl)phenoxybenzene

[0220] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =347.0.

[0221] Preparation Example 15: Preparation of 2-bromo-6-(4-trifluoromethyl)phenoxybenzonitrile

[0222] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =342.0.

[0223] Preparation Example 16: Preparation of 1-bromo-3-chloro-5-(4-trifluoromethyl)phenoxybenzene

[0224] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =350.9.

[0225] Preparation Example 17: Preparation of 3-bromo-5-(4-trifluoromethyl)phenoxybenzonitrile

[0226] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =342.0.

[0227] Preparation Example 18: Preparation of 7-bromo-2-methyl-5-(4-trifluoromethyl)phenoxy-2H-indazole

[0228] Using method i-e1, 7-bromo-5-iodo-2-methyl-2H-indazole (1.5 g), 4-trifluoromethylphenol (938 mg), cuprous chloride (88.1 mg), 2,2,6,6-tetramethyl-3,5-heptanedione (287 mg), and cesium carbonate (3.62 g) were dissolved in dry NMP (24 mL). The system was heated to 125°C and reacted for 20 hours. LC-MS analysis confirmed the complete reaction of the starting material. The product was filtered through celite, an appropriate amount of water was added, and the product was extracted with ethyl acetate. The organic phases were combined, the solvent was removed under reduced pressure, and the title compound was isolated and purified by silica gel column chromatography. MS (ESI) m / z (M+H) + =371.0.

[0229] Preparation Example 19: Preparation of 1-(3-bromophenoxy)-2,3-dihydro-1H-indene

[0230] Using method i-e3, 2,3-dihydro-1H-indene-1-ol (1.0 g), 3-bromophenol (1.42 g), and Ph3P (2.15 g) were dissolved in THF (50 mL). DIAD (1.81 g) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was allowed to react at room temperature for 16 hours. TLC confirmed the complete reaction of the starting material. The solvent was removed under reduced pressure, and the title compound was isolated and purified by silica gel column chromatography. MS (ESI) m / z (M+H) + =289.0.

[0231] Preparation Example 20: Preparation of 1-bromo-3-(4-(trifluoromethyl)benzyloxy)benzene

[0232] Referring to the preparation method of Preparation Example 19, the title compound was prepared using method i-e3. MS (ESI) m / z (M+H) + =331.0.

[0233] Preparation Example 21: Preparation of 1-bromo-3-(4-(trifluoromethoxy)phenoxy)benzene

[0234] Using method i-e4, (4-(trifluoromethoxy)phenyl)boronic acid (500 mg) was dissolved in dichloromethane (20 mL), followed by the addition of 3-bromophenol (455.5 mg), acetic acid ketone (483.2 mg), and triethylamine (491.8 mg). The reaction system was allowed to react at room temperature for 12 hours. TLC confirmed the complete reaction of the starting material. An appropriate amount of water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =333.0.

[0235] Preparation Example 22: Preparation of 2-(3-bromophenoxy)-4-trifluoromethylpyridine

[0236] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =318.0.

[0237] Preparation Example 23: Preparation of 2-bromo-4-(4-trifluoromethyl)phenoxybenzonitrile

[0238] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =342.0.

[0239] Preparation Example 24: Preparation of 1-bromo-3-(4-trifluoromethyl)cyclohexyloxybenzene

[0240] Referring to the preparation method of Preparation Example 19, the title compound was prepared using method i-e3. MS (ESI) m / z (M+H) + =323.0.

[0241] Preparation Example 27: Preparation of 2-(3-bromo-5-methylphenoxy)-5-(trifluoromethyl)pyridine

[0242] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =332.0.

[0243] Preparation Example 28: Preparation of 2-(3-bromo-2-chlorophenoxy)-5-(trifluoromethyl)pyridine

[0244] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =352.0.

[0245] Preparation Example 29: Preparation of 2-((tert-butyldimethylsilyl)oxy)-1-(pyrazin-2-yl)ethan-1-ol

[0246] 1-(Pyrazin-2-yl)ethane-1,2-diol (0.7 g) was dissolved in dichloromethane (20 mL), and N-methylimidazole (1.2 g) and tert-butyldimethylsilyl chloride (1.5 g) were added. After the addition was complete, the reaction system was stirred at room temperature for 2 hours. After LC-MS showed that the reaction was complete, water was added to the system, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 0.82 g of the title compound. MS (ESI) m / z (M+H) + =255.1.

[0247] Preparation Example 30: Preparation of 2-(3-bromo-5-methoxyphenoxy)-5-(trifluoromethyl)pyridine

[0248] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =348.0.

[0249] Preparation Example 32: Preparation of 2-(3-bromo-4-methoxyphenoxy)-5-(trifluoromethyl)pyridine

[0250] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =348.1.

[0251] Preparation Example 33: Preparation of 2-(3-bromo-2-methylphenoxy)-5-(trifluoromethyl)pyridine

[0252] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =332.0.

[0253] Preparation Example 34: Preparation of 2-(3-bromo-5-chlorooxy)-5-(trifluoromethyl)pyridine

[0254] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =352.0.

[0255] Preparation Example 37: Preparation of 2-(3-bromo-4-chlorophenoxy)-5-(trifluoromethyl)pyridine

[0256] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =352.0.

[0257] Preparation Example 41: Preparation of 2-(3-bromo-4-fluorophenoxy)-5-(trifluoromethyl)pyridine

[0258] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =336.0.

[0259] Preparation Example 42: Preparation of 8-bromo-6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoline

[0260] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =369.1.

[0261] Preparation Example 45: Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-ol

[0262] Step 1: Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-one

[0263] 7-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridine (1.5 g) was dissolved in tetrahydrofuran (15 mL). Under nitrogen, the reaction system was cooled to -78°C and n-butyllithium (3.5 mL, 1.6 M in hexane) was slowly added dropwise. The mixture was stirred for 0.5 hour, followed by the addition of DMAc (1.19 g). After the addition was complete, the reaction system was stirred at -78°C for 0.5 hour. After LCMS indicated the reaction was complete, ammonium chloride solution was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain 1.1 g of the title compound. MS (ESI) m / z (M+H) + =292.1.

[0264] Step 2: Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-ol

[0265] 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-one (0.21 g) was dissolved in methanol (10 mL), and sodium borohydride (0.17 g) was added. The reaction system was stirred at room temperature for 1 hour. After LCMS showed that the reaction was complete, the mixture was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain 0.3 g of the title compound. MS (ESI) m / z (M+H) + =294.1.

[0266] Preparation Example 49: Preparation of 2-(3-bromo-4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)pyridine

[0267] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =402.0.

[0268] Preparation Example 52: Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-7-yl)ethan-1-ol

[0269] The title compound was prepared by referring to step 2 of Preparation Example 45. MS (ESI) m / z (M+H) + =294.2.

[0270] Preparation Example 54: Preparation of tert-butyl 7-(1-hydroxyethyl)-1H-benzo[d]imidazole-1-carboxylate

[0271] Step 1: Preparation of 1-(tert-Butoxycarbonyl)-1H-benzo[d]imidazole-7-carboxylic acid

[0272] 1H-Benzo[d]imidazole-7-carboxylic acid (2.4 g) was dissolved in dichloromethane (30 mL), followed by the addition of triethylamine (3.0 g) and di-tert-butyl dicarbonate (6.55 g). After the addition was complete, the reaction system was stirred at room temperature for 16 hours. After LC-MS showed the reaction was complete, the reaction solution was concentrated under reduced pressure to yield 2.5 g of the title compound. MS (ESI) m / z (M+H) + =263.2.

[0273] Step 2: Preparation of tert-butyl 7-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylate

[0274] 1-(tert-Butoxycarbonyl)-1H-benzo[d]imidazole-7-carboxylic acid (3.0 g) was dissolved in dichloromethane (50 mL), and EDCI (2.6 g), HOBt (1.9 g), and dimethylhydroxylamine hydrochloride (1.4 g) were added. After the addition was complete, the reaction system was stirred at room temperature for 16 hours. After LC-MS showed that the reaction was complete, water was added to the system, and extraction was performed with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 3.0 g of the title compound. MS (ESI) m / z (M+H) + =306.2.

[0275] Step 3: Preparation of tert-butyl 7-acetyl-1H-benzo[d]imidazole-1-carboxylate

[0276] tert-Butyl 7-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylate (3 g) was placed in a three-necked flask and, under nitrogen, anhydrous tetrahydrofuran (25 mL) was added. The reaction system was cooled to 0°C and methylmagnesium bromide (11 mL, 1.4 M in THF and Tol) was slowly added dropwise. After the addition was complete, the reaction system was stirred at 0°C for 2 hours. After LC-MS indicated the reaction was complete, saturated ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to yield 1 g of the title compound. MS (ESI) m / z (M+H) + =261.1.

[0277] Step 4: Preparation of tert-butyl 7-(1-hydroxyethyl)-1H-benzo[d]imidazole-1-carboxylate

[0278] Dissolve tert-butyl 7-acetyl-1H-benzo[d]imidazole-1-carboxylate (1.2 g) in methanol (10 mL) and add sodium borohydride (0.35 g) at 0°C. After addition, stir the reaction system at room temperature for 1 hour. After LC-MS indicates the reaction is complete, add water to the system, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting crude product is purified by silica gel column chromatography to yield 1 g of the title compound. MS (ESI) m / z (M+H) + =263.1.

[0279] Preparation Example 55: Preparation of 5-bromo-7-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinoxaline

[0280] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =370.0.

[0281] Preparation Example 58: Preparation of 2-(3-bromo-2-fluorophenoxy)-5-(trifluoromethyl)pyridine

[0282] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =336.0

[0283] Preparation Example 61: Preparation of 2-(3-bromo-2-chlorophenoxy)-4-methyl-5-(trifluoromethyl)pyridine

[0284] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =366.0

[0285] Preparation Example 63: Preparation of 2-(3-bromo-4-(trifluoromethyl)phenoxy)-5-(trifluoromethyl)pyridine

[0286] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =386.0.

[0287] Preparation Example 64: Preparation of 2-(3-bromo-4-(difluoromethoxy)phenoxy)-5-(trifluoromethyl)pyridine

[0288] 2-Bromo-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenol (1.1 g, 3.29 mmol) was dissolved in a mixture of acetonitrile and water (20 mL). ((difluoromethyl)sulfonyl)benzene (1.9 g) and potassium tert-butoxide (1.11 g) were added. After the addition was complete, the reaction system was stirred at 100°C for 16 hours. After LC-MS indicated the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to yield 0.4 g of the title compound. MS (ESI) m / z (M+H) + =384.0.

[0289] Preparation Example 65: Preparation of 2-(3-bromophenoxy)-5-(trifluoromethyl)pyrimidine

[0290] Referring to the preparation method of Preparation Example 1, the title compound was prepared using method i-e2. MS (ESI) m / z (M+H) + =319.0.

[0291] Example 1: Preparation of 1-(1-(pyridin-2-yl)ethyl)-4-(3-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2(1H)-one

[0292] Step 1: Preparation of 4-bromo-1-(1-(pyridin-2-yl)ethyl)pyridin-2(1H)-one

[0293] 4-Bromopyridin-2(1H)-one (2.83 g) was dissolved in dry THF (20 mL), followed by the addition of 1-(pyridin-2-yl)ethane-1-ol (2 g) and Ph3P (8.52 g). DIAD (6.57 g) was then slowly added dropwise, and the reaction system was stirred at room temperature for 1 hour. After LC-MS showed that the raw materials had reacted completely, water was added to the system, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =279.1.

[0294] Step 2: Preparation of (2-oxo-1-(1-(pyridin-2-yl)ethyl)-1,2-dihydropyridin-4-yl)boronic acid

[0295] Dissolve 4-bromo-1-(1-(pyridin-2-yl)ethyl)-1,2-dihydropyridin-2-one (200 mg) in dioxane (10 mL), followed by the addition of pinacol diboronate (219.40 mg), potassium acetate (105.99 mg), and Pd(dppf)Cl2 (52.68 mg). After the addition is complete, the reaction system is heated to 90°C and stirred for 2 hours under nitrogen. LC-MS indicates that the reaction is complete, and the reaction solution is concentrated under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + =245.1.

[0296] Step 3: Preparation of 1-(1-(pyridin-2-yl)ethyl)-4-(3-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2(1H)-one

[0297] (2-Oxo-1-(1-(pyridin-2-yl)ethyl)-1,2-dihydropyridin-4-yl)boronic acid (205.5 mg) was dissolved in dioxane (12 mL), followed by the addition of 1-bromo-3-(4-trifluoromethyl)phenoxybenzene (200 mg), potassium carbonate (174.1 mg), and Pd(dppf)Cl2 (46.1 mg). Under nitrogen, the reaction system was heated to 90°C and stirred for 2 hours. After LC-MS indicated complete reaction of the starting material, the reaction solution was concentrated under reduced pressure. The resulting crude product was filtered through silica gel and then concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound.

[0298] MS (ESI) m / z (M+H) + =437.1.

[0299] 1 H NMR (400MHz, DMSO-d6) δ8.58–8.52(m,1H),7.83–7.72(m,4H),7.63–7.53(m,2H),7.50(t,J=2.0Hz,1H),7.38–7.29(m,2 H),7.24–7.16(m,3H),6.71(d,J=2.0Hz,1H),6.62(dd,J=7.2,2.0Hz,1H),6.18(q,J=7.2Hz,1H),1.72(d,J=7.2Hz,3H).

[0300] Example 22: Preparation of 4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-2(1H)-one:

[0301] Step 1: Preparation of 2-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0302] Referring to the reagents and conditions of Step 2 of Example 1, the preparation method of Step 1 of Method 2 was adopted. 1-Bromo-2-chloro-3-(4-(trifluoromethyl)phenoxy)benzene was dissolved in dioxane (10 mL), followed by the addition of pinacol diboron (219.40 mg), potassium acetate (105.99 mg), and Pd(dppf)Cl2 (52.68 mg). After the addition was complete, the reaction system was heated to 90°C and stirred for 2 hours under nitrogen. After LC-MS showed that the starting materials had reacted completely, the reaction solution was concentrated under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + =399.1.

[0303] Step 2: Preparation of 4-bromo-1-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-2(1H)-one

[0304] Referring to the reagents and conditions of step 1 of Example 1, the title compound was obtained by the preparation method of step 1 of method 1. MS (ESI) m / z (M+H) + =282.0.

[0305] Step 3: Preparation of 4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-2(1H)-one

[0306] Referring to the reagent conditions of step 3 of Example 1, the preparation method of step 2 of method 2 was adopted to dissolve 2-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (205.5 mg) in dioxane (12 mL), followed by the addition of 4-bromo-1-(1-(1-methyl-1H-pyrazol-3-yl)ethyl)pyridin-2(1H)-one (145.1 mg), potassium carbonate (174.1 mg) and Pd(dppf)Cl2 (46.1 mg). Under nitrogen protection, the mixture was heated to 90°C for 2 hours. After LC-MS showed that the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure and separated and purified by preparative high performance liquid chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =474.1. 1H NMR (400MHz, DMSO-d6) δ7.75(d,J=8.4Hz,2H),7.69(d,J=2.0Hz,1H),7.59(d,J=7.2Hz,1H),7.51(t,J=8.0Hz,1H),7.36(td,J=8.0,1 .6Hz,2H),7.15(d,J=8.4Hz,2H),6.47(d,J=2.0Hz,1H),6.37–6.26(m,2H),6.20(q,J=7.2Hz,1H),3.83(s,3H),1.63(d,J=7.2Hz,3H).

[0307] Example 24A: Preparation of tert-butyl 4-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)yl)ethyl)piperidine-1-carboxylate

[0308] Step 1: Preparation of tert-butyl 4-(1-toluenesulfonylhydrazonoethyl)piperidine-1-carboxylate

[0309] Dissolve tert-butyl 4-acetylpiperidine-1-carboxylate (2.0 g) in methanol (20 mL) and add p-toluenesulfonylhydrazide (1.64 g). After the addition is complete, heat the reaction system to 60°C and react for 1 hour. After LC-MS indicates the reaction is complete, concentrate under reduced pressure to obtain the title compound. MS (ESI) m / z (M+H) + =396.2.

[0310] Step 2: Preparation of tert-butyl 4-(1-(4-bromo-2-oxopyridin-1(2H)-yl)ethyl)piperidine-1-carboxylate

[0311] Dissolve tert-butyl 4-(1-toluenesulfonylhydrazineethyl)piperidine-1-carboxylate (400 mg) and 4-bromopyridin-2(1H)-one (351.5 mg) in 1,4-dioxane (10 mL), add cuprous iodide (38 mg) and cesium carbonate (658 mg), and heat the reaction system to 110°C under nitrogen for 16 hours. LC-MS analysis confirmed the completion of the reaction, followed by filtration through celite, addition of an appropriate amount of water, extraction with ethyl acetate, and concentration under reduced pressure. Purify the mixture by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =385.1.

[0312] Step 3: Preparation of tert-butyl 4-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)yl)ethyl)piperidine-1-carboxylate

[0313] 2-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (205.5 mg) was dissolved in dioxane (12 mL), followed by the addition of tert-butyl 4-(1-(4-bromo-2-oxopyridin-1(2H)-yl)ethyl)piperidine-1-carboxylate (199 mg), potassium carbonate (174.1 mg), and Pd(dppf)Cl2 (46.1 mg). Under nitrogen protection, the reaction system was heated to 90°C and stirred for 2 hours. After LC-MS showed that the raw material had reacted completely, the reaction solution was concentrated under reduced pressure, and the resulting crude product was filtered through silica gel and concentrated under reduced pressure. The residue was separated and purified by preparative high-performance liquid chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =577.2.

[0314] Example 24: Preparation of 4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-1-(1-(piperidin-4-yl)ethyl)pyridin-2(1H)-one

[0315] Tert-butyl 4-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)yl)ethyl)piperidine-1-carboxylate (Example 24A) (80 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.53 g) was added. The reaction system was allowed to react at room temperature for 1 hour. After LC-MS showed the reaction was complete, the mixture was concentrated under reduced pressure. The title compound was isolated and purified by preparative HPLC. MS (ESI) m / z (M+H) + =477.2. 1 HNMR(400MHz,DMSO-d6)δ7.79–7.70(m,3H),7.51(t,J=8.0Hz,1H),7.41–7.33(m,2H) ,7.15(d,J=8.4Hz,2H),6.43(d,J=2.0Hz,1H),6.36(dd,J=7.2,2.0Hz,1H),4.73(s,1H ),2.97(d,J=12.4Hz,1H),2.86(d,J=12.8Hz,1H),2.41(td,J=12.0,2.4Hz,1H),2.30 (td,J=12.0,2.4Hz,1H),1.81–1.65(m,2H),1.31(d,J=7.2Hz,3H),1.26–0.81(m,4H).

[0316] Example 50A: Preparation of N-(6-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)-yl)ethyl)pyridin-2-yl)pivalamide

[0317] Referring to Example 1, the title compound was prepared using the preparation method of Method 1. MS (ESI) m / z (M+H) + =570.2.

[0318] Example 50: Preparation of 1-(1-(6-aminopyridin-2-yl)ethyl)-4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2(1H)-one

[0319] N-(6-(1-(4-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-2-oxopyridin-1(2H)-yl)ethyl)pyridin-2-yl)pivalamide (Example 50A) (325 mg) was dissolved in a mixed solvent of 1,4-dioxane (10.0 mL) and concentrated hydrochloric acid (10.0 mL). The reaction system was heated to 90°C and stirred for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, the pH was adjusted to 8-9 with aqueous ammonia, and the solution was concentrated under reduced pressure. The title compound was obtained after separation and purification by preparative high-performance liquid chromatography. MS (ESI) m / z (M+H) + =486.1. 1 H NMR (400MHz, DMSO-d6) δ7.79–7.70(m,3H),7.51(t,J=8.0Hz,1H),7.40–7.34(m,3H),7.15(d,J= 8.4Hz, 2H), 6.46 (d, J = 7.2Hz, 2H), 6.42–6.32 (m, 2H), 6.03–5.97 (m, 3H), 1.63 (d, J = 7.2Hz, 3H).

[0320] Example 67A: Preparation of 1-(2-((tert-butyldimethylsilyl)oxy)-1-(pyrazin-2-yl)ethyl)-4-(2-chloro-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)pyridin-2(1H)-one

[0321] Referring to Example 22, the title compound was prepared using the preparation method of Method 2. MS (ESI) m / z (M+H) + =603.2.

[0322] Example 67: Preparation of 4-(2-chloro-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1-(2-hydroxy-1-(pyrazin-2-yl)ethyl)pyridin-2(1H)-one

[0323] 1-(2-((tert-butyldimethylsilyl)oxy)-1-(pyrazin-2-yl)ethyl)-4-(2-chloro-3-((5-(trifluoromethyl)pyridin-2-yl)oxyphenyl)pyridin-2(1H)-one (0.21 g) was dissolved in dichloromethane (5 mL), and a dioxane hydrochloride solution (5 mL, 4 M) was added. After the addition was complete, the reaction system was stirred at room temperature for 1 hour. After LC-MS showed that the reaction was complete, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the title compound. MS (ESI) m / z (M+H) + =489.1. 1 H NMR(400MHz, DMSO-d6)δ8.72(d,J=1.2Hz,1H),8.63–8.62(m,1H),8.59(d,J= 2.4Hz,1H),8.58–8.56(m,1H),8.28(dd,J=8.8,2.4Hz,1H),7.92(d,J=7.2Hz, 1H),7.53–7.45(m,2H),7.40–7.37(m,2H),6.45(d,J=2.0Hz,1H),6.38(dd,J= 7.2, 2.0Hz, 1H), 6.12–6.08 (m, 1H), 5.36 (t, J = 5.2Hz, 1H), 4.22–4.11 (m, 2H).

[0324] A series of compounds were prepared using corresponding commercial reagents and the products of the above-mentioned preparation examples and examples as raw materials, using a preparation method similar to the above-mentioned examples. The structures and characterization data of the compounds are shown in Table 1.

[0325] Table 1

[0326] Biological tests

[0327] Test Example 1: YAP-TEAD dual luciferase reporter gene experiment.

[0328] 1. Experimental Materials:

[0329] 2. Experimental Methods

[0330] a. HEK293T cells in logarithmic growth phase were co-transfected with 8xGTIIC-firefly luciferase and pRL-SV40-N plasmids;

[0331] b. Experimental wells: Plate 12,000 transfected cells as described above in a 96-well plate. Make a serial dilution of the test drug in DMEM supplemented with 0.5% DMSO. The highest final concentration in the experimental wells is 5 μM. Perform a 5-fold serial dilution, for a total of 9 concentrations. Add 50 μL of each test drug solution from concentrations 1-9 to the transfected wells. Repeat for each concentration in triplicate. Set up untreated control wells as follows: Plate 12,000 transfected cells as described above in a 96-well plate and add DMEM supplemented with 0.5% DMSO to each well. Repeat for 8 wells. Set up untransfected wells as follows: Plate 12,000 untransfected HEK293T cells in a 96-well plate and add DMEM supplemented with 0.5% DMSO to each well. Repeat for 8 wells.

[0332] c. After 24 hours of drug treatment, the cell fluorescence value was detected according to the instructions of the Promega Dual Luciferase Assay Kit.

[0333] d. Calculate the inhibition rate using the following formula:

[0334] Inhibition rate % = (average signal value of untreated control wells - signal value of experimental wells) / (average signal value of untreated control wells - average signal value of non-transfected control wells) × 100%

[0335] e. GraphPad Prism 9.0 was used to draw the inhibition rate-dose curve and calculate the IC50 value.

[0336] 3. Experimental Results

[0337] The TEAD transcriptional inhibitory activity of the compounds in this application on HEK293T cells is shown in Table A below.

[0338] Table A

[0339] In the table, “A” represents the IC of TEADs transcriptional inhibitory activity 50 Range is less than or equal to 25nM; "B" represents the IC of TEADs transcriptional inhibitory activity 50 The range is greater than 25nM and less than or equal to 50nM; "C" represents the IC of TEADs transcriptional inhibitory activity50 The range is greater than 50nM and less than or equal to 100nM; "H" represents the IC of TEADs transcriptional inhibitory activity 50 The range was greater than 5 μM or inactive.

[0340] The compounds in this application have TEADs transcriptional inhibitory activity on HEK293T cells. The experiments found that the IC values ​​of the compounds in this application for TEADs transcriptional inhibitory activity were 50 The IC value of some compounds in this application for TEADs transcriptional inhibition activity is less than or equal to 100 nM. 50 The IC values ​​of certain compounds in this application for TEADs transcriptional inhibition activity are greater than or equal to 50 nM and less than 100 nM. 50 The IC values ​​of certain compounds in this application for TEADs transcriptional inhibition activity are greater than or equal to 30 nM and less than 50 nM. 50 The IC50 value of the TEADs transcriptional inhibitory activity of some compounds in this application is greater than or equal to 10nM and less than 20nM. The IC50 value of the TEADs transcriptional inhibitory activity of some compounds in this application is greater than or equal to 10nM and less than 20nM. 50 The value was less than 10 nM.

[0341] Test Example 2: Cell proliferation inhibitory activity assay

[0342] 1. Experimental Materials

[0343] 2. Experimental Methods

[0344] a. NCI-H226 cells in the logarithmic growth phase were seeded into 96-well plates, with 180 μL per well. The same volume of blank culture medium (PRMI 1640 cell culture medium) was added to blank wells of the 96-well plate.

[0345] b. Experimental wells: Dilute the test drug in PRMI 1640 cell culture medium containing 0.5% DMSO to a final concentration of 10 μM. Perform a three-fold serial dilution series for a total of nine concentrations. Add 20 μL of each concentration (1-9) to the wells seeded with cells, repeating for three wells. Set up untreated control wells as follows: Add 20 μL of PRMI 1640 cell culture medium containing 0.5% DMSO to the wells seeded with cells, repeating for eight wells. Set up blank control wells as follows: Add 20 μL of PRMI 1640 cell culture medium containing 0.5% DMSO to the wells containing blank culture medium.

[0346] c. After 168 hours of treatment, cell viability was determined using the CellCounting-Lite™ 2.0 kit and luminescence signals were detected using a multifunctional microplate reader.

[0347] d. Calculate the inhibition rate using the following formula:

[0348] Inhibition rate % = (average signal value of untreated control wells - signal value of experimental wells) / (average signal value of untreated control wells - average signal value of blank control wells) × 100%

[0349] e. GraphPad Prism 9.0 was used to draw the inhibition rate-dose curve and calculate the IC50 value.

[0350] 3. Experimental Results

[0351] The cell proliferation inhibitory activities of the compounds in this application are shown in Table 2.

[0352] Table 2

[0353] In the table, “A” represents the IC50 of the inhibitory activity on NCI-H226 cell proliferation. 50 Range is less than or equal to 25nM; "B" represents the IC50 of the inhibitory activity on NCI-H226 cell proliferation 50 The range is greater than 25nM and less than or equal to 50nM; "C" represents the IC50 of the inhibitory activity on NCI-H226 cell proliferation. 50 The range is greater than 50nM and less than or equal to 100nM; "D" represents the IC50 of the inhibitory activity on NCI-H226 cell proliferation. 50 The range is greater than 100nM and less than or equal to 500nM; "E" represents the IC50 of the inhibitory activity on NCI-H226 cell proliferation. 50 The range is greater than 500 nM and less than or equal to 1 μM; "F" represents the IC50 of the inhibitory activity on NCI-H226 cell proliferation. 50 The range is greater than 1 μM and less than or equal to 3 μM; "G" represents the IC50 of the inhibitory activity on NCI-H226 cell proliferation. 50 The range is greater than 3μM and less than 5μM; "H" represents the IC50 of the inhibitory activity on NCI-H226 cell proliferation. 50 The range was greater than 10 μM or inactive.

[0354] The compounds in this application have the effect of inhibiting the proliferation of NCI-H226 cells. Experiments have found that the IC50 value of the inhibitory activity of some compounds in this application on the proliferation of NCI-H226 cells is less than or equal to 500nM. 50 The IC value of some compounds in this application for the proliferation inhibition activity of NCI-H226 cells is less than or equal to 100nM. 50 The IC value of some compounds in this application for the proliferation inhibition activity of NCI-H226 cells is less than or equal to 50nM.50 The IC value of some compounds in this application for the proliferation inhibition activity of NCI-H226 cells is less than or equal to 25nM. 50 The value is less than or equal to 10nM.

[0355] Test Example 3: Liver microsome metabolic stability test

[0356] 1. Experimental Materials

[0357] 2. Experimental Methods

[0358] The test compound was prepared to 10 mM with DMSO, and 2 μL was added to 198 μL of 50% acetonitrile / 50% aqueous solution to obtain a 100 μM solution. Liver microsomes were taken and prepared to 0.5 mg / mL with PBS, and NADPH cofactor (final concentration was 1 mM) was added. The mixture was preheated at 37°C for 10 min. 2.5 μL of the prepared test compound was taken and added to 222.5 μL of the above preheated mixture and placed in a 37°C water bath to start the reaction. At 0.5, 15, 30 and 45 min, the incubated centrifuge tubes were removed and 25 μL of the incubated liver microsome suspension (containing the compound) was taken out. 5 times the volume of the stop solution was added to terminate the reaction, and the mixture was centrifuged at 3220 g for 40 min. After the supernatant was taken, the residual compound content in the sample at each time point was detected by LC-MS / MS. The half-life (t 1 / 2 ).

[0359] The compounds of the present application have a certain stability in liver microsomal metabolism. Some compounds of the present application are metabolized in liver microsomes for a long time or are not metabolized by liver microsomes.

[0360] Test Example 3A: Hepatocyte Metabolic Stability Test

[0361] Hepatocyte source:

[0362] The test compound was diluted to 10 mM in DMSO, and 2 μL was added to 198 μL of a 50% acetonitrile / 50% aqueous solution to obtain a 100 μM solution. After cryopreserved hepatocytes were resuspended in culture medium (William's E Medium, Gibco, Cat. No. 22551032) to a density of 500,000 cells / mL. 198 μL of the hepatocyte suspension was transferred to a 96-well plate, and 2 μL of the prepared 100 μM test compound and positive compound solutions were added, respectively. The plates were then incubated in an incubator. At 0.5, 15, 30, 60, 90, and 120 minutes, the incubated 96-well plates were removed and 25 μL of the cell suspension (containing the compound) was aspirated. The reaction was terminated by adding 6 volumes of stop solution and centrifuged at 3220 g for 45 minutes. The supernatant was collected and the remaining compound content in the samples at each time point was analyzed by LC-MS / MS. The half-life of the compound in hepatocytes (t 1 / 2 ).

[0363] The compounds of the present application are stable in hepatocyte metabolism. The compounds of the present application have a long half-life in hepatocytes and good hepatocyte metabolic stability. For example, the half-life of the compounds of Examples 46 and 60 in human hepatocytes is 2-4 times longer than that of existing compounds.

[0364] Test Example 4: Caco-2 cell in vitro permeability test

[0365] 1. Experimental Materials

[0366] 2. Experimental Methods

[0367] a. Cell culture and plating

[0368] In HTS Transwell TM Caco-2 cells were inoculated into cell culture plates. The volume of culture medium in the plate wells was 50 μL, and the culture medium was replaced every 24 h.

[0369] b. Detection resistor

[0370] After 14-16 days of culture, Caco-2 cells formed a confluent monolayer and the resistance was measured. The transmembrane resistance of the monolayer reached 230Ω·cm. 2 , which can be used for the next penetration test.

[0371] c. Penetration testing

[0372] First, prepare the compound working solution. Use DMSO to prepare the compound to be tested to 2 mM, and then further dilute it to 10 μM with HBSS buffer (10 mM HEPES buffer containing 4% BSA, pH 7.4) to obtain the test working solution.TM Wash the cell surface three times with 37°C HBSS in the cell culture plate, then add 37°C HBSS and incubate in a 37°C incubator for 30 minutes. For A→B permeability testing, aspirate the buffer solution and add a working solution containing the test drug to the upper chamber (apical, side A) as the supply solution. Add a blank HBSS solution to the lower chamber (basolateral, side B) as the receiving solution. For B→A permeability (efflux) testing, aspirate the buffer solution and add a blank HBSS solution to the A side as the receiving solution. Add a working solution containing the compound to the B side as the dosing solution.

[0373] d. Sampling and testing

[0374] At Transwell TM An appropriate amount of the dosing solution was taken from the plate as the T0 sample and then incubated in a 37°C incubator for 2 hours. After incubation, a sample was taken at the receiving end. The sample was analyzed using LC-MS / MS.

[0375] e. Data analysis

[0376] Apparent permeability coefficient (P app , unit: ×10 -6 cm / s):

[0377] V R is the volume of the solution at the receiving end (A→B: the receiving end is the base end; B→A: the receiving end is the top end), and Area is the volume of the Transwell-96 well plate membrane (0.0804 cm 2 ), Time is the incubation time (unit: s), C R is the drug concentration at the sample receiving end, and C0 is the drug concentration at the initial T0 point of the sample.

[0378] Efflux rate (ER):

[0379] P app (B→A) is the apparent permeability coefficient from the base to the top, P app (A→B) is the apparent permeability from the top to the base.

[0380] The compounds of the present application have a certain Caco-2 cell permeability, but the Caco-2 cell efflux effect is not obvious. Some compounds of the present application have a high Caco-2 cell permeability and a low Caco-2 cell efflux effect. For example, the apparent permeability coefficient P of the compounds of Examples 1, 46, and 60 of the present application is app(A→B) were 3.01, 4.65, and 4.85, respectively, with good cell permeability, which was 2 to 3 times higher than that of the prior art compounds, and no obvious efflux was observed.

[0381] Test Example 5: Compound Solubility Test

[0382] 1. Experimental Materials

[0383] 2. Experimental Methods

[0384] a. Compound Preparation.

[0385] The test compound was prepared into a 10 mM solution using DMSO.

[0386] b. Solubility test

[0387] Add 15 μL of the test compound at a 10 mM concentration to a 96-well plate and add 485 μL of PBS. Seal the plate wells and incubate on a shaker at 25°C, 1100 rpm for 2 hours. After 2 hours, transfer 500 μL of the incubated sample to a filter plate and filter using a vacuum manifold. Take 5 μL of the filtrate, mix with 5 μL of DMSO, and then add 490 μL of ultrapure water. The compound concentration is then measured by LC-MS.

[0388] c. Standards

[0389] Take 6 μL of the test compound with a concentration of 10 mM in a 96-well plate, add 194 μL of DMSO solution, mix well, take 5 μL and mix with 5 μL of PBS buffer, then add 490 μL of ultrapure water and mix well. Use LC-MS to test the compound concentration simultaneously with the sample in step 2.

[0390] d. Data analysis

[0391] The injection concentration of the standard is known to be 10 μM. The solubility is calculated by comparing the peak areas of the test compound and the standard in LC-MS. The specific formula is as follows:

[0392] The compounds of the present application may have a certain solubility. Some compounds of the present application have a higher solubility. The compounds of the present application may have a solubility of >50μM, and some compounds of the present application may also have a solubility of >100μM. The compounds of the present application have an improved solubility of at least 10 times compared to the prior art compounds, some compounds have an improvement of more than 100 times, and some compounds have an improvement of more than 1000 times. For example, the solubility of the compounds of Examples 60 and 67 are 63.0μM and 112.2μM, respectively, and the equivalent solubility is 27.62μg / mL and 54.85μg / mL, respectively, which is a huge improvement in solubility compared to the compounds of the prior art.

[0393] Test Example 6: DMPK Metabolism Test

[0394] Six-week-old ICR male mice were purchased from Jicui Yaokang Biotechnology Co., Ltd. Mice (n=3) were administered intravenously (IV) or orally (PO) at doses of 1 mpk and 10 mpk, respectively. Blood samples were collected at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h for the IV group, and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h for the PO group. Blood samples were placed on ice within 1 h of collection and plasma was separated by centrifugation (6800 g, 6 min, 2-8°C). Plasma samples were stored at -80°C until analysis. LC-MS / MS was used to determine the concentration of the test compound in ICR mouse plasma following administration. Phoenix WinNonlin7.0 was used to calculate the pharmacokinetic parameters, and parameters such as AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞), Cmax, Tmax, and T1 / 2, as well as their mean and standard deviations, were provided.

[0395] The compounds of the present application have good PK exposure in mice, with a 10 mpk AUC(0-t) of at least 10,000 h*ng / mL. For example, the 10 mpk AUC(0-t) of the compounds of Examples 46, 66, 90, and 92 are 13,000 h*ng / mL, 17,000 h*ng / mL, 25,000 h*ng / mL, and 10,500 h*ng / mL, respectively, which are at least 5 times higher than those of existing compounds (e.g., ≤2,000 h*ng / mL). At the same time, some existing compounds are not metabolized in mice and may have safety issues such as in vivo accumulation toxicity. The compounds of the present application can still be metabolized normally under high exposure, and have lower in vivo accumulation toxicity and higher safety compared to existing compounds.

Claims

1. A compound represented by formula (I), its stereoisomer, its tautomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, X and Y are each independently selected from CR 0 or N, Z is a C1-C6 chain hydrocarbon group, W 2 , W 3 Each independently selected from C, CR 2 or N, W 1 Does not exist, CR 1 or N, W 4 Select from C or N, W 5 Selected from C=O, CR 3 or N, and when W 1 is not present or when W 5 When C=O, W 4 For N, represents an aromatic ring, Ring C is absent, an aromatic heterocycle, an unsaturated alicyclic heterocycle or an unsaturated alicyclic ring, Ring A is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic ring, an unsaturated alicyclic ring, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle. Ring B is selected from an aromatic ring, an aromatic heterocycle, a saturated alicyclic heterocycle, an unsaturated alicyclic heterocycle, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a cyclic ring consisting of an aromatic ring and an unsaturated alicyclic heterocycle, and a cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic heterocycle. m, n, and o are each independently selected from 0, 1, 2, 3, and 4, R A , R B , R 0 , R 1 , R 2 , R 3 each independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, in, The R 0 , R 1 , R 2 , R 3 , R A , R B , Ring C are each optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C1-C6 alkyl, C1-C6 alkoxy, The Z is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C1-C6 alkyl, C1-C6 alkoxy, 3-8-membered cycloalkyl, 3-8-membered heterocycloalkyl, The aromatic heterocycle, unsaturated aliphatic heterocycle and saturated aliphatic heterocycle each independently contain 1 to 4 heteroatoms; the heterocycloalkyl group contains 1 to 2 heteroatoms, and the heteroatoms are independently selected from N, O and S.

2. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The ring C does not exist, and W 2 , W 3 Each independently selected from CR 2 or N; or W 2 , W 3 are all selected from C, the ring C is a 5-membered aromatic heterocycle, preferably a 5-membered aromatic heterocycle containing 1 to 3 heteroatoms, more preferably an aromatic heterocycle containing 1 to 2 heteroatoms, the heteroatoms are selected from N, O, and S, and the ring C is optionally substituted by one or more of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano, ester, carboxyl, amide, =O, C1-C6 alkyl, and C1-C6 alkoxy.

3. The compound according to claim 1 or 2, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: W 1 Selected from CR 1 , W 2 , W 3 Selected from C or CR 2 , W 4 Selected from C, W 5 Selected from CR 3 .

4. The compound according to any one of claims 1 to 3, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The Z is selected from wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, and R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, aldehyde, amine, halogen, cyano, ester, carboxyl, amide, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl; or The Z is selected from Wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, and R is selected from 3-8 membered cycloalkyl and 3-8 membered heterocycloalkyl.

5. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The compound has a structure shown in formula (II), X and Y are each independently selected from CR 0 or N and not N at the same time, the R 0 is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, W 2 , W 3 are each independently selected from CH or N, W 1 Does not exist, CH or N, W 4 Select from C or N, W 5 is selected from C═O, CH or N, and when W 1 is not present or when W 5 When C=O, W 4 For N, R C Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, q is selected from 0, 1, 2, 3, Z is selected from wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, and R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, aldehyde, amine, halogen, cyano, ester, carboxyl, amide, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl; Preferably, the compound has any structure shown in formula (II-a) to (II-g), 6. The compound according to claim 1, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The compound has a structure shown in formula (III), X and Y are each independently selected from CR 0 or N and not N at the same time, the R 0 is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, W 1 Does not exist, CH or N, W 4 Select from C or N, W 5 is selected from C═O, CH or N, and when W 1 is not present or when W 5 When C=O, W 4 For N, V 1 、V 2 、V 3 are each independently selected from CH, N, NH, O, S, and V 1 、V 2 、V 3 Not at the same time CH, R C Each is independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, q is selected from 0, 1, 2, 3, Z is selected from wherein * is connected to ring B, p is selected from 0, 1, 2, 3, 4, and R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, aldehyde, amine, halogen, cyano, ester, carboxyl, amide, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl; Preferably, the W 1 , W 5 All CH, W 4 For C.

7. The compound according to claim 6, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The compound has any structure shown in formula (III-a) to (III-f), 8. The compound according to any one of claims 1 to 7, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The R 0 Selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, -COCH3, -COCH2CH3, -CO(CH2)2CH3 , -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl; and / or The R A Selected from deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl; and / or The R B selected from deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -C ONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy.

9. The compound according to any one of claims 4 to 7, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The R is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CON H2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxyn-propyl, 2-hydroxyn-propyl, 3-hydroxyn-propyl, preferably, R is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, and cyclopentyloxy.

10. The compound according to any one of claims 5 to 7, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The R C Selected from deuterium, tritium, nitro, hydroxyl, mercapto, fluorine, chlorine, bromine, iodine, cyano, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH2CH3)2, -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, -OC(O)CH(CH3)2, aldehyde, carboxyl, -COCH3, -COCH2CH3, -CO(CH2)2CH3, -COCH(CH3)2, -CONH2, -CONHCH3, -CON(CH3)2, -NHCOH, -NHCOCH3, -N(CH3)COCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, trifluoromethoxy, trifluoroethoxy, trichloromethoxy, trichloroethoxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl.

11. The compound according to any one of claims 1 to 7, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The ring A is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered saturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered paracyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring, wherein the aromatic heterocyclic ring contains 1-4 heteroatoms independently selected from N, O, and S, and the unsaturated alicyclic heterocyclic ring contains 1-2 heteroatoms independently selected from N, O, and S; preferably, the ring A is selected from and / or The ring B is selected from a 6-10 membered aromatic ring, a 5-10 membered aromatic heterocycle, a 3-14 membered saturated alicyclic ring, a 3-14 membered unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered cyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an unsaturated alicyclic ring, wherein the aromatic heterocycle contains 1-4 heteroatoms independently selected from N, O, and S, and the saturated alicyclic heterocycle and the unsaturated alicyclic heterocycle each contain 1-2 heteroatoms independently selected from N, O, and S; preferably, the ring B is selected from 12. The compound according to any one of claims 1 to 4, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: X and Y are each independently selected from CR 0 or N, R 0 is selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, fluorine, chlorine, bromine, amino and methyl; Z is C1-C6 alkylene, and Z is optionally substituted by any one of deuterium, tritium, nitro, hydroxyl, aldehyde, amine, imine, halogen, cyano or =O; W 2 , W 3 All are C, or W 2 , W 3 Each independently selected from CR 2 , each R 2 independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy; W 1 CR 1 or N, R 1 Selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C1-C6 alkyl and C1-C6 haloalkyl; W 4 is C; W 5 CR 3 , R 3 Selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C1-C6 alkyl, C1-C6 haloalkyl; represents an aromatic ring; Ring C is absent, a 5-6 membered aromatic heterocycle or a 5-6 membered unsaturated aliphatic heterocycle, and Ring C is optionally substituted by deuterium, tritium or C1-C6 alkyl; Ring A is selected from C6~C 10 Aromatic ring, 5-10 membered aromatic heterocyclic ring, C5-C 10 Saturated alicyclic, C5~C 10 Unsaturated alicyclic, C6~C 10 Aromatic ring and C5~C 10 Unsaturated alicyclic rings, 6-10 membered aromatic heterocyclic rings and C5-C 10 A fused ring consisting of unsaturated alicyclic rings; Ring B is selected from C6~C 10 Aromatic ring, 5-10 membered aromatic heterocyclic ring, C3-C 10 Saturated heterocyclic aliphatic ring, 5-10 membered unsaturated heterocyclic aliphatic ring, 5-10 membered aromatic heterocyclic ring and C5-C 10 Unsaturated alicyclic ring, C6~C 10 A fused ring consisting of an aromatic ring and a 5- to 10-membered unsaturated aliphatic heterocyclic ring; m, n, and o are each independently 0, 1, or 2; R A Selected from deuterium, tritium, hydroxyl, halogen, C1-C6 alkyl and C1-C6 haloalkyl; R B is selected from deuterium, tritium, hydroxyl, cyano, amine, C1-C6 alkyl and C1-C6 haloalkyl, R B optionally substituted with deuterium, tritium or halogen; The aromatic heterocycle, unsaturated aliphatic heterocycle, and saturated aliphatic heterocycle each independently contain 1 to 3 heteroatoms, and the heteroatoms are independently selected from N, O, and S; Preferably, X and Y are each independently selected from CR 0 or N and not both N and R 0 are each independently selected from hydrogen, deuterium and tritium, Z is selected from wherein * is connected to ring B, p is 0, 1 or 2, and R is selected from hydrogen, deuterium, tritium, hydroxyl, C1-C6 alkyl and C1-C6 hydroxyalkyl, W 2 , W 3 All are C, or W 2 , W 3 Each independently selected from CR 2 , each R 2 independently selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy and C1-C6 haloalkoxy, W 1 CR 1 or N, R 1 independently selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 haloalkyl, W 4 For C, W 5 CR 3 , R 3 independently selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl and C1-C6 haloalkyl, represents an aromatic ring, Ring C is a 5-6 membered aromatic heterocyclic ring without or with 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, and S, and the ring C is optionally substituted with deuterium, tritium, or C1-C6 alkyl, Ring A is selected from Ring B is selected from m, n, o are each 0, 1 or 2, R A is selected from deuterium, tritium, halogen, C1-C6 alkyl, and C1-C6 haloalkyl, R B Selected from deuterium, tritium, amine and C1-C6 alkyl.

13. The compound according to any one of claims 1 to 12, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, wherein: The compound is selected from:

14. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 13, its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, and at least one pharmaceutically acceptable excipient.

15. A compound, stereoisomer, tautomer or mixture thereof according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition according to claim 14 for use as a medicament; Preferably, the drug is a TEAD inhibitor; More preferably, the medicament is used to treat a disease or condition associated with increased TEAD expression or increased TEAD activity; Still more preferably, the drug is used to treat tumor cell proliferative diseases (such as mesothelioma tumor cell proliferative diseases, malignant pleural mesothelioma tumor cell proliferative diseases), inhibit tumor invasion and metastasis, reduce resistance to targeted drugs or chemotherapeutic drugs, reduce tumor immune escape, treat polycystic kidney disease or liver fibrosis; Even more preferably, the medicament is used to treat acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (e.g. monocytic, granulocytic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, undesirable Proliferative changes (dysplasia and metaplasia), embryonal carcinoma, endometrial carcinoma, endothelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid cancer, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, and breast cancer.

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