WO2024255856A1 - Composé pour réguler l'activité de tead, procédé de préparation associé et utilisation associée - Google Patents

Composé pour réguler l'activité de tead, procédé de préparation associé et utilisation associée Download PDF

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WO2024255856A1
WO2024255856A1 PCT/CN2024/099277 CN2024099277W WO2024255856A1 WO 2024255856 A1 WO2024255856 A1 WO 2024255856A1 CN 2024099277 W CN2024099277 W CN 2024099277W WO 2024255856 A1 WO2024255856 A1 WO 2024255856A1
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ring
membered
tritium
deuterium
aromatic
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Chinese (zh)
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王豪
周瑞捷
胡东杰
贾志强
陈泠颖
胡凯
李雪玉
易韬
王刚
刘青天
李建宗
李楠
王静
唐元清
张晓东
唐军
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Scinnohub Pharmaceutical Co Ltd
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Scinnohub Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00

Definitions

  • the present application relates to a compound for regulating TEAD activity, a preparation method and use 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 use thereof for preparing a drug, and belongs to the field of medicinal chemistry.
  • the Hippo signaling pathway is a highly conserved signaling pathway composed of a series of kinase cascades. It is involved in regulating physiological processes such as cell proliferation, cell differentiation, cell stemness, extracellular matrix deposition, damage repair, and organ development. It is an important pathway for cancer biogenesis and tumor maintenance. In many cancer indications, the Hippo signaling pathway is caused by the loss of protein function encoded by genes such as NF2, which leads to the overactivation of downstream co-transcriptional activators, including YAP (Yes Associated Protein) and TAZ (Transcriptional coactivator with PDZ-binding motif).
  • YAP includes multiple domains and specific amino acid sequences, 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 domains and functions to YAP, but lacks the proline-rich domain and the second WW domain.
  • Overactivated YAP/TAZ translocates to the 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.
  • CTGF Connective tissue growth factor
  • Cyr61 Mysteine rich angiogenic inducer 61
  • AXL AXL receptor tyrosine kinase
  • TEADs/TEAD transcription enhancer associated domain
  • the human TEAD family transcription factors include 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 the YAP/TAZ-binding domain are highly conserved in mammals, but they differ greatly 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.
  • YAP/TAZ can promote the survival of tumor stem cells, and is closely related to tumor cell metastasis and drug resistance, promoting the occurrence and development of various tumors.
  • chemotherapy drug treatment anti-microtubule drugs, anti-metabolism drugs, and DNA damaging agents can affect the Hippo signaling pathway, leading to YAP/TAZ activation and transcription, thereby producing drug resistance.
  • YAP/TAZ can cause the high expression of various drug transporters, which can transfer drugs to the extracellular space, leading to the upregulation of anti-apoptotic proteins such as Bcl and survivin, thereby inhibiting cell apoptosis.
  • Many studies have shown that the activation of YAP/TAZ caused by the downregulation of the Hippo pathway is the main mechanism of multiple targeted drug resistance; YAP/TAZ activation is not only related to drug resistance, but studies have shown that YAP gene amplification is also associated with the recurrence of colon cancer and pancreatic cancer.
  • YAP/TAZ-TEADs have a significant promoting effect on tumor development.
  • cancers such as malignant mesothelioma, ovarian cancer, and cholangiocarcinoma
  • the YAP/TAZ-TEADs complex is often overactivated or overexpressed, leading to the deterioration and development of cancer. This overactivation is usually caused by changes in upstream genes of the Hippo signaling pathway.
  • 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.
  • EMT epithelial to mesenchymal transition
  • YAP/TAZ-TEADs can induce tumor cells to develop resistance to chemotherapeutic drugs such as paclitaxel.
  • YAP/TAZ-TEADs has become an alternative survival pathway for drug-resistant cancer cells.
  • inhibiting the interaction between YAP/TAZ and TEADs has the potential to be anti-tumor and treat tumors, especially tumors with overactivation or mutations in the upstream of the Hippo signaling pathway. Inhibition of the interaction between YAP/TAZ and TEADs is a promising new tumor therapy.
  • 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, and They interact with each other, inhibit the proliferation of tumor cells (such as mesothelioma tumor cells, malignant pleural mesothelioma tumor cells, etc.), inhibit the invasion and metastasis of tumors, reduce the resistance of targeted drugs or chemotherapy drugs, and reduce the immune escape of tumors, thereby achieving the effect of treating tumors.
  • tumor cells such as mesothelioma tumor cells, malignant pleural mesothelioma tumor cells, etc.
  • 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.
  • the present application provides a compound represented by formula (I), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,
  • X and Y are each independently selected from CR 0 or N,
  • Z is a C 1 to C 6 chain hydrocarbon group
  • W 2 and W 3 are each independently selected from C, CR 2 or N,
  • W1 is absent, CR1 or N
  • W4 is selected from C or N
  • Ring C is absent, an aromatic ring, an aromatic heterocyclic ring, an unsaturated alicyclic ring or an unsaturated alicyclic heterocyclic 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.
  • n, and o are each independently selected from 0, 1, 2, 3, and 4,
  • R A , R B , R 0 , R 1 , R 2 , and R 3 are each independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy,
  • 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.
  • ring C is absent, an aromatic ring, an aromatic heterocycle, an unsaturated alicyclic ring, or an unsaturated alicyclic heterocycle.
  • the ring C does not exist or is a 5-10-membered aromatic heterocycle, preferably a 5-6-membered aromatic heterocycle.
  • the ring C does not exist, and W 2 and W 3 are each independently selected from CR 2 or N, and the definition of R 2 is consistent with the above;
  • W 1 is selected from CR 1
  • W 2 and W 3 are simultaneously selected from C or CR 2
  • W 4 is selected from C
  • W 5 is selected from CR 3
  • R 1 , R 2 , and R 3 are consistent with the above definitions;
  • W 1 is selected from CR 1 or N
  • W 2 and W 3 are simultaneously selected from C or W 2 and W 3 are each independently selected from CR 2
  • W 4 is selected from C
  • W 5 is selected from CR 3
  • R 1 , R 2 , and R 3 are consistent with the above definitions;
  • W 1 is CR 1 or N
  • R 1 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C 1 ⁇ C 6 alkyl and C 1 ⁇ C 6 haloalkyl (preferably, R 1 is selected from hydrogen, deuterium, tritium and C 1 ⁇ C 6 alkyl);
  • W 2 and W 3 are both selected from C or are independently selected from CR 2 , and each R 2 is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1 ⁇ C 6 alkoxy and C 1 ⁇ C 6 haloalkoxy (preferably, W 2 and W 3 are both selected from C; or W 2 is selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C 1 ⁇ C 6 alkyl and C 1
  • W 1 is CR 1
  • R 1 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C 1 ⁇ C 6 alkyl and C 1 ⁇ C 6 haloalkyl (preferably, R 1 is selected from hydrogen, deuterium, tritium and C 1 ⁇ C 6 alkyl);
  • W 2 and W 3 are each independently selected from CR 2 , and each R 2 is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1 ⁇ C 6 alkoxy and C 1 ⁇ C 6 haloalkoxy (preferably, W 2 is selected from CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1
  • 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, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 haloalkyl , C 1 ⁇ C 6 haloalkoxy, C 1 ⁇ C 6 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;
  • the ring A is selected from a 6- to 10-membered aromatic ring (also referred to as a C 6 -C 10 aromatic ring), a 5- to 10-membered aromatic heterocyclic ring, a 3- to 14-membered saturated alicyclic ring (also referred to as a C 3 -C 14 saturated alicyclic ring), a 3- to 14-membered unsaturated alicyclic ring (also referred to as a C 3 -C 14 unsaturated alicyclic ring), a 3- to 14-membered unsaturated alicyclic heterocyclic ring, a 7- to 14-membered cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring, a 7- to 14-membered cyclic ring composed of an aromatic heterocyclic ring and an unsaturated alicyclic ring, and a 3- to 14-membered unsaturated alicyclic ring.
  • 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 7-14-membered cyclic ring composed of an aromatic ring and an unsaturated alicyclic ring, and a 7-14-membered cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring; more preferably, the ring A is selected from a 6-10-membered aromatic ring, a 5-10-membered aromatic heterocycle, and a 7-14-membered cyclic ring composed of an aromatic heterocycle and an unsaturated alicyclic ring;
  • the ring A is selected from a C 6 -C 10 aromatic ring, a 5- to 10-membered aromatic heterocycle, a C 5 -C 10 saturated alicyclic ring, a C 5 -C 10 unsaturated alicyclic ring, a C 6 -C 10 aromatic ring and a C 5 -C 10 unsaturated alicyclic ring, and a C 6 -C 10 aromatic ring and a C 5 -C 10 unsaturated alicyclic ring.
  • the ring A is selected from a C 6 -C 10 aromatic ring, a 6 -10-membered aromatic heterocycle, a C 5 -C 8 saturated alicyclic ring, and a C 6 aromatic ring and a C 5 -C 6 unsaturated alicyclic ring, and the aromatic heterocycle contains 1 to 3 (preferably 1 to 2) heteroatoms independently selected from N, O, and S. More preferably, ring A is selected from benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, pyrimidine (eg ring A is selected from benzene ring, indane, pyridine, cyclohexane).
  • 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, 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 heterocycle and an unsaturated alicyclic ring, and a 7-14 membered cyclic ring consisting of an aromatic heterocycle and an
  • the aromatic heterocycle contains 1 to 4 heteroatoms independently selected from N, O, and S, and the unsaturated aliphatic heterocycle and the 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 the saturated aliphatic heterocycle each contain 1 heteroatom independently selected from N, O, and S.
  • the ring B is selected from a C 6 -C 10 aromatic ring, a 5-10 membered aromatic heterocycle, a C 3 -C 10 saturated alicyclic ring, a 5-10 membered unsaturated alicyclic ring, a cyclic ring formed by a 5-10 membered aromatic heterocycle and a C 5 -C 10 unsaturated alicyclic ring, and a cyclic ring formed by a C 6 -C 10 aromatic ring and a 5-10 membered unsaturated alicyclic ring; preferably, ring B is a 5-10 membered aromatic heterocycle or a C 4 -C 8 saturated alicyclic ring, and the aromatic heterocycle, unsaturated alicyclic ring, and saturated alicyclic ring each contain 1 to 3 (preferably 1 to 2) heteroatoms independently selected from N, O, and S.
  • Ring B is selected from pyridine, pyrazole, pyrazine, pyrimidine, tetrahydropyran, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, piperidine, oxazole, isoxazole, indazole and azetidine (e.g., Ring B is selected from pyridine, pyrazole, pyrazine, piperidine, oxazole, isoxazole, indazole and azetidine).
  • the ring A is selected from a benzene ring, a cyclohexane, a bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1 to 4 (preferably 1 to 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 to 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 to 4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1 to 2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1 to 2 heteroatoms,
  • n, o are each independently selected from 0, 1 or 2.
  • RA is selected from deuterium, tritium, hydroxyl, halogen, C1 ⁇ C6 alkyl, C1 ⁇ C6 haloalkoxy and C1 ⁇ C6 haloalkyl; preferably, RA is selected from deuterium, tritium, halogen, C1 ⁇ C6 alkyl and C1 ⁇ C6 haloalkyl; more preferably, RA is deuterium, tritium, methyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, trichloromethyl, trichloromethoxy, tribromomethoxy or tribromomethyl.
  • RB 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, RB is deuterium, tritium, methyl, ethyl, propyl or -NH2 ; RB is optionally substituted by deuterium, tritium, or halogen.
  • the present application also provides a compound represented by formula (II), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,
  • X and Y are each independently selected from CR 0 or N and are not N at the same time, and the R 0 is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 halogen alkyl, C 1 -C 6 hydroxyalkyl,
  • W 2 and W 3 are each independently selected from CH or N,
  • W1 is absent, CH or N
  • W4 is selected from C or N
  • R and C are each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 haloalkoxy, C 1 ⁇ C 6 hydroxyalkyl, q is selected from 0, 1, 2, 3,
  • Ring A is selected from aromatic rings, aromatic heterocycles, saturated alicyclic rings, unsaturated alicyclic rings, unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, and cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings;
  • Ring B is selected from aromatic rings, aromatic heterocyclic rings, saturated alicyclic rings, unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, and cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings;
  • the aromatic heterocyclic rings, unsaturated alicyclic rings, and saturated alicyclic rings each independently contain 1 to 4 heteroatoms, and the heteroatoms
  • 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 heterocycle and an 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 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 heterocycle and
  • 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 paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an 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 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 heterocycle and an
  • the ring A is selected from a benzene ring, a cyclohexane, a bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1 to 4 (preferably 1 to 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 to 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 to 4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1 to 2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1 to 2 heteroatoms,
  • the compound represented by formula (II) provided in the present application has any structure represented by the following formula (II-a) to (II-g), its stereoisomer, its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its prodrug,
  • the present application also provides a compound represented by formula (III), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,
  • X and Y are each independently selected from CR 0 or N and are not N at the same time, and the R 0 is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 haloalkoxy, C 1 ⁇ C 6 hydroxyalkyl,
  • W1 is absent, CH or N
  • W4 is selected from C or N
  • V 1 , V 2 , and V 3 are each independently selected from CH, N, NH, O, and S, and V 1 , V 2 , and V 3 are not CH at the same time,
  • R and C are each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, halogen, cyano, amine, ester, aldehyde, carboxyl, carbonyl, amide, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 haloalkoxy, C 1 ⁇ C 6 hydroxyalkyl, q is selected from 0, 1, 2, 3,
  • Ring A is selected from aromatic rings, aromatic heterocycles, saturated alicyclic rings, unsaturated alicyclic rings, unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, and cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings;
  • Ring B is selected from aromatic rings, aromatic heterocyclic rings, saturated alicyclic rings, unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, cyclic rings consisting of aromatic rings and unsaturated alicyclic rings, and cyclic rings consisting of aromatic heterocyclic rings and unsaturated alicyclic rings;
  • the aromatic heterocyclic rings, unsaturated alicyclic rings, and saturated alicyclic rings each independently contain 1 to 4 heteroatoms, and the heteroatoms
  • W 1 and W 5 are both CH, and W 4 is C.
  • 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 heterocycle and an 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 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 heterocycle and
  • 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 paracyclic ring consisting of an aromatic ring and an unsaturated alicyclic ring, a 7-14 membered paracyclic ring consisting of an aromatic heterocycle and an 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 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 heterocycle and an
  • the ring A is selected from a benzene ring, a cyclohexane, a bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocycle containing 1 to 4 (preferably 1 to 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 to 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 to 4 heteroatoms, a 3-10 membered saturated alicyclic ring containing 1 to 2 heteroatoms, and a 3-10 membered unsaturated alicyclic ring containing 1 to 2 heteroatoms,
  • the compound represented by formula (III) provided in the present application has any structure represented by the following formula (III-a) to (III-f), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its prodrug,
  • the present application also provides a compound represented by formula (IV), its stereoisomer, its tautomer or a mixture thereof, or its pharmaceutically acceptable salt, or its solvate (such as a hydrate), or its prodrug,
  • V 4 and V 5 are each independently CH or N, and V 4 and V 5 are not CH at the same time.
  • the compound represented by formula (IV) provided in the present application is selected from the compounds represented by formula (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.
  • 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.
  • the R 0 is selected from hydrogen, deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine, cyano, aldehyde, carboxyl, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)O(CH 2 ) 2 CH 3 , -C(O)OCH(CH 3 ) 2 , -OC(O)CH 3 , -OC(O)CH 2 CH 3 , -OC(O)(CH 2 CH 3 , -OC(O)(CH 2 CH 3 , -OC(O)(CH 2 CH 3 , -OC(O)(CH 2 CH 3 , -OC(O)(CH 2 CH 3 , -OC(O)
  • the RA and RB are each independently selected from deuterium, tritium, nitro, hydroxyl, thiol, fluorine, chlorine, bromine, iodine , cyano , -NH2, -NHCH3 , -N( CH3 ) 2 , -NHCH2CH3 , -N ( CH2CH3 ) 2
  • 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 .
  • the RC is 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
  • 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 their mixtures, or A pharmaceutically acceptable salt thereof, or a solvate thereof (e.g., a hydrate), or a prodrug thereof, wherein in certain embodiments, the ring A is selected from a benzene ring, cyclohexane, bicyclo[1,1,1]pentane, a 5-10 membered aromatic heterocyclic ring containing 1-3 (preferably 1-2) heteroatoms, an 8-12 membered cyclic ring consisting of a benzene ring and an
  • 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 their mixtures, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs.
  • 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, and the heteroatoms are each independently selected from N, O, and S.
  • the ring B is selected from Preferably, the ring B is selected from a 5- to 10-membered aromatic heterocycle containing 1 to 3 heteroatoms, a 3- to 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
  • 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.
  • X and Y are each independently selected from N, CH, CCH 3 , CCl, CCN, CCF 3 , 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, C 1 to C 6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), C 1 to C 6 hydroxyalkyl (e.g., hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, etc.)
  • the RA is selected from halogen (e.g., fluorine, chlorine, bromine), C 1 to C 6 haloalkyl (e.g., trifluoromethyl), C 1 to C 6 haloalkoxy (e.g., trifluoromethoxy)
  • the RB is selected from halogen (e.g., fluorine, chlorine, bromine), C 1 to C 6 6 alkyl (e
  • 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 their mixtures, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs.
  • ring B is selected from a 5-10 membered aromatic heterocycle containing 1 to 3 heteroatoms (e.g., the ring B is selected from More preferably, the ring B is selected from ),
  • 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 consisting of an aromatic ring and an unsaturated alicyclic ring, and a 7- to 10-membered cyclic ring consisting of an aromatic heterocyclic ring and an unsaturated alicyclic ring (for example, Ring A is selected from ).
  • X, 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 is selected from hydrogen, deuterium and tritium;
  • Ring A is selected from a C 6 ⁇ C 10 aromatic ring, a 5-10 membered aromatic heterocycle, a C 5 ⁇ C 10 saturated alicyclic ring, a C 5 ⁇ C 10 unsaturated alicyclic ring, a C 6 ⁇ C 10 aromatic ring and a C 5 ⁇ C 10 unsaturated alicyclic ring, and a C 6 ⁇ C 10 unsaturated alicyclic ring (preferably, Ring A is selected from a C 6 ⁇ C 10 aromatic ring, a 6-10 membered aromatic heterocycle, a C 5 ⁇ C 8 saturated alicyclic ring, and a C 6 aromatic ring and a C 5 ⁇ C 6 unsaturated alicyclic ring. More preferably, Ring A is selected from a benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, and pyrimidine);
  • Ring B is selected from a C 6 ⁇ C 10 aromatic ring, a 5 ⁇ 10 membered aromatic heterocycle, a C 3 ⁇ C 10 saturated alicyclic heterocycle, a 5 ⁇ 10 membered unsaturated alicyclic heterocycle, a 5 ⁇ 10 membered aromatic heterocycle and a C 5 ⁇ C 10 unsaturated alicyclic ring, a C 6 ⁇ C 10 aromatic ring and a 5 ⁇ 10 membered unsaturated alicyclic heterocycle (preferably, Ring B is a 5 ⁇ 10 membered aromatic heterocycle or a C 4 ⁇ C 8 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, benz
  • o 0, 1 or 2 (preferably, o is 0);
  • n 0, 1 or 2 (preferably, m is 0 or 1);
  • n 0, 1 or 2 (preferably, n is 0 or 1);
  • RA is selected from deuterium, tritium, hydroxyl, halogen, C1 - C6 alkyl, C1 -C6 haloalkoxy and C1 - C6 haloalkyl (preferably, RA is selected from deuterium, tritium, halogen , C1 - C6 alkyl, C1 - C6 haloalkoxy and C1 - C6 haloalkyl; more preferably, RA is deuterium, tritium, fluorine, chlorine, bromine, trifluoromethyl, trichloromethyl, tribromomethyl, trifluoromethoxy, trichloromethoxy or tribromomethoxy);
  • RB 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, RB is hydrogen, deuterium, tritium, methyl, ethyl, propyl or -NH2 ), RB is optionally substituted by 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.
  • X, 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 is selected from hydrogen, deuterium and tritium;
  • W 2 and W 3 are both C, or W 2 and W 3 are each independently selected from CR 2 , and each R 2 is independently selected from hydrogen, deuterium, tritium, nitro, hydroxyl, mercapto, halogen, cyano, amine, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl, C 1 to C 6 alkoxy and C 1 to C 6 haloalkoxy (preferably, W 2 is selected from C or CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, cyano, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl, C 1 to C 6 alkoxy and C 1 to C 6 haloalkoxy; W 3 is selected from C or CR 2 , R 2 is selected from hydrogen, deuterium, tritium, halogen, C 1 to C 6 alkyl, C 1 to C 6 haloalkyl, C 1 to C 6 alkoxy and C 1 to C 6
  • W 1 is CR 1 or N, R 1 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C 1 ⁇ C 6 alkyl and C 1 ⁇ C 6 haloalkyl (preferably, R 1 is selected from hydrogen, deuterium, tritium and C 1 ⁇ C 6 alkyl);
  • W 5 is CR 3 , R 3 is selected from hydrogen, deuterium, tritium, hydroxyl, halogen, amine, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl (preferably, R 3 is selected from hydrogen, deuterium, tritium, halogen and C 1 ⁇ C 6 alkyl);
  • 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 C 1 -C 6 alkyl;
  • Ring A is selected from a C 6 ⁇ C 10 aromatic ring, a 5-10 membered aromatic heterocycle, a C 5 ⁇ C 10 saturated alicyclic ring, a C 5 ⁇ C 10 unsaturated alicyclic ring, a C 6 ⁇ C 10 aromatic ring and a C 5 ⁇ C 10 unsaturated alicyclic ring, and a C 6 ⁇ C 10 unsaturated alicyclic ring (preferably, Ring A is selected from a C 6 ⁇ C 10 aromatic ring, a 6-10 membered aromatic heterocycle, a C 5 ⁇ C 8 saturated alicyclic ring, and a C 6 aromatic ring and a C 5 ⁇ C 6 unsaturated alicyclic ring. More preferably, Ring A is selected from a benzene ring, indane, pyridine, cyclohexane, bicyclo[1,1,1]pentyl, and pyrimidine);
  • Ring B is selected from a C 6 -C 10 aromatic ring, a 5-10 membered aromatic heterocycle, a C 3 -C 10 saturated aliphatic heterocycle, a 5-10 membered unsaturated aliphatic heterocycle, a 5-10 membered aromatic heterocycle and a C 5 -C 10 unsaturated aliphatic heterocycle, and a C 6 -C 10 aromatic ring and a 5-10 membered unsaturated aliphatic heterocycle (preferably, Ring B is a 5-10 membered aromatic heterocycle or a C 4 -C 8 saturated aliphatic heterocycle, more preferably, Ring B is a 5-10 membered aromatic heterocycle containing 1 to 3 heteroatoms selected from N, O, and S.
  • Ring B is preferably selected from pyridine, pyrazole, pyrazine, pyrimidine, tetrahydropyran, imidazole, thiazole, pyridoimidazole, pyridopyrazole, benzimidazole, quinoline, piperidine, oxazole, isoxazole, pyrimidine, indazole, and azetidine);
  • o 0, 1 or 2 (preferably, o is 0);
  • n 0, 1 or 2 (preferably, m is 0 or 1);
  • n 0, 1 or 2 (preferably, n is 0 or 1);
  • RA is selected from deuterium, tritium, hydroxyl, halogen, C1 - C6 alkyl and C1 - C6 haloalkyl (preferably, RA is selected from deuterium, tritium, halogen, C1 - C6 alkyl and C1 - C6 haloalkyl; more preferably, RA is deuterium, tritium, fluorine, chlorine, bromine, trifluoromethyl, trichloromethyl or tribromomethyl);
  • RB is selected from deuterium, tritium, hydroxyl, cyano, amine, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl (preferably, RB is selected from deuterium, tritium, amine and C 1 -C 6 alkyl; more preferably, RB is deuterium, tritium, methyl, ethyl, propyl or -NH 2 ), RB is optionally substituted by deuterium, tritium or halogen;
  • 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.
  • X, Y are each independently selected from CR 0 or N and are not N at the same time, 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, C 1 ⁇ C 6 alkyl and C 1 ⁇ C 6 hydroxyalkyl,
  • W 2 and W 3 are both selected from C, or W 2 and W 3 are each independently CR 2 , and each R 2 is independently selected from hydrogen, deuterium, tritium, halogen, cyano, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 haloalkyl, C 1 ⁇ C 6 alkoxy and C 1 ⁇ C 6 haloalkoxy,
  • W 1 is CR 1 or N, R 1 is independently selected from hydrogen, deuterium, tritium, halogen, C 1 ⁇ C 6 alkyl and C 1 ⁇ C 6 haloalkyl,
  • W 5 is CR 3 , R 3 is independently selected from hydrogen, deuterium, tritium, halogen, C 1 ⁇ C 6 alkyl and C 1 ⁇ C 6 haloalkyl,
  • Ring C is a 5-6 membered aromatic heterocyclic ring without or containing 1-2 heteroatoms, wherein the heteroatoms are selected from N, O, and S, and the ring C is optionally substituted by deuterium, tritium, or C 1 -C 6 alkyl.
  • Ring A is selected from (Preferred ),
  • Ring B is selected from (Preferred ),
  • n, o are each 0, 1 or 2 (preferably, o is 0, m is 0 or 1, and n is 0 or 1),
  • RA is selected from deuterium, tritium, halogen, C1 - C6 alkyl and C1 - C6 haloalkyl,
  • RB is selected from deuterium, tritium, an amine group and a C1 - C6 alkyl group.
  • the present application provides the compounds shown below, their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates (e.g., hydrates), or their prodrugs,
  • Another object of the present application is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the aforementioned compounds, their stereoisomers, their tautomers or their mixtures, or their pharmaceutically acceptable salts, or their solvates, or their prodrugs, and at least one pharmaceutically acceptable excipient.
  • Another object of the present application is to provide a use of the aforementioned compound, its stereoisomer, or its tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or a pharmaceutical composition for the preparation of a drug.
  • the drug is a TEAD inhibitor, which can be used to treat diseases associated with increased levels of unwanted TEAD activity.
  • the present application provides a aforementioned compound, or its stereoisomer, tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or a pharmaceutical composition for use as a drug (preferably a TEAD inhibitor).
  • the present application provides a method for treating or preventing a TEAD-related disease, comprising administering the aforementioned compound, or its stereoisomer, tautomer or its mixture form, or its pharmaceutically acceptable salt, or its solvate, to a subject in need thereof. Or its prodrug, or pharmaceutical composition.
  • the TEAD-related disease herein refers to a disease or its complications that can achieve clinically beneficial effects such as alleviation, improvement, cessation of progression, alleviation or no longer deterioration by inhibiting TEAD.
  • 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 other genes. In certain embodiments, the drug or method is used to treat a disease associated with a mutation or inactivation of the Hippo pathway.
  • 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 the resistance of targeted drugs or chemotherapeutic drugs, reduce the immune escape of tumors, 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,
  • 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 a straight chain or a branched chain.
  • the C 1 -C 6 chained hydrocarbon group used in the present application refers to a straight chained hydrocarbon group or a branched chained hydrocarbon group consisting of 1 to 6 (e.g., 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, -CH 2 -, -CHCH 3 -, -CHCH 2 CH 3 -, -CHCH(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, etc.
  • Alkyl is a type of 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.
  • C1 - C6 alkyl used in this application refers to a straight-chain alkyl or branched-chain alkyl composed of 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned 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, etc.
  • Alkylene is a type of saturated aliphatic chain hydrocarbon group, including straight-chain alkylene and branched-chain alkylene, and refers to a group formed by removing two hydrogen atoms from an alkane molecule, wherein the missing hydrogen atoms may be connected to the same carbon atom or to different carbon atoms.
  • the C 1 -C 6 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 aforementioned values) carbon atoms.
  • Typical alkylene includes, but is not limited to, -CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -CH[CH(CH 3 ) 2 ]-, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, etc.
  • Alkoxy refers to -O-alkyl
  • C1 - C6 alkoxy used in the present application refers to a straight chain alkoxy or branched alkoxy 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, isopentyloxy, tert-pentyloxy, n-hexyloxy, and the like.
  • Halogen or halo refers to fluorine, chlorine, bromine or iodine.
  • 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 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the foregoing values) carbon atoms, 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 wait.
  • 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 group or a branched chain alkoxy group consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms, 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.
  • Hydroalkyl means that any one hydrogen in an alkyl group is replaced by a hydroxyl group.
  • the C1 - C6 hydroxyalkyl used in this application refers to a straight-chain alkyl or branched alkyl group consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms, and any one hydrogen on the alkyl group is replaced by a hydroxyl group.
  • Common hydroxyalkyl groups include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-n-propyl, 2-hydroxy-n-propyl, 3-hydroxy-n-propyl, 2-hydroxyisopropyl, 4-hydroxy-n-butyl, and the like.
  • Ring refers to any cyclic covalently closed structure, including, for example, carbocycle (e.g., aromatic ring or alicyclic ring), heterocycle (e.g., aromatic heterocycle or alicyclic heterocycle).
  • Carbocycle refers to a ring consisting of only carbon atoms
  • heterocycle refers to a closed structure formed by covalent bonding of carbon atoms and heteroatoms.
  • a "ring” can be a monocyclic, bicyclic, tricyclic or polycyclic ring. When the ring is bicyclic, tricyclic or polycyclic, the relationship between the rings may include fused rings, spirocyclic rings, and bridged rings.
  • 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.
  • “Member” refers to the number of atoms constituting 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, benzene, and the like.
  • Alicyclic ring or “alicyclic group” refers to a saturated or partially unsaturated aliphatic carbocyclic group.
  • a saturated aliphatic carbocyclic ring is called, for example, a saturated alicyclic ring, and may also be called a "cycloalkyl group”; a partially unsaturated carbocyclic ring may be called, for example, an unsaturated alicyclic ring.
  • An alicyclic ring may be a monocyclic ring, a spirocyclic ring, a fused ring, or a bridged ring.
  • a 3- to 14-membered alicyclic ring refers to an aliphatic carbocyclic group consisting of 3 to 14 backbone carbon atoms.
  • “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 foregoing values) saturated carbon atoms.
  • Typical saturated alicyclic rings include but are not limited to wait.
  • Unsaturated alicyclic ring is an aliphatic cyclic group composed of saturated carbon atoms and unsaturated carbon atoms as a skeleton.
  • 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 foregoing values) carbon atoms and unsaturated carbon atoms as a skeleton structure.
  • Typical unsaturated alicyclic rings include but are not limited to wait.
  • Aliphatic heterocycle or "aliphatic heterocyclic group” refers to a non-aromatic cyclic group formed by replacing carbon atoms in an alicyclic ring with one or more heteroatoms.
  • Aliphatic heterocycles or aliphatic heterocyclic groups may include saturated aliphatic heterocycles and unsaturated aliphatic heterocycles.
  • a 3-14-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) skeleton atoms, and may be a saturated aliphatic heterocyclic group or an unsaturated aliphatic heterocyclic group.
  • saturated heterocyclic alicyclic ring is also called “heterocycloalkyl”, which means that the carbon atoms constituting the ring skeleton of the heterocyclic alicyclic ring are all saturated.
  • the 3-14-membered saturated heterocyclic alicyclic ring used in this application refers to a 3-14-membered saturated heterocyclic alicyclic ring (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
  • Typical saturated heterocyclic rings include but are not limited to:
  • Unsaturated heterocyclic ring or “unsaturated heterocyclic group” refers to a non-aromatic cyclic structure containing some unsaturated carbon atoms as the ring skeleton in the heterocyclic ring.
  • “unsaturated heterocyclic ring” refers to the presence of unsaturated carbon atoms in the skeleton constituting the heterocyclic ring.
  • the 3-14-membered unsaturated heterocyclic ring 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 heterocyclic rings include but are not limited to wait.
  • Aromatic ring or “aryl group” 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 ⁇ electron system and contains 4n+2 ⁇ electrons, where n is an integer.
  • the aromatic ring can be composed of six, eight, ten or more carbon atoms, and 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, and the like.
  • the 6-10 membered aromatic ring or 6-10 membered aryl group used in this application refers to an aromatic ring group composed of 6 to 10 (e.g., 6, 7, 8, 9, 10 or a range consisting of any two of the foregoing values) skeleton carbon atoms.
  • Aromatic heterocycle or “heteroaryl” refers to an aromatic cyclic structure formed by replacing carbon atoms in an aromatic ring with one or more heteroatoms.
  • the 5-10 membered aromatic heterocycle or 5-10 membered heteroaryl used in this application refers to an aromatic cyclic group containing heteroatoms composed of 5-10 (e.g., 5, 6, 7, 8, 9, 10 or a range consisting of any two of the foregoing values) backbone atoms.
  • Typical aromatic heterocycles or heteroaryl groups include, but are not limited to: wait.
  • Aromatic ring refers to a group with aromatic properties formed by the cyclic skeleton relying on the substituents on the ring as a whole, and its planar ring has a delocalized ⁇ electron system and contains 4n+2 ⁇ electrons.
  • pyridone is an "aromatic ring" group.
  • Cyclic ring refers to a cyclic structure formed by sharing two adjacent ring atoms between rings. Cyclic rings can be bicyclic, tricyclic or polycyclic.
  • a ring formed by an aromatic ring and an unsaturated alicyclic ring refers to a ring structure formed by the aromatic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms.
  • a ring formed by an aromatic ring and an unsaturated alicyclic ring refers to a ring structure formed by the aromatic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms.
  • a ring formed by an aromatic heterocyclic ring and an unsaturated alicyclic ring refers to a ring structure formed by the aromatic heterocyclic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms.
  • a ring formed by an aromatic heterocyclic ring and an unsaturated alicyclic ring refers to a ring structure formed by the aromatic heterocyclic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms.
  • a 7-14-membered ring formed by an aromatic ring and an unsaturated alicyclic ring refers to a 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 the aromatic ring and the unsaturated alicyclic ring sharing two adjacent ring atoms.
  • a 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.
  • a 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 ring and the aromatic heterocycle sharing two adjacent ring atoms.
  • 7- to 14-membered cyclic rings formed by aromatic rings and unsaturated alicyclic rings refers to cyclic ring structures with 7 to 14 (e.g., 7, 8, 9, 10, 11, 12, 13, 14 or a range consisting of any two of the foregoing) skeleton ring atoms formed by unsaturated alicyclic rings and aromatic rings sharing two adjacent ring atoms.
  • Common cyclic rings formed by aromatic rings and unsaturated alicyclic rings include but are not limited to etc.
  • 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:
  • “Amine” or “amine” refers to a chemical structure having -NR S R T , wherein RS , RT are each independently selected from hydrogen, deuterium, tritium, alkyl , cycloalkyl .
  • Common "amine” includes but is not limited to -NH2 , -NHCH3 , -N( CH3 ) 2 , -NHCH2CH3 , -N( CH2CH3 ) 2 .
  • Carbonyl refers to a chemical structure having -COR Z , wherein R Z is selected from alkyl, cycloalkyl, heterocycloalkyl. Common carbonyls include, but are not limited to, -COCH 3 , -COCH 2 CH 3 , -CO(CH 2 ) 2 CH 3 , and -COCH(CH 3 ) 2 .
  • Amide or “amide group” refers to a chemical structure having -C(O) NRUR or -NRUC (O) RV , wherein R U and RV are each 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 .
  • Aminoalkyl refers to a group in which any hydrogen in an alkyl group is replaced by an amino group.
  • the C1 - C6 aminoalkyl used in this application refers to a straight-chain or branched alkyl group consisting 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, and any hydrogen 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 , -CH2N ( CH2CH3 ) 2 , etc.
  • Acylamide alkyl refers to a group in which any hydrogen in an alkyl group is replaced by an amide group.
  • the C 1 -C 6 acylamide alkyl used in this application refers to a straight chain alkyl or branched chain alkyl consisting of 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6, or a range consisting of any two of the aforementioned values) carbon atoms, and any hydrogen on the alkyl group is replaced by an amide group.
  • Common acylamide alkyl groups include but are not limited to -CH 2 NHCOCH 3 , -CH 2 CONH 2 , etc.
  • Ester group refers to a chemical structure having the formula -C(O)OR a or -OC(O)R b , wherein Ra and R b are selected from alkyl, cycloalkyl, and heterocycloalkyl groups.
  • Common ester groups include, but are not limited to, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)O(CH 2 ) 2 CH 3 , -C(O)OCH(CH 3 ) 2 , -OC(O)CH 3 , -OC(O)CH 2 CH 3 , -OC(O)(CH 2 ) 2 CH 3 , and -OC(O)CH(CH 3 ) 2 .
  • Replacement refers to that one or more hydrogen atoms in a group are replaced by a corresponding number of substituents independently of one another. It goes without saying that substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible replacements without making too much effort.
  • amino or hydroxyl with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.
  • Inhibitor refers to a substance that reduces the activity of an enzyme.
  • 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 or does not occur.
  • “optionally substituted” includes substitution or non-substitution
  • “heterocyclic group optionally substituted with alkyl” means that alkyl may but need not be present, and the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and 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, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, and are compatible with the intended use. The benefit/risk ratio is commensurate with the treatment.
  • salts with organic bases 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.
  • Tautomers or “tautomeric forms” refer to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • 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 by reorganization of some of the bonding electrons.
  • Non-limiting examples of tautomers include, but are not limited to,
  • Stepoisomers 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, including cis-trans isomers and chiral isomers. Chiral isomers include two major categories: enantiomers and diastereomers.
  • 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 stereoisomers that are mirror images of each other and cannot be superimposed.
  • 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 real-life mirror-image relationship with each other.
  • a straight covalent bond "—" in a compound structure may represent being in the same plane as the paper.
  • the straight covalent bond represents 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 various arrangements.
  • the present application also provides a method for synthesizing the above-mentioned compounds.
  • the method for synthesizing the present application is mainly based on the preparation methods reported in chemical literature or using commercially available chemical reagents as starting materials for related synthesis.
  • Step 1) the compound represented by formula (i-a) is subjected to a condensation reaction with the compound represented by formula (i-d) under the action of a condensation agent (e.g., diethyl azodicarboxylate) to obtain a compound represented by formula (i-b);
  • Step 2) the compound represented by formula (i-b) is subjected to borylation reaction with a borylation agent (e.g., bipyralidinol borate) to obtain a compound represented by formula (i-c);
  • Step 3) the compound represented by formula (i-c) is subjected to a coupling reaction with the compound represented by formula (i-e) to obtain a compound represented by formula (I).
  • Step 1) The compound represented by formula (i-e) in method 1 is subjected to the action of a boration reagent (e.g., biboric acid pinacol ester) 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 (i-b) obtained in method 1 to obtain a compound represented by formula (I).
  • a boration reagent e.g., biboric acid pinacol ester
  • Step 1) The compound represented by formula (iii-a) is treated with p-toluenesulfonyl hydrazide to obtain the compound represented by formula (iii-b); Step 2) The compound represented by formula (iii-b) is coupled under the action of metal catalysis to obtain the 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 the compound represented by formula (I).
  • 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).
  • the protecting group can be further removed under the action of a strong acid such as trifluoroacetic acid or hydrochloric acid.
  • the compound represented by formula (i-e) can be a commercially available product, or can be prepared by a person skilled in the art through a preparation method disclosed in the prior art.
  • i-e can be prepared by the following methods i-e1, i-e2, i-e3, i-e4, etc.,
  • 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, W 1 , W 2 , W 3 , W 4 , W 5 , m, o, RA , 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-, and when L' is -NHCH3, L is -NCH3- .
  • Ring A is selected from aromatic rings, aromatic heterocyclic rings (such as benzene rings, 5 to 10 rings containing 1 to 3 heteroatoms) wherein 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- .
  • 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, such as cyclohexane, cyclopentan
  • the compound represented by formula (i-7) undergoes coupling reaction with the compound represented by formula (i-6) to obtain the compound represented by formula (ie), wherein ring A, ring C, W 1 , W 2 , W 3 , W 4 , W 5 , m, o, RA , Consistent with the above definition.
  • Step 1 Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-one
  • Step 2 Preparation of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-c]pyridin-7-yl)ethan-1-ol
  • Step 2 Preparation of tert-butyl 7-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylate
  • Step 3 Preparation of tert-butyl 7-acetyl-1H-benzo[d]imidazole-1-carboxylate
  • Step 4 Preparation of tert-butyl 7-(1-hydroxyethyl)-1H-benzo[d]imidazole-1-carboxylate
  • Step 1 Preparation of 4-bromo-1-(1-(pyridin-2-yl)ethyl)pyridin-2(1H)-one
  • Step 2 Preparation of (2-oxo-1-(1-(pyridin-2-yl)ethyl)-1,2-dihydropyridin-4-yl)boronic acid
  • Step 3 Preparation of 1-(1-(pyridin-2-yl)ethyl)-4-(3-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2(1H)-one
  • Step 1 Preparation of 2-(2-chloro-3-(4-(trifluoromethyl)phenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
  • step 1 in example 1 the preparation method of step 1 in method 1 was used to obtain the title compound.
  • MS (ESI) m/z (M+H) + 282.0.
  • 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
  • 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-dioxaborane (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)Cl 2 (46.1 mg), and the mixture was heated to 90° C. for 2 hours under nitrogen protection.
  • 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
  • Step 1 Preparation of tert-butyl 4-(1-toluenesulfonylhydrazineethyl)piperidine-1-carboxylate
  • Step 2 Preparation of tert-butyl 4-(1-(4-bromo-2-oxopyridin-1(2H)-yl)ethyl)piperidine-1-carboxylate
  • 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
  • Example 50A 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), and the reaction system was heated to 90°C and stirred for 16 hours. LC-MS showed that the reaction was complete, and the reaction solution was cooled to room temperature, the pH was adjusted to 8-9 with ammonia water, and concentrated under reduced pressure.
  • Test Example 1 YAP-TEAD dual luciferase reporter gene experiment.
  • HEK293T cells in logarithmic growth phase were co-transfected with 8xGTIIC-firefly luciferase and pRL-SV40-N plasmid;
  • mice 12,000 transfected cells were plated in a 96-well plate.
  • the drug to be tested was graded diluted with DMEM medium containing 0.5% DMSO. The highest final concentration of the drug in the experimental wells was 5 ⁇ M.
  • the drug solution to be tested was graded diluted 5-fold, with a total of 9 graded concentrations. 50 ⁇ L of each concentration of the drug to be tested from 1 to 9 was added to the transfected cell wells. Each concentration was repeated for 3 wells.
  • the untreated control wells were set as follows: 12,000 transfected cells were plated in a 96-well plate. DMEM medium containing 0.5% DMSO was added to the wells. The wells were repeated for 8 wells.
  • the untransfected wells were set as follows: 12,000 untransfected HEK293T cells were plated in a 96-well plate. Then DMEM medium containing 0.5% DMSO was added to the wells. The wells were repeated for 8 wells.
  • Inhibition rate % (average signal value of control wells without drug addition - signal value of experimental wells) / (average signal value of control wells without drug addition - average signal value of non-transfected control wells) ⁇ 100%
  • TEAD transcriptional inhibitory activity of the compounds in the present application on HEK293T cells is shown in Table A below.
  • A represents that the IC50 range of TEADs transcriptional inhibitory activity is less than or equal to 25nM
  • B represents that the IC50 range of TEADs transcriptional inhibitory activity is greater than 25nM and less than or equal to 50nM
  • C represents that the IC50 range of TEADs transcriptional inhibitory activity is greater than 50nM and less than or equal to 100nM
  • H represents that the IC50 range of TEADs transcriptional inhibitory activity is greater than 5 ⁇ M or inactive.
  • the compounds in the present application have TEADs transcriptional inhibition activity on HEK293T cells.
  • the IC 50 value of the compounds in the present application for TEADs transcriptional inhibition activity is less than or equal to 100nM
  • the IC 50 value of some compounds in the present application for TEADs transcriptional inhibition activity is greater than or equal to 50nM and less than 100nM
  • the IC 50 value of some compounds in the present application for TEADs transcriptional inhibition activity is greater than or equal to 30nM and less than 50nM
  • the IC 50 value of some compounds in the present application for TEADs transcriptional inhibition activity is greater than or equal to 20nM and less than 30nM
  • the IC50 value of some compounds in the present application for TEADs transcriptional inhibition activity is greater than or equal to 10nM and less than 20nM
  • the IC 50 value of some compounds in the present application for TEADs transcriptional inhibition activity is less than 10nM.
  • the cell viability was determined using the CellCounting-LiteTM 2.0 kit and the luminescent signal was detected using a multifunctional microplate reader.
  • Inhibition rate % (average signal value of control wells without drug addition - signal value of experimental wells) / (average signal value of control wells without drug addition - average signal value of blank control wells) ⁇ 100%
  • A represents the IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is less than or equal to 25nM;
  • B represents the IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 25nM and less than or equal to 50nM;
  • C represents the IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 50nM and less than or equal to 100nM;
  • D represents the IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 100nM and less than or equal to 500nM;
  • E represents the IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 500nM and less than or equal to 1 ⁇ M;
  • F represents the IC50 range of the inhibitory activity on the proliferation of NCI-H226 cells is greater than 1 ⁇ M and less than or equal to 3 ⁇ M;
  • G represents the IC50 range of the
  • the compounds in the present application have the effect of inhibiting the proliferation of NCI-H226 cells.
  • the IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 500nM
  • the IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 100nM
  • the IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 50nM
  • the IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 25nM
  • the IC50 value of the proliferation inhibition activity of some compounds in the present application on NCI-H226 cells is less than or equal to 10nM.
  • test compound was prepared to 10mM with DMSO, 2 ⁇ L was added to 198 ⁇ L 50% acetonitrile/50% aqueous solution to obtain a 100 ⁇ M solution. Liver microsomes were taken and prepared to 0.5mg/mL with PBS, NADPH cofactor (final concentration of 1mM) was added, and the mixture was preheated at 37°C for 10min. 2.5 ⁇ L of the prepared test compound was taken and added to 222.5 ⁇ L of the above preheated mixture and placed in a 37°C water bath to start the reaction.
  • the incubated centrifuge tubes were taken out and 25 ⁇ L of the incubated liver microsome suspension (containing the compound) was taken out respectively, and 5 times the volume of the stop solution was added to terminate the reaction, and the supernatant was centrifuged at 3220g for 40min. After taking the supernatant, the remaining compound content in the sample at each time point was detected by LC-MS/MS. After nonlinear linear regression of the remaining drug percentage-time, the half-life (t 1/2 ) of the compound in liver microsomes was calculated.
  • the compounds of the present application have certain stability in liver microsome metabolism. Some compounds of the present application are metabolized in liver microsomes for a long time or are not metabolized by liver microsomes.
  • test compound was prepared to 10mM with DMSO, and 2 ⁇ L was added to 198 ⁇ L 50% acetonitrile/50% aqueous solution to obtain a 100 ⁇ M solution.
  • frozen hepatocytes were revived, they were resuspended in culture medium (William's E culture medium, Gibco, catalog number: 22551032) to a density of 500,000 cells per milliliter.
  • culture medium Wild's E culture medium, Gibco, catalog number: 22551032
  • 198 ⁇ L of the hepatocyte suspension was added to a 96-well plate, and 2 ⁇ L of the prepared 100 ⁇ M test compound and positive compound solution were added respectively, and placed in an incubator for incubation.
  • 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.
  • the half-life of the compounds of Examples 46 and 60 in human hepatocytes is 2 to 4 times higher than that of existing compounds.
  • Caco-2 cells were seeded in HTS Transwell TM cell culture plates.
  • the volume of culture medium in the wells was 50 ⁇ L, and the culture medium was replaced every 24 h.
  • DMSO DMSO to prepare the test compound to 2mM, and then further dilute it to 10 ⁇ M with HBSS buffer (10mM HEPES buffer containing 4% BSA, pH 7.4) to obtain the test working solution.
  • HBSS buffer 10mM HEPES buffer containing 4% BSA, pH 7.4
  • Discard the culture medium in the Transwell TM cell culture plate wash the cell surface with 37°C HBSS three times, then add 37°C HBSS solution, and incubate in a 37°C incubator for 30min.
  • a ⁇ B permeability test aspirate the buffer solution, add the working solution containing the test drug to the upper chamber (apical, A side) as the supply solution, and add blank HBSS solution to the lower chamber (basolateral, B side) as the receiving solution.
  • VR is the volume of the receiving end solution (A ⁇ B: the receiving end is the base end; B ⁇ A: the receiving end is the top end), Area is the Transwell-96 well plate membrane (0.0804 cm2 ), Time is the incubation time (unit: s), CR is the drug concentration at the sample receiving end, and C0 is the drug concentration at the initial T0 point of the sample.
  • P app (B ⁇ A) is the apparent permeability from the base end to the apex
  • P app (A ⁇ B) is the apparent permeability from the apex to the base end.
  • the compounds of the present application have a certain Caco-2 cell permeability, and the Caco-2 cell efflux effect is not obvious.
  • the Caco-2 cell permeability of some compounds of the present application is high, and the Caco-2 cell efflux effect is low.
  • the apparent permeability coefficients P app (A ⁇ B) of the compounds of Examples 1, 46, and 60 of the present application are 3.01, 4.65, and 4.85, respectively, with good cell permeability, which is 2 to 3 times higher than that of the prior art compounds, and no obvious efflux is observed.
  • test compound was prepared into a 10 mM solution with DMSO.
  • the injection concentration of the standard is known to be 10 ⁇ M.
  • the solubility is calculated by comparing the peak areas of the test compound and the standard in LC-MS. The formula is as follows:
  • 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 >50 ⁇ M, and some compounds of the present application may also have a solubility of >100 ⁇ M. The compounds of the present application have an improvement in 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.
  • solubility of the compounds in Examples 60 and 67 are 63.0 ⁇ M and 112.2 ⁇ M, respectively, and the equivalent solubility is 27.62 ⁇ g/mL and 54.85 ⁇ g/mL, respectively, which is a huge improvement in solubility compared to the compounds of the prior art.
  • IV intravenously injected
  • PO orally gavaged
  • the blood sampling time points for the IV group were: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h;
  • the blood sampling time points for the PO group were: 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h.
  • the blood samples were placed on ice and centrifuged within 1 hour to separate plasma (centrifugation conditions: 6800g, 6 minutes, 2-8°C).
  • Plasma samples were stored in a -80°C refrigerator before analysis.
  • LC-MS/MS was used to determine the concentration of the test substance in the plasma of ICR mice after administration of the test substance.
  • 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 and their mean and standard deviations were provided.
  • the mouse PK exposure of the compounds of the present application is good, and the 10mpk AUC (0-t) is at least 10000 h*ng/mL.
  • the 10mpk AUC (0-t) of the compounds of Examples 46, 66, 90, and 92 are 13000 h*ng/mL, 17000 h*ng/mL, 25000 h*ng/mL, and 10500 h*ng/mL, respectively, which is at least 5 times higher than that of existing compounds (e.g., ⁇ 2000 h*ng/mL); at the same time, some existing compounds are not metabolized in mice, and there may be 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 than existing compounds.

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Abstract

La présente invention concerne un composé de formule (I) pour réguler l'activité de TEAD, un stéréoisomère ou un tautomère de celui-ci ou un mélange des deux, ou un sel pharmaceutiquement acceptable de celui-ci, ou un solvate de celui-ci, ou un promédicament de celui-ci, une composition pharmaceutique le comprenant, et une utilisation de celui-ci pour inhiber l'activité de TEAD.
PCT/CN2024/099277 2023-06-14 2024-06-14 Composé pour réguler l'activité de tead, procédé de préparation associé et utilisation associée Ceased WO2024255856A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
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