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WO2023137634A1 - Composé tricyclique, sa préparation, composition pharmaceutique et utilisation - Google Patents

Composé tricyclique, sa préparation, composition pharmaceutique et utilisation Download PDF

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Publication number
WO2023137634A1
WO2023137634A1 PCT/CN2022/072781 CN2022072781W WO2023137634A1 WO 2023137634 A1 WO2023137634 A1 WO 2023137634A1 CN 2022072781 W CN2022072781 W CN 2022072781W WO 2023137634 A1 WO2023137634 A1 WO 2023137634A1
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Prior art keywords
substituted
alkyl
unsubstituted
halogen
compound
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Chinese (zh)
Inventor
郑乾刚
江相清
曾庆龙
许明
刘景�
朱继东
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Etern Biopharma Shanghai Co Ltd
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Etern Biopharma Shanghai Co Ltd
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Priority to PCT/CN2022/072781 priority Critical patent/WO2023137634A1/fr
Priority to CN202280089566.9A priority patent/CN118574832A/zh
Publication of WO2023137634A1 publication Critical patent/WO2023137634A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a tricyclic compound, its preparation, pharmaceutical composition and application.
  • the Hippo pathway is involved in the regulation of cell growth, proliferation and apoptosis, and plays an important role in the regulation of organ size, cancer occurrence, tissue regeneration, and renewal and differentiation of stem cells and precursor cells. Studies have found that in mammals, this pathway has a tumor suppressive effect, and the abnormal activation of the main effector molecules in the pathway is closely related to the occurrence and development of various tumors. In addition, the Hippo pathway interacts with other pathways such as Wnt, Notch, Hedgehog, and MAPK/ERK to jointly regulate cell fate. Dysregulation of this pathway also has important implications for diseases other than cancer.
  • the Hippo signaling pathway is highly conserved during evolution.
  • the core part of the Hippo signaling pathway in mammalian cells is a kinase chain composed of MST1/2 (member of Ste20-like kinase, the homologous gene in Drosophila is Hippo) and LATS1/2 (large tumor suppressor 1/2, the homologous gene in Drosophila is Warts) protein kinases, and their adapter proteins SAV1 and Mob1 (Mps one binder kinase activator-like 1A and 1B, the homologous gene in Drosophila is composed of Mats).
  • This kinase chain can phosphorylate the transcriptional co-activators YAP (Yes-Associated Protein) and TAZ (Transcription co-activator with PDZ binding motif, also known as WWTR1) (corresponding to Yorkie in Drosophila)).
  • LATS1/2 The core component of the mammalian Hippo pathway, LATS1/2, belongs to the Dbf2-realted (NDR) family of kinases. Activated by binding to the scaffold protein Mob1A/B. LATS1/2 can also be activated directly after phosphorylation by MST1/2. LATS1/2 kinases can phosphorylate multiple sites on the downstream effector YAP, among which phosphorylation at Ser127 plays a key role in YAP inhibition. Ser127-phosphorylated YAP binds to 14-3-3 protein in the cytoplasm, is trapped in the cytoplasm, and cannot perform transcriptional functions in the nucleus, thereby inhibiting the pro-proliferation and anti-apoptosis activities of YAP.
  • NDR Dbf2-realted
  • LATS1/2 kinases can phosphorylate multiple sites on the transcription factor TAZ, among which phosphorylation at Ser89 plays a key role in TAZ repression. Phosphorylated TAZ is retained or sequestered in the cytoplasm. At the same time, phosphorylated YAP or TAZ can be further recognized and degraded by the ubiquitinase SCF ⁇ -TRCP. Therefore, if the Hippo pathway is "on", YAP and/or TAZ will be inactivated by phosphorylation and retained in the cytoplasm. Conversely, if the Hippo pathway is 'off', YAP and/or TAZ are dephosphorylated and activated, and are often found localized in the nucleus.
  • YAP itself does not contain a DNA binding region. After the activated YAP enters the nucleus, it must combine with transcription factors to perform the transcription function together.
  • the most tightly bound transcription factor after YAP enters the nucleus is TEAD.
  • Human TEAD family proteins include TEAD1/TEAD2/TEAD3/TEAD4.
  • YAP together with TEAD can initiate the transcription of a series of downstream genes, including CTGF (connective tissue growth factor), Gli2, Birc5, Birc2, FGF1 (fibroblast growth factor 1) and AREG (amphiregulin).
  • non-phosphorylated TAZ enters the nucleus, where it binds to a variety of DNA-binding transcription factors, such as PPAR ⁇ (peroxisome proliferation-activated receptor ⁇ ), TTF-1 (thyroid transcription factor-1), Pax3, TBX5, RUNX, TEAD1, and Smad2/3/4.
  • PPAR ⁇ peroxisome proliferation-activated receptor ⁇
  • TTF-1 thyroid transcription factor-1
  • Pax3, TBX5, RUNX, TEAD1, and Smad2/3/4 Most of the genes activated by YAP or TAZ transcription factor complexes are related to cell growth and proliferation.
  • the Hippo-YAP pathway regulates the size of organs and normal physiological functions by regulating cell proliferation and apoptosis, and is strictly regulated under normal physiological conditions. Inactivation of protein kinases or activation of YAP in the Hippo pathway promotes tumorigenesis. In fact, abnormal activation of the Hippo pathway is a major event in the development of various malignant tumors. Increased expression levels and nuclear localization of YAP or TAZ have been found in tumors including non-small cell lung cancer, breast cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, prostate cancer, mesothelioma and skin cancer.
  • MPM Malignant pleural mesothelioma
  • MMM Malignant pleural mesothelioma
  • the treatment options for surgically unresectable MPM are extremely limited.
  • the effect of the current first-line pemetrexed/platinum therapy is not satisfactory, and the median overall survival rate is only about one year.
  • Abnormal activation of the Hippo-YAP pathway exists in about 70% of MPM patients and is considered an important cancer driver gene. Reducing the activity of the Hippo-YAP pathway through biological means and small chemical molecules has shown good tumor growth inhibitory activity, indicating that Hippo-YAP is a potential target for the treatment of MPM.
  • Lung cancer is currently one of the cancers with the highest mortality rate in the world.
  • a number of studies have shown that the YAP signaling pathway can induce drug resistance to lung cancer drugs such as EGFR inhibitors through mechanisms such as mediating tumor cell dormancy and resisting apoptosis.
  • Inhibition of the Hippo-YAP signaling pathway can increase the sensitivity of tumor cells to EGFR-targeted drugs, suggesting that a combined strategy can be used clinically to improve the therapeutic effect.
  • Liver cancer is a cancer with a high incidence in China, and the current breakthroughs in clinical treatment methods are very limited, and there is a large unmet clinical need.
  • YAP is an important gene that regulates the occurrence and development of liver cancer.
  • Multiple in vivo experiments have shown that overexpressing YAP alone in the liver of mice or knocking out the upstream regulatory factor MST1-2 without introducing other oncogenes can lead to the occurrence of hepatocellular carcinoma.
  • knocking down the expression of YAP can significantly inhibit tumors and promote the differentiation of tumor cells into functional liver parenchyma-like cells, accompanied by the recovery of liver function, suggesting that YAP is a potential target for the treatment of liver cancer.
  • KRas mutations are widespread in pancreatic ductal adenocarcinoma (PDAC), and targeting KRas is considered to have broad clinical application prospects in PDAC.
  • PDAC pancreatic ductal adenocarcinoma
  • targeting KRas can inhibit tumor growth and also face tumor recurrence.
  • YAP plays an important role in inducing EMT (epithelial-mesenchymal transition) by regulating Fos; knocking down YAP expression in recurrent tumors can re-inhibit tumor growth. Indicating that targeting YAP also has potential clinical application prospects in pancreatic ductal adenocarcinoma.
  • Inhibitors targeting BRAF and MEK have a wide range of clinical applications in a variety of tumors including melanoma, colon cancer, and thyroid cancer, but they also face the problem of resistance to recurrence after treatment.
  • YAP or TAZ in mammalian epithelial cells leads to transformation of the cells.
  • Enhanced YAP/TAZ transcriptional activity induces EMT (epithelial-mesenchymal transition) and confers breast cancer cell properties on stem cells.
  • the therapeutic strategy targeting the Hippo-Yap pathway is likely to provide new ideas for the treatment of various tumors.
  • the development of specific small molecules to destroy the interaction between YAP/TAZ and TEAD, weaken the transcriptional activity of YAP, and thus inhibit the occurrence of tumors with abnormal Hippo pathway is expected to become a new strategy for tumor treatment and has broad clinical application prospects.
  • the first aspect of the present invention provides the compound represented by the following formula I, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, tautomers, solvates, isotope substitutions, polymorphs, prodrugs or metabolites:
  • a 1 is selected from N or CR a ;
  • a 2 is selected from NH, O or CR b R c ;
  • a 3 is selected from N or CR 3 ;
  • a 4 is selected from N or CR 4 ;
  • a 5 is selected from N or CR 5 ;
  • R is selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
  • R is selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl;
  • R 3 , R 4 and R s are each independently selected from H, hydroxyl, halogen, carboxyl, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted amino, and substituted or unsubstituted alkoxy;
  • R is selected from H, hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy;
  • R and R are each independently selected from: H, hydroxy, halogen, carboxy, substituted or unsubstituted alkyl, and substituted or unsubstituted alkoxy;
  • Ring A is a 5-8 membered carbocyclyl, a 4-8 membered heterocyclic group or a 5 or 6 membered heteroaryl group, optionally substituted by 1 to 3 substituents selected from hydroxyl, halogen, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy.
  • the second aspect of the present invention provides a pharmaceutical composition, which contains the I, II or III compound according to any embodiment of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite, and a pharmaceutically acceptable carrier or excipient.
  • the third aspect of the present invention provides the application of the I, II or III compound according to any embodiment of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite in the preparation of a drug for treating or preventing diseases mediated by the interaction between YAP/TAZ and TEAD.
  • the fourth aspect of the present invention provides a method for treating or preventing diseases mediated by the interaction of YAP/TAZ and TEAD, comprising administering to a subject in need a therapeutically effective amount of the compound I, II or III described in any embodiment of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite, or a pharmaceutical composition thereof.
  • the compounds described herein generally contain an axial chirality, including a pair of axial chiral isomers.
  • the axial chirality of the compounds described herein is the S configuration.
  • the axial chirality of the compounds described herein is in the R configuration.
  • reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
  • the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.
  • halogen means fluorine, chlorine, bromine or iodine.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below substituted with a hydroxyl group (-OH).
  • Niro means -NO2 .
  • Amino refers to -NH2 .
  • Acyl refers to -COR, wherein R is H or alkyl, such as C 1-5 alkyl.
  • Substituted amino refers to an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, aryl, heteroaryl, heterocyclyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino, heteroarylamino and arylamino.
  • substituted amino is represented as -NR'R", wherein R' and R" are each independently selected from H, amino, and substituted or unsubstituted alkyl.
  • Carboxy means -COOH.
  • alkyl refers to a fully saturated straight or branched chain hydrocarbon chain group, consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and connected to the rest of the molecule by a single bond, such as but not limited to methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • halogen such as fluorine, chlorine, bromine or iodine substituted alkyl group, etc.
  • alkenyl as a group or part of another group, means a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 20 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as but not limited to vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1-enyl, 1,4-dienyl, etc.
  • cyclic hydrocarbon group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group (such as an alkyl, alkenyl or alkynyl group) consisting only of carbon atoms and hydrogen atoms, which may include fused ring systems, bridged ring systems or spiro ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, such as 3, 4, 5, 6, 7 or 8 carbon atoms, and is saturated or not Saturated and can be single bonded to the rest of the molecule via any suitable carbon atom.
  • cyclic hydrocarbon group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group (such as an alkyl, alkenyl or alkynyl group) consisting only of carbon atoms and hydrogen atoms, which may include fused ring systems, bridged ring systems or spiro ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon
  • carbon atoms in a cycloalkyl group may be optionally oxidized.
  • the cycloalkyl is cycloalkyl, preferably C3-C8 cycloalkyl.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9- Tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo
  • heterocyclyl means a stable 3- to 20-membered non-aromatic cyclic group composed of 2 to 14 carbon atoms (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; the nitrogen, carbon or sulfur atoms in the heterocyclic group thereof may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and by a single bond.
  • heterocyclyl groups comprising fused rings
  • one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclyl group is preferably a stable 4- to 12-membered, 5- to 12-membered, or 4- to 9-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 9-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclyl groups described in various embodiments herein include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, Tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, quinozinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydro
  • aryl as a group or part of another group, means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms, for example 6, 7, 8, 9 or 10 carbon atoms.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the aryl group is connected to the rest of the molecule via a single bond via an atom of the aromatic ring.
  • aryl groups described in various embodiments herein include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-on-7-yl, and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group, means a 5- to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur in the ring.
  • a heteroaryl group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and may also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heteroaryl group is attached to the rest of the molecule by a single bond via an atom on the aromatic ring.
  • a nitrogen, carbon or sulfur atom in a heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • heteroaryl is preferably a stable 5- to 12-membered aromatic group comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic group comprising 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups described in various embodiments herein include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isindazolyl, purinyl, quinolinyl , isoquinolyl, naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl,
  • heteroarylalkyl refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.
  • substituents described in the claims and description of the present invention include but are not limited to alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclic.
  • moiety As used herein, the terms “moiety”, “structural moiety”, “chemical moiety”, “group”, “chemical group” refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules.
  • the functional groups of intermediate compounds may need to be protected by appropriate protecting groups.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl esters, aryl esters or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the compound with wedge-shaped bond drawing (such as compound 67 in Example 33) is a single-configuration compound with an absolute stereochemical structure.
  • the present invention provides the compound represented by the following formula I, its pharmaceutically acceptable salt, or its enantiomers, diastereomers, tautomers, solvates, isotope substitutions, polymorphs, prodrugs or metabolites:
  • a 1 Choose from N or CR a ;
  • a 2 Choose from NH, O or CR b R c ;
  • a 3 Choose from N or CR 3 ;
  • a 4 Choose from N or CR 4 ;
  • a 5 Choose from N or CR 5 ; 1 selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
  • R 2 selected from H, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
  • the alkyl is preferably C 1-6 alkyl, more preferably C 1-4 alkyl; the alkoxy is preferably C 1-6 alkoxy, more preferably C 1-4 alkoxy; the cycloalkyl is preferably C 3-8 cycloalkyl ; the aryl is preferably 6-14 aryl; 2-membered heterocyclic group, more preferably 4-9 membered heterocyclic group; preferably, the heteroatoms in the heterocyclic group and heteroaryl group include nitrogen, oxygen and/or sulfur, and the number of heteroatoms is 1, 2 or 3. ⁇ , ⁇ , ⁇ 1-6 ⁇ , ⁇ : ⁇ ,C 1-4 ⁇ , ⁇ C 1-4 ⁇ , ⁇ ,C 1-4 ⁇ , ⁇ C 1-4 ⁇ , ⁇ C 1-4 ⁇ , ⁇ , ⁇ , ⁇ , ⁇ 1-3 ⁇ C 1-4 ⁇ C 1-4 ⁇ C 1-4 ⁇ C 1-4 ⁇ 6-14 ⁇ 5-12 ⁇ 4-12 ⁇ , ⁇ NR'R”-C(O)-(CH 2 ) n
  • a 1 is N.
  • a 1 is CR a , wherein R a is selected from H and substituted or unsubstituted C 1-4 alkyl.
  • ring A is a 5-8 membered saturated carbocyclic ring or a 4-8 membered heterocyclic group.
  • Ring A is a 4-8 membered nitrogen-containing heterocyclic group.
  • the nitrogen-containing heterocyclic group optionally further contains 1 or 2 heteroatoms selected from N and O, preferably further optionally contains 1 or 2 nitrogen atoms.
  • ring A is a piperidine ring, especially, the ring nitrogen atom of the piperidine ring is A 1 .
  • ring A is a piperazine ring, especially, one ring nitrogen atom of the piperazine ring is A 1 .
  • Ring A is a 5- or 6-membered heteroaryl, preferably containing 1 or 2 nitrogen atoms, one of which is at the A 1 position.
  • Ring A is a benzene ring.
  • the substituent on ring A is preferably selected from hydroxyl, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted alkoxy; more preferably, the substituent on ring A is selected from substituted or unsubstituted C 1-4 alkyl.
  • the alkyl group is substituted by 1-6 substituents selected from hydroxyl, halogen and NR 12 R 13 , wherein each of R 12 and R 13 is independently selected from H and C 1-4 alkyl.
  • a 2 is CR b R c , wherein, preferably, R b and R c of A 2 are each independently H and C 1-4 alkyl, more preferably both are H.
  • A2 is NH or O.
  • a 3 is CR 3 ; preferred R 3 is H, halogen, C 1-4 alkoxy, cyano and substituted or unsubstituted C 1-4 alkyl, more preferably halogen.
  • the substituents may be 1-3 substituents selected from halogen, hydroxyl and amino.
  • preferred A 4 is CR 4 ; preferred R 4 is H, halogen, C 1-4 alkoxy, cyano and substituted or unsubstituted C 1-4 alkyl, more preferably halogen.
  • the substituent may be 1-3 substituents selected from halogen, hydroxyl and amino.
  • R3 and R4 are each independently halogen.
  • preferred A 5 is CR 5 ; preferred R 5 is H, halogen, cyano, C 1-4 alkoxy and substituted or unsubstituted C 1-4 alkyl, more preferably H.
  • the substituents may be 1-3 substituents selected from halogen, hydroxyl and amino.
  • any one or any two of A 3 , A 4 and A 5 is N, and the rest are corresponding CR 3 , CR 4 or CR 5 .
  • R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.
  • the substituents on R can be 1-3 substituents selected from halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy and -NR 12 R 13 , wherein, R 12 and R 13 are each independently H or C 1-4 alkyl.
  • the cycloalkyl group is a C3-8 cycloalkyl group; a preferred aryl group is an aryl group having 6 to 14 ring carbon atoms; a preferred heteroaryl group is a heteroaryl group having 5 to 12 ring atoms, more preferably a heteroaryl group having at least a ring nitrogen atom among the heteroatoms; a preferred heterocyclyl group is a heterocyclyl group having 4 to 9 ring atoms.
  • R is an unsubstituted 6-14 membered aryl group, such as phenyl, or a 6-14 membered aryl group, such as phenyl, optionally substituted with 1-3 substituents selected from hydroxyl, halogen, C 1-4 alkyl and C 1-4 alkoxy.
  • R is H, substituted or unsubstituted alkyl, halogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.
  • the substituents may be 1-5 selected from halogen, hydroxyl, carboxyl, cyano and -NR 12 R 13 , wherein R 12 and R 13 are each independently H or C 1-4 alkyl.
  • the substituted or unsubstituted alkyl is a substituted or unsubstituted C 1-4 alkyl, preferably an unsubstituted C 1-4 alkyl or a halogenated C 1-4 alkyl.
  • R is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.
  • ⁇ C 3-8 ⁇ ; ⁇ 6-14 ⁇ , ⁇ ; ⁇ 5 ⁇ 12 ⁇ , ⁇ , ⁇ ; ⁇ 4 ⁇ 9 ⁇ , ⁇ / ⁇ / ⁇ , ⁇ ,R 2 ⁇ 1-3 ⁇ NR'R”-C(O)-(CH 2 ) n - ⁇ C 1- 4 ⁇ C 1-4 ⁇ 4-9 ⁇ , ⁇ ,R' ⁇ R” ⁇ H ⁇ C 1-4 ⁇ ,n ⁇ 0-4 ⁇ ; ⁇ , ⁇ , ⁇ 1-5 ⁇ ; ⁇ , ⁇ , ⁇ 1-5 ⁇ C 1-4 ⁇ 5-12 ⁇ ; ⁇ , ⁇ , ⁇ 1-5 ⁇ C 1-4 ⁇ C 1-4 ⁇ ; ⁇ , ⁇ , ⁇ 1 ⁇ 4-9 ⁇ 1 ⁇ 2 ⁇ C 1-4 ⁇ C 1-4 ⁇ , ⁇ , ⁇ N ⁇ O ⁇ S ⁇ 4-9 ⁇ , ⁇ , ⁇ , ⁇ 1 ⁇ 2 ⁇ C 1-4 ⁇ , ⁇ 1 ⁇ 2 ⁇
  • R 3 , R 4 , R 5 , R a , R b , R c and the alkyl and alkoxy groups in the definition of ring A are substituted, their respective substituents can be 1-3 selected from halogen, hydroxyl, carboxyl or amino groups optionally substituted by 1 or 2 C 1-4 alkyl groups, and the amino group in the definition of these groups can be substituted by 1 or 2 C 1-4 alkyl groups.
  • R 1 selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted cycloalkyl
  • R 2 selected from H, substituted or unsubstituted alkyl, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted cycloalkyl
  • R 3 , R 4 and R the s each independently selected from H, hydroxy, halogen, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted amino and substituted or unsubstituted alkoxy
  • R 11 is H or substituted or unsubstituted alkyl.
  • R 1 when R 1 is a group with a substituent, the substituent is 1-3 substituents selected from halogen, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy and -NR 12 R 13 , wherein, R 12 and R 13 are each independently H or C 1-4 alkyl.
  • R 1 is a substituted or unsubstituted 6-14 membered aryl group or a substituted or unsubstituted 5-12 membered heteroaryl group; the preferred substituent on R 1 is selected from one or more of hydroxyl, halogen, C 1-4 alkyl and C 1-4 alkoxy.
  • R is a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-12 membered nitrogen-containing heteroaryl group, such as pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl and pyridazinyl, etc.; preferably, when it is a group with a substituent, the substituent is selected from one or more of hydroxyl, halogen, C 1-4 alkyl and C 1-4 alkoxy.
  • R 3 is H, halogen, C 1-4 alkoxy and C 1-4 alkyl, in particular, halogen and C 1-4 alkyl.
  • R 4 is H, halogen, C 1-4 alkoxy and C 1-4 alkyl, in particular, halogen.
  • R 5 is H, halogen, C 1-4 alkoxy and C 1-4 alkyl, especially, H.
  • each of R3 and R4 is independently halogen, and R5 is H.
  • R 11 is H or C 1-6 alkyl that is unsubstituted or optionally substituted with 1-3 substituents selected from halogen and hydroxy, in particular, R 11 is H.
  • the number of substituents is at least two; preferably, at least one, more preferably at least two substituents are located in the ortho position.
  • the at least two substituents include at least halogen and the NR'R"-C(O)-(CH 2 ) n -; preferably, the substituents also include one selected from the group consisting of substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 1-4 alkoxy, substituted or unsubstituted heterocyclic group and substituted or unsubstituted amino.
  • R 1 It is a substituted or unsubstituted phenyl or a substituted or unsubstituted 5-12 membered nitrogen-containing heteroaryl group, such as pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl and pyridazinyl, etc., wherein, when it is a group with substituents, the number of substituents is 1-3, and is selected from hydroxyl, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, preferably R 1 For unsubstituted phenyl; R 2 It is a 4-9 membered heterocyclic group, preferably a 4-9 membered heterocyclic group containing N and/or O and/or S, including azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, t
  • R 1 It is a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-12 membered nitrogen-containing heteroaryl group, such as pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl and pyridazinyl, etc., wherein, when it is a group with substituents, the number of substituents is 1-3, and is selected from halogen, C 1-4 Alkyl and C 1-4 Alkoxy, preferably R 1 For unsubstituted phenyl; R 2 It is a 5-12 membered heteroaryl group, preferably a 5-12 membered heteroaryl group containing N, including pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyr
  • R 1 , R 3 -R s are as described in any embodiment of the aforementioned formula I or II;
  • B 1 is C or N;
  • B 2 is CR 6 or N;
  • B 3 is CR 7 or N;
  • B 4 is CR 8 or N;
  • B 5 is CR 9 or N;
  • B 6 is CR 10 or N;
  • R 6 is selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, carboxyl, NR 12 R 13 and NR'R"-C(O)-(CH 2 ) n -, wherein R 12 and R 13 are each independently selected from H, C 1-4 acyl and substituted or unsubstituted C 1-4 alkyl, n is an integer of 0-4;
  • R 7 is H, halogen, NR 12 R 13 , C 1-4 alkoxy or C 1-4 alkyl;
  • R 8 is H, halogen or C 1-4 alkyl
  • R9 is H, halogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 1-4 Alkoxy, substituted or unsubstituted 4-9 membered heterocyclic group (such as nitrogen and/or oxygen and/or sulfur-containing 4-9 membered heterocyclic group, including tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and dioxothiomorpholinyl, etc.), or substituted or unsubstituted amino;
  • Substituents preferably, when the alkoxy group is substituted, its substituents can be 1-5 selected from hydroxyl, halogen, carboxyl, amino, halogenated C 1-4 Alkyl and substituted or unsubstituted 5-12 membered heteroaryl substituents; in some embodiments, when the heterocyclic group is
  • R 10 is H, halogen, alkyl or halogenated C 1-4 alkyl
  • R 11 is H or substituted or unsubstituted C 1-4 alkyl, preferably H.
  • R 12 and R 13 are each independently H or substituted or unsubstituted C 1-4 alkyl.
  • B 1 is CH; B 2 is CR 6 ; B 3 is CR 7 ; B 4 is CR 8 ; B 5 is CR 9 ; ⁇ R 6 ⁇ C 1-4 ⁇ C 1-4 ⁇ NR 12 R 13 ⁇ NR'R”-C(O)-(CH 2 ) n -, ⁇ ,R 12 ⁇ R 13 ⁇ H ⁇ C 1-4 ⁇ C 1-4 ⁇ ,n ⁇ 0-4 ⁇ R 7 ⁇ H ⁇ NR 12 R 13 , ⁇ H ⁇ NH 2 ⁇ R 8 ⁇ H ⁇ R 9 ⁇ : ⁇ C 1-4 ⁇ C 1-4 ⁇ 4-9 ⁇ ( ⁇ N ⁇ O ⁇ / ⁇ S ⁇ 4-9 ⁇ ) ⁇ , ⁇ : ⁇ 1-3 ⁇ C 1-4 ⁇ , ⁇ 1-3 ⁇ C 1-4 ⁇ C 1-4 ⁇ , ⁇ , ⁇ 1 ⁇ 2 ⁇ C 1-4 ⁇ 1 ⁇ 4-9 ⁇ ( ⁇ 5-12 ⁇ , ⁇ ) ⁇ R 10 ⁇ R 11 ⁇ H ⁇ 1-3 ⁇ C 1-4 ⁇
  • R is substituted or unsubstituted phenyl, preferably , when it is a group with substituents, the number of substituents is 1, 2 or 3, selected from hydroxyl, halogen, C 1-4 alkyl and C 1-4 alkoxy; R is H, halogen, C 1-4 alkoxy and C 1-4 alkyl, preferably hal
  • R is substituted or unsubstituted phenyl , preferably, when it is a group with substituents, the number of substituents is 1, 2 or 3, selected from hydroxyl, halogen, C 1-4 alkyl and C 1-4 alkoxy; R is H, halogen, C 1-4 alkoxy and C 1-4 alky
  • the compound of Formula I has the structure shown in Formula IV below:
  • R 1 , R 3 -R 5 and R 11 are as described in any embodiment of the aforementioned formula I or II;
  • each m is independently 1, 2 or 3;
  • X is CH2 , O or NH
  • R d is H, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, carboxyl or NR'R"-C(O)-(CH 2 ) n -, wherein, R' and R" are each independently selected from H and C 1-4 alkyl, n is an integer of 0-4; the number of R d can be 1, 2 or 3.
  • Rd is located ortho to the nitrogen atom to which the heterocyclyl is attached to the remainder of Formula IV.
  • Rd is H, carboxy, or NR'R"-C(O)-( CH2 ) n- .
  • the X-containing heterocycle is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
  • R 1 It is a substituted or unsubstituted phenyl group or a substituted or unsubstituted 5-12 membered nitrogen-containing heteroaryl group, such as pyridyl, pyrimidyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, pyrazinyl and pyridazinyl, etc., wherein, when it is a group with substituents, the number of substituents is 1-3, and is selected from halogen, C 1-4 Alkyl and C 1-4 Alkoxy, preferably R 1 For unsubstituted phenyl; R 3 is H, halogen, C 1-4 Alkoxy and C 1- 4 Alkyl, preferably H and halogen; R 4 is H, halogen, C 1-4 Alkoxy and C 1-4 Alkyl, preferably halogen; R 5 is H, halogen, C 1-4 Alkoxy and C 1-4 Alky
  • n is 0, and R' and R" are independently H and C 1-4 alkyl.
  • the compounds described herein generally contain an axial chirality, including a pair of axial chiral isomers.
  • the axial chirality of the compounds described herein is the S configuration.
  • the axial chirality of the compounds described herein is in the R configuration.
  • the formula I has the structural formula shown in the following formula V:
  • B 1 , B 3 -B 5 , R 1 , R 3 -R 5 , and R 11 are as described in any embodiment of formula I, II or III;
  • R 6 is selected from H, halogen, alkyl, carboxyl, NR 12 R 13 and NR'R"-C(O)-(CH 2 ) n -, wherein R' and R" are each independently selected from H, amino, and substituted or unsubstituted alkyl, and n is an integer of 0-4;
  • R 10 is H, halogen, alkyl or halogenated C 1-4 alkyl
  • R 12 and R 13 are each independently H, C 1-4 acyl or substituted or unsubstituted C 1-4 alkyl; preferably, the alkyl is substituted by 1-6 substituents selected from hydroxyl and halogen, or unsubstituted;
  • R 6 and R 10 are not H at the same time.
  • the formula I has the structural formula shown in the following formula VI:
  • B 1 , B 3 -B 5 , R 1 , R 3 -R 5 , and R 11 are as described in any embodiment of formula I, II or III;
  • R 6 is selected from H, halogen, alkyl, carboxyl, NR 12 R 13 and NR'R"-C(O)-(CH 2 ) n -, wherein R' and R" are each independently selected from H, amino, and substituted or unsubstituted alkyl, n is an integer of 0-4;
  • R 10 is H, halogen, alkyl or halogenated C 1-4 alkyl
  • R 12 and R 13 are each independently H, C 1-4 acyl or substituted or unsubstituted C 1-4 alkyl; preferably, the alkyl is substituted by 1-6 substituents selected from hydroxyl and halogen, or unsubstituted;
  • R 6 and R 10 are not H at the same time.
  • the formula I has the structural formula shown in the following formula VII:
  • R 1 , R 3 -R s , R 7 -R 9 , and R 11 are as described in any embodiment of formula I, II or III;
  • R 6 is selected from H, halogen, alkyl, carboxyl, NR 12 R 13 and NR'R"-C(O)-(CH 2 ) n -, wherein R' and R" are each independently selected from H, amino, and substituted or unsubstituted alkyl, n is an integer of 0-4;
  • R 10 is H, halogen, alkyl or halogenated C 1-4 alkyl
  • R 12 and R 13 are each independently H, C 1-4 acyl or substituted or unsubstituted C 1-4 alkyl; preferably, the alkyl is substituted by 1-6 substituents selected from hydroxyl and halogen, or unsubstituted;
  • R 6 and R 10 are not H at the same time.
  • R 1 , R 3 -R s , R 7 -R 9 , and R 11 are as described in any embodiment of formula I, II or III;
  • R 6 is selected from H, halogen, alkyl, carboxyl, NR 12 R 13 and NR'R"-C(O)-(CH 2 ) n -, wherein R' and R" are each independently selected from H, amino, and substituted or unsubstituted alkyl, and n is an integer of 0-4;
  • R 10 is H, halogen, alkyl or halogenated C 1-4 alkyl
  • R 12 and R 13 are each independently H, C 1-4 acyl or substituted or unsubstituted C 1-4 alkyl; preferably, the alkyl is substituted by 1-6 substituents selected from hydroxyl and halogen, or unsubstituted;
  • R 6 and R 10 are not H at the same time.
  • the following compounds, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, solvates, isotope substitutions, polymorphs, prodrugs or metabolites thereof are provided, wherein the compound is selected from:
  • stereoisomer refers to a compound composed of the same atoms bonded by the same bond, but having a different three-dimensional structure.
  • the present invention will encompass each stereoisomer and mixtures thereof.
  • the compounds of the present invention are intended to include both E- and Z-geometric isomers.
  • Tautomer refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • the present invention also includes all suitable isotopic variations of the compounds of the present invention or pharmaceutically acceptable salts thereof.
  • Isotopic variations of a compound of the present invention, or a pharmaceutically acceptable salt thereof are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that normally found in nature.
  • Isotopes that may be incorporated into compounds of the present invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl, and 125 I.
  • Isotopic variations of the compounds described herein, or pharmaceutically acceptable salts thereof may be prepared by conventional techniques using appropriate isotopic variations of suitable reagents.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, Oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-to
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, Lucaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine,
  • the pharmaceutically acceptable salts of the compounds of the present invention preferably include hydrochloride (such as compound 1-4, 7-23, 26-29, 33-38, 41, 46, 48-49), formate (such as compound 30-32, 39-40, 44-45) and hydrobromide (such as compound 43).
  • hydrochloride such as compound 1-4, 7-23, 26-29, 33-38, 41, 46, 48-49
  • formate such as compound 30-32, 39-40, 44-45
  • hydrobromide such as compound 43.
  • compound of formula II can be prepared by following method:
  • X 1 and X 2 are halogen; PG 1 and G 2 P are protecting groups; LG 1 is a leaving group; R 1 -R 5 and R 11 are as defined in formula II.
  • the Grignard reagent is preferably isopropyl Grignard reagent, and the inert solvent is preferably toluene;
  • II-b is reduced to II-c by a reducing agent in a polar protic solvent
  • the reducing agent is preferably sodium borohydride
  • the polar protic solvent is preferably a methanol/tetrahydrofuran mixed solvent
  • II-c is obtained through halogenation/mesylation/p-toluenesulfonation to obtain II-d;
  • the halogenation reagent is preferably NBS/triphenylphosphine, and the solvent is preferably a halogenated alkane;
  • II-d is alkylated to II-e under the action of a strong base to obtain II-f;
  • the strong base is preferably LDA, and the ether solvent is preferably tetrahydrofuran;
  • the protecting group PG 1 is preferably BOC
  • the deprotection condition is preferably an acid such as trifluoroacetic acid
  • the solvent is preferably a halogenated alkane
  • II-g is ring-closed by a strong base to obtain II-h;
  • the strong base is preferably sodium hydride, and the solvent used is preferably DMAc;
  • II-h obtains II-i by reducing the amide with a reducing agent such as borane; the solvent used is preferably tetrahydrofuran;
  • the bis-boron pinacol ester replaces the bromine in II-i to obtain boron ester II-j;
  • the palladium catalyst is preferably PdCl 2 dppf, the base is preferably potassium phosphate, and the solvent used is preferably p-toluene;
  • Boron ester II-j and aromatic halide R 2 -X 2 are catalyzed by a Pd catalyst and a phosphorus ligand, and a coupling reaction is carried out in a base and an inert solvent to obtain II-k;
  • the Pd catalyst is preferably Pd 2 (dba) 3
  • the phosphorus ligand is preferably XantPhos
  • the base is preferably potassium phosphate
  • the solvent used is preferably a toluene/water mixed solvent;
  • the protecting group is preferably benzyl
  • the deprotection conditions used are preferably chloroethyl chloroformate
  • the solvent used is preferably a halogenated alkane
  • the compound of formula II is obtained through reductive amination reaction of II-1 and aldehyde compound in a polar solvent;
  • the reducing agent used is preferably sodium cyanoborohydride, and the solvent is preferably methanol.
  • the compounds of formulas I, II and III of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs and metabolites are inhibitors of the interaction between YAP/TAZ and TEAD, more specifically, inhibitors of the interaction between YAP and TEAD. Therefore, the compounds of formulas I, II and III of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs and metabolites can be used for the treatment or prevention of diseases mediated by the interaction of YAP/TAZ and TEAD.
  • disease mediated by the interaction between YAP/TAZ and TEAD refers to a disease in which the interaction between YAP/TAZ and TEAD is involved in the occurrence and/or development of the disease, and the purpose of remission, treatment and/or prevention can be achieved by inhibiting the expression and/or activity of YAP and TEAD or by inhibiting or blocking the interaction of YAP-TEAD protein.
  • diseases mediated by the interaction of YAP/TAZ and TEAD include but are not limited to lung cancer (such as non-small cell lung cancer), breast cancer, head and neck cancer, esophageal cancer, ovarian cancer, liver cancer, prostate cancer, mesothelioma, pancreatic cancer, melanoma, colon cancer, thyroid cancer and skin cancer.
  • lung cancer such as non-small cell lung cancer
  • breast cancer breast cancer
  • head and neck cancer esophageal cancer
  • ovarian cancer liver cancer
  • prostate cancer mesothelioma
  • pancreatic cancer pancreatic cancer
  • melanoma colon cancer
  • thyroid cancer thyroid cancer and skin cancer.
  • the disease mediated by the interaction of YAP/TAZ and TEAD is malignant pleural mesothelioma (MPM), a rare thoracic malignancy.
  • MPM malignant pleural mesothelioma
  • Abnormal activation of the Hippo-YAP pathway exists in about 70% of MPM patients and is considered to be an important cancer driver gene. Reducing the activity of the Hippo-YAP pathway through biological means and small chemical molecules has shown good tumor growth inhibitory activity.
  • the disease mediated by the interaction of YAP/TAZ and TEAD is pancreatic ductal adenocarcinoma (PDAC).
  • PDAC pancreatic ductal adenocarcinoma
  • the YAP signaling pathway can produce drug resistance to a variety of anti-cancer targeted drugs by mediating tumor cell dormancy and resisting apoptosis. Inhibiting the Hippo-YAP signaling pathway can increase the sensitivity of tumor cells to targeted drugs. In addition, as a pathway that promotes tumor cell growth, Hippo-YAP is overactivated in multiple drug-resistant tumor models. Inhibiting its activity can significantly increase the sensitivity of therapeutic cells to related inhibitors.
  • compounds I, II and III of the present invention their pharmaceutically acceptable salts, enantiomers, diastereoisomers, tautomers, solvates, isotope substitutions, polymorphs, prodrugs and metabolites can be used to improve the sensitivity of therapeutic cells to targeted drugs (such as EGFR inhibitors, BRAF-targeted inhibitors, MEK-targeted inhibitors, etc.), and improve the therapeutic effect of these tumor-targeted drugs.
  • targeted drugs such as EGFR inhibitors, BRAF-targeted inhibitors, MEK-targeted inhibitors, etc.
  • the present invention provides a method of treating or preventing a disease mediated by the interaction of YAP/TAZ and TEAD as described herein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention I, II or III, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite, or a pharmaceutical composition thereof.
  • Subject or “individual” as used herein refers to mammals, especially primates, more specifically humans.
  • prevent and preventing include reducing the likelihood of a disease or condition occurring or worsening in a patient; the term also includes preventing the occurrence of a disease or condition in a mammal, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with the disease or condition.
  • Treatment and other similar synonyms include the following meanings: (i) inhibiting a disease or condition, i.e. arresting its development; (ii) ameliorating a disease or condition, i.e. causing regression of the state of the disease or condition; or (iii) alleviating the symptoms caused by the disease or condition.
  • the terms “effective amount”, “therapeutically effective amount”, “administered amount”, and “pharmaceutically effective amount” refer to the amount of at least one agent or compound that is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated after administration. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system.
  • a therapeutically "effective amount” is the amount of a composition comprising a compound I, II or III disclosed herein, a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotopic substitution, polymorph, prodrug or metabolite thereof, required to provide a clinically significant disease-modifying effect.
  • the dose can be determined according to the subject's age, sex, disease and its severity and other factors. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to the desired site of biological action.
  • Administration methods known in the art can be used in the present invention. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • the compounds I, II or III of the present invention are administered orally.
  • the compounds I, II or III of the present invention can be used in combination with other pharmacologically active compounds, especially for the treatment of cancer.
  • compounds I, II or III of the present invention pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites, or pharmaceutical compositions thereof of the present invention may be administered simultaneously, sequentially or separately in combination with one or more drugs selected from the group consisting of chemotherapeutic agents such as mitotic inhibitors such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinca Ruibine or vinflunine, other anticancer agents such as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine, etc.
  • chemotherapeutic agents such as mitotic inhibitors such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinca Ruibine or vinflunine
  • the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers, or the pharmaceutical composition containing the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers can also be used together with tumor immunotherapy drugs known in the art, such as anti-PD1 antibodies, etc. for the treatment of cancer.
  • tumor immunotherapy drugs known in the art, such as anti-PD1 antibodies, etc. for the treatment of cancer.
  • the compounds I, II or III of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof can also be used in combination with conventional radiotherapy.
  • combination refers to the drug treatment obtained by mixing or combining more than one active ingredient, which includes fixed and non-fixed combinations of active ingredients, or refers to the combination of two or more different therapeutic means.
  • fixed combination refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form.
  • variable combination refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
  • the present invention also provides a pharmaceutical composition, which contains the compound I, II or III of the present invention, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, solvate, isotope substitution, polymorph, prodrug or metabolite, and a pharmaceutically acceptable carrier or excipient.
  • pharmaceutical composition refers to a preparation containing compound I, II or III, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites thereof and vehicles generally accepted in the art for delivering biologically active compounds to mammals (such as humans).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds I, II or III of the present invention, their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites, and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting with any components contained in the composition in an adverse manner.
  • “Pharmaceutically acceptable carrier or excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent approved by the relevant government regulatory agency as acceptable for human or livestock use.
  • the active ingredients of the pharmaceutical composition of the present invention may contain other known anticancer agents, including but not limited to taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, Vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide and gemcitabine, etc.
  • taxanes including but not limited to taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, Vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide and gemcitabine, etc.
  • the present invention relates to compounds I, II or III of the present invention, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotope substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof in the treatment or prevention of diseases mediated by YAP/TAZ and TEAD interactions described herein, or in the preparation of drugs for the treatment or prevention of diseases mediated by YAP/TAZ-TEAD interactions described herein.
  • the present invention also provides compounds I, II or III described in the present invention, pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, solvates, isotopic substitutions, polymorphs, prodrugs or metabolites or pharmaceutical compositions thereof for the treatment or prevention of diseases mediated by the interaction of YAP/TAZ and TEAD as described herein.
  • the starting materials used in the following examples can be purchased from chemical distributors such as Aldrich, TCI, Alfa Aesar, Bi De, Anaiji, etc., or can be synthesized by known methods.
  • Step 1 Add 1,3-dibromo-5-fluoro-2-iodobenzene (7.50 g, 19.7 mmol), toluene (45 mL) to a dry three-necked flask successively under nitrogen protection, and add isopropylmagnesium chloride (12.8 mL, 25.6 mmol, 2.0 M) dropwise at -30°C, and the obtained brown solution is stirred at -30°C for 30 minutes. Then DMF (4.75g, 65.0mmol) was added to the solution, and the reaction solution was naturally warmed to 0°C in 30 minutes, and continued to stir at 0°C for 30 minutes. Spot plate showed complete reaction.
  • reaction solution was quenched by pouring into saturated ammonium chloride solution.
  • the resulting mixture was extracted with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel chromatography (petroleum ether) to obtain yellow solid A-1 (4.10 g, yield: 73.9%).
  • Step 2 Add compound A-1 (4.10 g, 14.5 mmol), tetrahydrofuran (40 mL), methanol (6 mL) and sodium borohydride (329 mg, 8.70 mmol) sequentially into a dry one-necked bottle.
  • the reaction solution was stirred at 20°C for 0.5 hours. Spot plate showed complete reaction.
  • the reaction solution was concentrated under reduced pressure.
  • the concentrate was diluted with water, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow solid A-2 (4.12 g, crude product).
  • Step 3 Add compound A-2 (4.12g, 14.5mmol), dichloromethane (60mL), triphenylphosphine (4.56g, 17.4mmol) and NBS (3.10g, 17.4mmol) sequentially into a dry single-necked bottle at 20°C. The reaction solution was stirred at 20°C for 0.5 hours. Spot plate showed complete reaction. The reaction solution was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel chromatography (petroleum ether) to obtain white solid A (4.40 g, yield: 87.5%).
  • Step 4 Ethyl 2-bromo-2-phenylacetate (13g, 53.48mmol, 1.0eq), tert-butyl (2-aminoethyl)carbamate (9.42g, 58.82mmol, 1.1eq) were dissolved in ethanol (130mL) and triethylamine (8.12g, 80.21mmol, 1.5eq) was added and stirred at 60°C for 12 hours, TLC showed that the raw material was completely reacted New spots were formed, the reaction solution was spin-dried under reduced pressure, placed in water and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain A1-1 (14 g, crude product) as a yellow oil.
  • Step 5 Dissolve A1-1 (14g, 43.42mmol) in dichloromethane (90mL) and add trifluoroacetic acid (30mL), then react at 20°C for 2h, TLC shows that the reaction of the raw materials is complete and new spots are formed, the reaction solution is spin-dried under reduced pressure, placed in water, adjusted to neutral with saturated NaHCO 3 aqueous solution and extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure to obtain A1-2 (10g , crude product) as a yellow oil.
  • Step 6 Dissolve A1-2 (9.65g, 43.41mmol) in ethanol (100mL) and heat to 85°C, add triethylamine (6.59g, 65.12mmol) and react at this temperature for 12h, TLC shows that the reaction of raw materials is complete and new spots are formed, the reaction solution is spin-dried under reduced pressure, put into water, adjust the pH to neutral with saturated NaHCO 3 aqueous solution and extract with ethyl acetate, and dry the organic phase with anhydrous sodium sulfate. Filtration and spin-drying under reduced pressure gave A1-3 (5.6 g, crude product) as a white solid.
  • Step 8 Compound A1-4 (6.82g, 24.7mmol) was dissolved in tetrahydrofuran (120mL), and 60% sodium hydrogen (1.09g, 27.2mmol) was added in one batch at 20°C, and stirred for 5 minutes. Benzyl bromide (4.83 g, 28.4 mmol) was then added and stirred overnight. After spotting the plate to follow the reaction to completion, the reaction was quenched with methanol (5 mL) and diluted with water (80 mL). Concentrate under reduced pressure to remove most of the solvent.
  • Step 9 To a solution of compound A1-5 (3.59 g, 9.80 mmol) in tetrahydrofuran (40 mL) was added dropwise lithium diisopropylamide solution (6.4 mL, 12.7 mmol, 2.0 M) at -50°C. The reaction solution was stirred at -30°C for 1 hour. Then the temperature was lowered to -50°C, and a solution of compound A (3.40 g, 9.8 mmol) in tetrahydrofuran (10 mL) was added to the reaction solution. The temperature of the reaction solution was gradually raised to 20°C, and stirring was continued for 12 hours. After the reaction was completed, it was quenched by adding saturated ammonium chloride solution.
  • Step ten Add trifluoroacetic acid (20 mL) to a solution of A1-6 (6.10 g, 9.65 mmol) in dichloromethane (40 mL). The reaction solution was stirred at 30°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure. To the residue obtained by concentration was added saturated sodium bicarbonate solution (60 mL), and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow solid A1-7 (5.10 g, yield: 99.2%).
  • Step 12 Add compound A1-8 (4.0 g, 8.86 mmol), tetrahydrofuran (40 mL) and borane dimethyl sulfide (35.5 mL, 70.9 mmol, 2M) sequentially into a dry one-necked bottle. The reaction solution was stirred at 65°C for 20 hours. The reaction solution was quenched with methanol, then concentrated to dryness under reduced pressure. The obtained residue was dissolved in methanol (40 mL) and 4N dioxane hydrochloride (20 mL), and the reaction solution was stirred at 20° C. for 1 hour.
  • reaction solution was concentrated to dryness under reduced pressure, added with saturated sodium bicarbonate solution (150 mL), and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain colorless oil A1-9 (4.10 g, crude product).
  • Step 13 Add compound A1-9 (4.10 g, 8.86 mmol), 1,2-dichloroethane (40 mL) and 2-chloroethyl chloroformate (3.17 g, 22.2 mmol) sequentially into a dry one-necked bottle.
  • the reaction solution was stirred at 80°C for 16 hours.
  • the reaction solution was concentrated to dryness under reduced pressure.
  • the obtained residue was dissolved in methanol and stirred at 75°C for 1.5 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain compound 6 (3.10 g, crude product) as a yellow oil.
  • Step 14 Add compound 6 (3.08g, 8.86mmol), dichloromethane (50mL), triethylamine (3.58g, 35.4mmol) and Boc 2 O (2.90g, 13.3mmol) sequentially into a dry one-necked bottle.
  • the reaction solution was stirred at 20°C for 1 hour and then concentrated under reduced pressure.
  • Step 16 Add compound A1-11 (600mg, 1.25mmol), bis-pinacol borate (635mg, 2.50mmol), xylene (10mL), Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (102mg, 0.125mmol) and potassium pivalate (526mg, 3.75mmol) in a dry three-necked flask.
  • Step 1 Add tetraisopropyl titanate (24 g, 84.9 mmol) dropwise to a solution of 3-benzyloxybenzaldehyde (A2-1, 45 g, 212.3 mmol) in dichloromethane (900 mL) under the protection of argon at 0°C. After slowly warming to room temperature, TMSCN (84.2 g, 849.2 mmol) was added. Stir at room temperature for 4h. TLC showed that the reaction was complete, and the reaction was quenched by adding aqueous hydrochloric acid (20ml, 1.5M) at 0°C. Water (270 mL) was added and extracted with ethyl acetate (3 x 200 mL).
  • Step 2 2-(3-(benzyloxy)phenyl)-2-hydroxyacetonitrile (44g, 183.9mmol) was dissolved in HCl/MeOH (4N, 500ml). The reaction was stirred at 80°C for 14h. TLC confirmed complete reaction. The reaction solution was concentrated under reduced pressure to nearly dryness. The residue was added with water (400 mL) and extracted with ethyl acetate (3*300 mL). The organic phases were combined, washed with water (2*150 mL) and saturated brine (100 mL).
  • Step 3 To a solution of methyl 2-(3-(benzyloxy)phenyl)-2-hydroxyacetate (37.3 g, 137.0 mmol) in dichloromethane (100 mL) was added SOCl 2 (18 g, 150.7 mmol). The temperature was raised to 60°C for 5h. TLC showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure. Water (100 mL) was added to the residue, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. Extracted with ethyl acetate (3*400 mL). The organic phases were combined, washed with water (2*200mL) and saturated brine (3*200mL).
  • Step 4 Add triethylamine (18.5 g, 183.2 mmol) and N-tert-butoxycarbonyl-1,2-ethylenediamine (25.4 g, 158.6 mmol) to a solution of methyl 2-(3-(benzyloxy)phenyl)-2-chloroacetate (35.5 g, 122.1 mmol) in methanol (350 mL). The temperature was raised to 60°C and the reaction was stirred for 18h. TLC and LCMS showed the reaction was complete. The reaction solution was concentrated under reduced pressure. The residue was added with water (600 mL) and extracted with ethyl acetate (3*200 mL). The combined organic phases were washed with saturated brine (3 ⁇ 200 mL).
  • Step 5 Trifluoroacetic acid (60 mL) was added dropwise to a solution of methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-(3-(benzyloxy)phenyl)acetate (30.0 g, 72.4 mmol) in dichloromethane (300 mL). Reaction at 20°C for 2h. The reaction solution was concentrated to dryness under reduced pressure. Ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate (300 mL) were added to the residue. The organic phase was collected and the aqueous phase was extracted with ethyl acetate (3*150 mL).
  • Step 6 To a solution of methyl 2-((2-aminoethyl)amino)-2-(3-(benzyloxy)phenyl)acetate (27.0 g, 85.85 mmol) in ethanol (50 mL) was added triethylamine (13.0 g, 128.77 mmol). The reaction was stirred at 85°C for 3h.
  • reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate (100 mL), washed with water (3*100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude 3-(3-(benzyloxy)phenyl)piperazin-2-one (A2-7, 17.0 g, two-step yield: 83%), which was directly used in the next reaction.
  • Step 7 Di-tert-butyl dicarbonate (14.5 g, 66.3 mmol) and triethylamine (18.3 g, 180.8 mmol) were added to a solution of 3-(3-(benzyloxy)phenyl)piperazin-2-one (17.0 g, 60.3 mmol) in 1,4-dioxane (150 ml). Stir at 90°C for 1.5h.
  • reaction solution was concentrated to dryness, diethyl ether (100 mL) was added to stir for slurry, and a white solid 2-(3-(benzyloxy)phenyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (A2-8, 18.0 g, yield: 78.2%) was obtained by filtration.
  • Step 8 Add NaH (60% dispersion in oil, 785 mg, 19.6 mmol) to a solution of tert-butyl 2-(3-(benzyloxy)phenyl)-3-oxopiperazine-1-carboxylate (5.0 g, 13.1 mmol) in THF (75 mL) at 20°C under the protection of argon. After stirring for 30 min benzyl bromide (3.4 g, 19.62 mmol) was added. Greenhouse stirring reaction 16h. The reaction solution was diluted with ethyl acetate (100 mL), and poured into ice water (150 mL).
  • Step 9 Add LDA (2.0M in THF, 14.9mL, 29.8mmol) dropwise to a solution of tert-butyl 4-benzyl-2-(3-(benzyloxy)phenyl)-3-oxopiperazine-1-carboxylate (10.8g, 22.9mmol) in tetrahydrofuran (150mL) under the protection of argon at -50°C. After dropping, stir at -30°C for 1h. The temperature was lowered to -50°C, and a solution of 1,3-dibromo-2-(bromomethyl)-5-fluorobenzene (7.2 g, 20.8 mmol) in tetrahydrofuran (50 mL) was added dropwise.
  • LDA 2.0M in THF, 14.9mL, 29.8mmol
  • Step ten Trifluoroacetic acid (45 mL) was added dropwise to a solution of 4-benzyl-2-(3-(benzyloxy)phenyl)-2-(2,6-dibromo-4-fluorobenzyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester (13.0 g, 17.6 mmol) in dichloromethane (85 mL). Reaction at 30°C for 2h. Concentrate to dryness under reduced pressure. The residue was added dichloromethane (200 mL) and saturated aqueous sodium bicarbonate (300 mL). The aqueous phase was further extracted with dichloromethane (3*150 mL).
  • Step eleven 1-benzyl-3-(3-(benzyloxy)phenyl)-3-(2,6-dibromo-4-fluorobenzyl)piperazin-2-one (3.0 g, 4.70 mmol) was dissolved in trifluoroacetic acid (50 mL). Heated to 60°C and stirred for 2h.
  • reaction solution was concentrated to dryness under reduced pressure, then diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium bicarbonate (400 mL), washed with saturated brine (2*400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (0 to 50% gradient of ethyl acetate: petroleum ether) to obtain 1-benzyl-3-(2,6-dibromo-4-fluorobenzyl)-3-(3-hydroxyphenyl)piperazine-2 as a white solid - Ketone (A2-12, 2.1 g, yield: 82%).
  • Step twelve To a solution of 1-benzyl-3-(2,6-dibromo-4-fluorobenzyl)-3-(3-hydroxyphenyl)piperazin-2-one (1.9 g, 3.47 mmol) and potassium carbonate (1.4 g, 10.40 mmol) in MeCN (30 mL) was added dimethyl sulfate (525 mg, 4.16 mmol). The reaction was heated to 60°C and stirred for 4h. The reaction solution was diluted with ethyl acetate (100mL), washed with saturated aqueous sodium bicarbonate (100mL), washed with saturated brine (2*100mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 2-13, 1.16 g, yield: 60%).
  • Step 1 Add N-bromosuccinimide (34.40 g, 193.26 mmol) and azobisisobutyronitrile (9.76 g, 59.46 mmol) to a solution of methyl 3-fluoro-phenylacetate (25.00 g, 148.66 mmol) in carbon tetrachloride (250 mL) under the protection of argon. Heated to 70°C for 20h. LCMS monitored the completion of the reaction.
  • Step 1 to Step 9 Refer to the synthesis method of intermediate A3, replace A3-1 with A5-1, and perform nine-step reaction to obtain intermediate A5-10.
  • Step 10 Add compound A5-10 (585mg, 1.29mmol), tetrahydrofuran (10mL) and borane dimethyl sulfide (5.2mL, 10.3mmol, 2M) sequentially into a dry single-necked bottle. The reaction solution was stirred at 35°C for 50 hours. The reaction solution was quenched with methanol, then concentrated to dryness under reduced pressure. The obtained residue was dissolved in methanol (10 mL) and 4N dioxane hydrochloride (2 mL), and the reaction solution was stirred at 20° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, saturated sodium bicarbonate solution (20 mL) was added, and extracted twice with ethyl acetate.
  • Step 12 Add compound A5-12 (310mg, 0.656mmol), bis-pinacol borate (333mg, 1.31mmol), xylene (6mL), Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (54mg, 0.066mmol) and potassium pivalate (276mg, 1.97mmol) in a dry three-necked flask.
  • the reaction solution was stirred under nitrogen protection at 100°C for 12 hours. After the reaction was completed, the reaction solution was diluted with water and extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow oil A5 (250 mg, crude product).
  • Step 1 Add compound A1-11 (200mg, 0.42mmol) and sodium methoxide solution (6mL, 5.4M) into a single-necked bottle. The mixture was heated to 80°C overnight. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50 mL*2), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain yellow oil A6-1 (250 mg, crude product).
  • Step 2 Refer to the synthesis method of intermediate A1, replace A1-11 with A6-1, and perform a one-step reaction to obtain intermediate A6.
  • Step 1 Add compound A1-10 (390 mg, 0.87 mmol) and anhydrous tetrahydrofuran (5 mL) into a three-neck flask. LDA (0.865 mL, 2M, 1.73 mmol) was added dropwise at -50°C. The mixture was continued to react at -50°C for 45 minutes. Then iodomethane (246 mg, 1.73 mmol) was added dropwise.
  • Step 2 Refer to the synthesis method of intermediate A1, replace A1-11 with A7-1, and perform a one-step reaction to obtain intermediate A7.
  • Step 1 At 25 degrees Celsius, add dichloromethane (20mL), 2-bromo-3,4-difluorobenzoic acid (B1-1, 2g, 8.44mmol, 1.0eq), HATU (4.83g, 12.7mmol, 1.5eq), triethylamine (5.5mL, 42.2mmol, 5.0eq) and ammonium chloride (1.35g, 25.3 mmol, 3.0 eq). The yellow reaction was stirred at this temperature for 12 hours. TLC showed the reaction was complete.
  • Step 2 At 25°C, tetrahydrofuran (20mL), 2-bromo-3,4-difluorobenzamide (B1-2, 1.8g, 7.63mmol, 1.0eq), triethylamine (2.12mL, 15.3mmol, 2.0eq) and trifluoroacetic anhydride (2.39g, 11.4mmol, 1.5eq) were successively added into a round bottom flask. The yellow reaction was stirred at this temperature for 12 hours. TLC showed the reaction was complete.
  • Step 3 Add dimethylsulfoxide (11.5mL), 2-bromo-3,4-difluorobenzonitrile (B1-3, 1.5g, 6.88mmol, 1.0eq), potassium carbonate (4.75g, 34.4mmol, 5.0eq) and acetylhydroxamic acid (1.55g, 20.6mmol, 3.0eq) into a round-bottomed flask successively.
  • the yellow reaction solution was warmed up to 80°C and stirred for 4 hours. TLC showed the reaction was complete.
  • Step 1 Add tetrahydrofuran (20mL), 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (B2-1, 1.76g, 10.0mmol, 1.0eq), imidazole (2.04g, 30.0mmol, 3.0eq), triphenylphosphine (3.93g, 15.0mmol, 1.5eq ) and elemental iodine (3.04g, 12.0mmol, 1.2eq). The pale yellow reaction was stirred at this temperature for 2 hours. TLC showed the reaction was complete.
  • Step 2 Add compound B1 (500 mg, 2.31 mmol), DMF (10 mL), compound B2-2 (727 mg, 2.54 mmol) and potassium carbonate (638 mg, 4.62 mmol) sequentially into a dry single-necked bottle.
  • the reaction solution was stirred at 80° C. for 12 hours.
  • the reaction solution was diluted with water, and the aqueous phase was extracted twice with petroleum ether/ethyl acetate (1/1, 30 mL).
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 1 At 25°C, add anhydrous methanol (42mL), 2-bromo-3,4-difluorobenzoic acid (B1-1, 3.3g, 14.8mmol, 1.0eq) into a round bottom flask in sequence, and then add thionyl chloride (7mL) dropwise. The yellow reaction was stirred at this temperature for 4 hours. TLC showed the reaction was complete. The volatiles were removed under reduced pressure, and the resulting residue was purified by silica gel chromatography (petroleum ether) to give methyl 2-bromo-3,4-difluorobenzoate (B3-1, 3.4 g, yield: 92.6%) as a yellow oil.
  • 2-bromo-3,4-difluorobenzoic acid B1-1, 3.3g, 14.8mmol, 1.0eq
  • Step 2 refer to the synthesis method of intermediate B1 step 3 to obtain yellow solid methyl 2-bromo-3-fluoro-4-hydroxybenzoate (B3-2, 3.5 g, yield: 93.5%).
  • Step 3 Refer to the synthesis method of intermediate B2 step 2 to obtain colorless oily product 2-bromo-4-(2-(((tert-butyldimethylsilyl)oxy)ethoxy)-3-fluorobenzoic acid methyl ester (B3, 1.44g, yield: 88.3%).
  • Step 1 Add compound B1 (500mg, 2.31mmol), DMF (10mL), ethyl bromoacetate (463mg, 2.77mmol) and potassium carbonate (638mg, 4.62mmol) sequentially into a dry one-necked bottle.
  • the reaction solution was stirred at 20°C for 12 hours.
  • the reaction solution was diluted with water, and the aqueous phase was extracted twice with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 1 Add compound B1-3 (1.0 g, 4.59 mmol), diethyl malonate (883 mg, 5.51 mmol), DMF (10 mL) and potassium carbonate (1.27 g, 9.18 mmol) sequentially into a dry one-necked bottle.
  • the reaction solution was stirred at 35°C for 12 hours.
  • the reaction solution was diluted with water and extracted twice with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 2 Add compound B5-1 (1.60 g, 4.47 mmol), dimethyl sulfoxide (16 mL), water (0.8 mL) and lithium chloride (379 mg, 8.94 mmol) sequentially into a dry one-necked bottle.
  • the reaction solution was stirred at 85°C for 36 hours.
  • the reaction solution was diluted with water and extracted twice with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 4 Add compound B5-3 (100mg, 0.410mmol), dichloromethane (3mL), DMF (1mL), tert-butyldimethylsilyl chloride (93mg, 0.615mmol) and N,N-diisopropylethylamine (106mg, 0.820mmol) sequentially into a dry one-necked bottle.
  • the reaction solution was stirred at 20°C for 1 hour.
  • the reaction solution was diluted with water and extracted twice with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 1 Add L-methyl lactate (1.0g, 9.61mmol), dichloromethane (15mL), tert-butyldimethylsilyl chloride (1.88g, 12.5mmol), triethylamine (1.46g, 14.4mmol) and 4-dimethylaminopyridine (117mg, 0.961mmol) sequentially into a dry one-necked bottle.
  • the reaction solution was stirred at 20°C for 12 hours.
  • the reaction solution was diluted with water and extracted twice with dichloromethane.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 2 Add compound B10-1 (1.70g, 7.78mmol), tetrahydrofuran (20mL) and diisobutylaluminum hydride (13.0mL, 19.5mmol, 1.5M) sequentially into a dry one-necked flask at 0°C.
  • the reaction solution was stirred at 25°C for 2 hours.
  • the reaction was quenched by adding 1.0 M sodium potassium tartrate solution (30 mL) at 0°C, and stirring was continued at 25°C for 30 minutes.
  • the resulting mixture was extracted twice with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 3 Add compound B10-2 (500mg, 2.63mmol), dichloromethane (10mL), triethylamine (798mg, 7.89mmol) and methanesulfonic anhydride (688mg, 3.95mmol) sequentially into a dry one-necked bottle at 0°C.
  • the reaction solution was stirred at 25°C for 2 hours.
  • the reaction solution was diluted with water and extracted twice with dichloromethane.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 4 Add compound B1 (200mg, 0.926mmol), DMF (6mL), compound B10-3 (274mg, 1.02mmol), sodium iodide (274mg, 1.85mmol) and potassium carbonate (256mg, 1.85mmol) sequentially into a dry single-necked bottle.
  • the reaction solution was stirred at 80° C. for 12 hours.
  • the reaction solution was diluted with water and extracted twice with petroleum ether/ethyl acetate (1/1, 15 mL).
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • a colorless oily substance B12 (1.32 g, yield: 85.7%) was synthesized referring to the synthesis method of intermediate B3.
  • Step 1 B13-1 (6.5g, 27.8mmol, 1.0eq), DMF-DMA (13mL, 61.1mmol, 2.2eq), triethylamine (4.25mL, 61.1mmol, 2.2eq) and DMF (25mL) were sequentially added to a 500mL round bottom flask, then heated to 110°C and stirred for 3 hours. TLC showed that the reaction was complete, and the reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (50 mL*3).
  • Step 2 Under nitrogen protection, compound B13-2 (3.7g, 17.3mmol, 1.0eq), zinc cyanide (1.34g, 11.42mmol, 0.66eq) and t-BuXPhos-Pd-G3 (686mg, 0.86mmol, 0.05eq) were sequentially added into a dry three-necked flask, and then THF/H 2 O (10mL/50mL) was added, The reaction solution was stirred at 40°C for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (0-40% ethyl acetate/petroleum ether) to obtain yellow solid B13-3 (2.85 g, yield: 93%).
  • Step 3 Under nitrogen protection, compound B13-3 (0.68g, 4.25mmol, 1.0eq), triethylsilylhydrogen (1mL, 26.6mmol, 6.25eq) and tetrahydrofuran (6mL) were sequentially added to a dry round bottom flask, and the reaction solution was stirred at 60°C for 5 hours. TLC showed that the reaction was complete, and the reaction solution was spin-dried, diluted with water (10 mL), and extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with saturated aqueous sodium bicarbonate (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (0-50% ethyl acetate/petroleum ether) to obtain yellow solid B13-4 (566 mg, yield: 82.2%).
  • Step 4 Under cooling in an ice bath, compound B13-4 (562mg, 3.47mmol, 1.0eq) and acetonitrile (10mL) were sequentially added to a dry round bottom flask, and then a solution of NBS (617mg, 3.47mmol, 1.0eq) in acetonitrile (10mL) was added dropwise. The reaction solution was stirred at 0°C for 0.5 hours. TLC showed that the reaction was complete, and the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL*3).
  • Step 5 Add compound B13-5 (50mg, 0.2mmol, 1.0eq) and dichloromethane (4mL) sequentially to a dry round bottom flask under ice cooling, then add (Boc) 2 O (66mg, 0.3mmol, 1.5eq) and DMAP (24.4mg, 0.2mmol, 1.0eq). The reaction solution was stirred at room temperature for 2 hours. TLC showed that the reaction was complete, and the reaction solution was concentrated. The resulting residue was purified by silica gel chromatography (0-20% ethyl acetate/petroleum ether) to afford white solid B13 (50 mg, yield: 73%).
  • Step 2 Acetic acid (20 mL), B14-2 (21.0 g, 4.65 mmol, 1.0 eq) and NIS (1.57 g, 6.98 mmol, 1.5 eq) were sequentially added to a dry one-necked bottle. The reaction solution was stirred at 25° C. for 12 hours. After the reaction was complete, the reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (35 mL*3).
  • Step 3 Add tetrahydrofuran (20mL), B14-3 (1.5g, 4.4mmol, 1.0eq), ditriphenylphosphinepalladium dichloride (154mg, 0.22mmol, 0.05eq), cuprous iodide (84mg, 0.44mmol, 0.1eq) and triethylamine (1.22mL, 8.8mmol, 2.0eq), and ethynyltrimethylsilane (682uL, 4.84mmol, 1.1eq) was added dropwise with stirring. The reaction solution was stirred at 25° C. for 12 hours.
  • reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (45 mL*3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in anhydrous methanol (20 mL), then potassium carbonate (1.22 g, 8.8 mmol, 2.0 eq) was added, and the reaction solution was stirred for 2 hours. After the reaction was complete, it was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-13% ethyl acetate/petroleum ether) to obtain yellow solid B14-4 (700 mg, yield: 66.7%).
  • Step 4 Under nitrogen protection, pyridine (10 mL), compound B14-4 (700 mg, 2.93 mmol, 1.0 eq) and CpRuCl(PPh 3 ) 2 (233 mg, 0.29 mmol, 0.1 eq) were sequentially added into a dry three-necked flask. The reaction solution was stirred at 90°C for 12 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (0-13% ethyl acetate/petroleum ether) to obtain yellow solid B14-5 (170 mg, yield: 24.3%).
  • Step 5 Add dichloromethane (2mL), B14-5 (70mg, 0.29mmol, 1.0eq), Boc 2 O (96mg, 0.44mmol, 1.5eq), triethylamine (82uL, 0.59mmol, 2.0eq) and N,N-lutidine (4mg, 0.03mmol, 0.1eq) into a dry one-necked bottle in sequence.
  • the reaction solution was stirred at 25°C for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (0-7.2% ethyl acetate/petroleum ether) to obtain white solid B14 (94 mg, yield: 94.9%).
  • Step 2 Dissolve 5-bromo-3-fluoropyridin-2-amine (B15-2, 74.50g, 390.05mmol) in tetrahydrofuran (260mL) and water (1000mL), add Zn(CN) 2 (30.22g, 257.45mmol), and replace with argon in vacuum three times. Add t-BuXPhos-Pd G3. (6.80 g, 8.56 mmol), and replace with argon in vacuum 3 times. React at 40°C for 15 hours.
  • reaction solution was slowly poured into ice water (1.0L), extracted with ethyl acetate (3*400mL), and the insoluble matter was filtered off with diatomaceous earth, and the filter residue was rinsed with tetrahydrofuran (300mL).
  • Step 3 6-amino-5-fluoronicotinonitrile (B15-3, 28.53 g, 208.10 mmol) was dissolved in acetone (290 mL) and tert-butanol (145 mL), and DMAP (82.84 g, 677.9 mmol) was added.
  • Step 4 Dissolve tert-butyl N-(3-fluoro-5-cyanopyridin-2-yl)-N-[(2-methylpropan-2-yl)oxycarbonyl]carbamate (B15-4, 58.32g, 172.85mmol) in tetrahydrofuran (630mL), add iodine (87.72g, 345.64mmol), protect with nitrogen, and cool down to -65°C. LDA (2.0M in THF, 440 mL, 888.00 mmol) was added dropwise. After dropping, stir for 10 minutes, then rise to room temperature and react for 16 hours.
  • iodine 87.72g, 345.64mmol
  • reaction solution was slowly poured into ice water (1.0L), extracted with ethyl acetate (3*400mL), the organic phase was washed with saturated brine (2*500mL), the organic phase was dried and concentrated, purified by silica gel column chromatography (0-10% ethyl acetate/petroleum ether), and then slurried with dichloromethane/petroleum ether (1/50) to obtain light yellow powder (5-cyano-3-fluoro-4-iodopyridin-2-yl) tert-butyl carbamate ( B15-5, 23.27g, yield: 37.1%).
  • Step 5 To a solution of tert-butyl (5-cyano-3-fluoro-4-iodopyridin-2-yl)carbamate (B15-5, 32.06g, 88.29mmol) in dichloromethane (360mL) was added dropwise trifluoroacetic acid (130mL) at 0°C. React at room temperature for 2 hours. The reaction solution was concentrated to remove most of the solvent and trifluoroacetic acid.
  • Step 6 Dissolve 6-amino-5-fluoro-4-iodonicotinonitrile (B15-6, 4.58g, 17.43mmol) in tetrafluoroboric acid (150mL), cool down to -10°C, add NaNO 2 (3.32g, 48.13mmol) in batches, and react for 2 hours.
  • reaction solution was poured into icy sodium carbonate aqueous solution (800mL), stirred for 5 minutes, extracted with ethyl acetate (3*200mL), the organic phase was washed with saturated brine (100mL), dried, concentrated, and purified by silica gel column chromatography (0-5% ethyl acetate/petroleum ether) to obtain white solid 5,6-difluoro-4-iodonicotinonitrile (B15-7, 1.47g, yield: 31.7%).
  • Step 7 Dissolve 2-((tert-butyldimethylsilyl)oxy)ethyl-1-hydroxyl (B15-7, 72mg, 0.40mmol) in tetrahydrofuran (8mL), cool down to 0°C, add sodium hydrogen (32mg, 0.76mmol, 60%) in batches, and react for 30 minutes. Then a tetrahydrofuran solution (2 mL) of 5,6-difluoro-4-iodonicotinonitrile (100 mg, 0.37 mmol) was added dropwise, and stirred at room temperature for 2 hours.
  • Step 1 Referring to the synthesis of compound B4, compound B18-1 was synthesized through one-step reaction.
  • Step 2 Referring to the synthesis of compound B17, intermediate compound B18 was synthesized through one-step reaction.
  • Step 1 N,N-dimethylformamide (15mL), 2-bromo-3-fluoro-4-hydroxybenzonitrile (B1, 1.0g, 4.63mmol, 1.0eq), cesium carbonate (3.01g, 9.26mmol, 2.0eq) and sodium chlorodifluoroacetate (1.06g, 6.94mmol, 1.5eq) were sequentially added to a round bottom flask. The yellow reaction solution was warmed up to 90°C and stirred for 6 hours (gas evolution occurred). TLC showed the reaction was complete.
  • Embodiment one the synthesis of compound 1
  • Step 1 Dissolve HMPA (3.0mL) and LDA (7.7mL, 15.4mmol, 2.0M) in anhydrous THF (100mL), and slowly add A1-5 (1.7g, 4.64mmol) in THF (25mL) dropwise at -60°C. After the drop, the reaction solution is heated to -30°C and stirred for 30 minutes, and then stirred at -60°C for another 30 minutes. Then a solution of compound 1-1 (2.20 g, 8.35 mmol) in tetrahydrofuran (10 mL) was added dropwise at -60°C.
  • Embodiment 2 the synthesis of compound 6
  • Step 1 Add compound A1-9 (4.10 g, 8.86 mmol), 1,2-dichloroethane (40 mL) and 2-chloroethyl chloroformate (3.17 g, 22.2 mmol) sequentially into a dry one-necked bottle. The reaction solution was stirred at 80°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure. The obtained residue was dissolved in methanol and stirred at 75°C for 1.5 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain a yellow oil (compound 6, 3.10 g).
  • Embodiment 3 the synthesis of compound 7
  • Embodiment 4 the synthesis of compound 8
  • Step 2 Referring to the synthesis of compound 7, compound 8 was obtained by one-step reaction.
  • Embodiment 5 the synthesis of compound 15
  • Step 2 Add compound 15-1 (19mg, 0.040mmol), methanol (5mL), and hydrogen chloride dioxane solution (1mL, 4mmol) into a single-necked flask in sequence, and stir the reaction solution at 25°C for 3 hours. The solvent was removed under reduced pressure to obtain compound 15 (12 mg, yield: 65.57%) as a yellow solid.
  • Embodiment 6 the synthesis of compound 30
  • Step 1 Referring to the synthesis of compound 15-1, compound 30-2 was obtained in one step.
  • Step 3 Referring to the synthesis of compound B1-2, a one-step reaction was carried out to obtain compound 30-4.
  • Step 4 Referring to the synthesis of compound 15, carry out a one-step reaction to obtain compound 30.
  • Embodiment seven the synthesis of compound 41
  • Step 3 sequentially add compound 41-2 (5 mg, 0.008 mmol), methanol (2 mL) and dioxane hydrochloride (1 mL, 4.0 M) into a single-necked flask, and stir the reaction solution at 20° C. for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was lyophilized to obtain white solid compound 41 (3.7 mg, hydrochloride, yield: 82.2%).
  • Embodiment eight the synthesis of compound 42
  • compound 42-1 was used instead of compound 41-1, and compound 42 was obtained by two-step reaction.
  • Embodiment nine the synthesis of compound 43
  • compound B2 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a three-step reaction to obtain compound 43.
  • Embodiment ten the synthesis of compound 44
  • compound 44-1 was used instead of compound 41-1, and compound 44 was obtained by two-step reaction.
  • Embodiment eleven the synthesis of compound 45
  • Step 1 and Step 2 Refer to the synthesis method of compound 41-2, using compound B4 instead of compound B20, and XantPhos instead of NiXantPhos to carry out two-step reactions to obtain compound 45-2.
  • Step 3 Add compound 45-2 (100mg, 0.156mmol), tetrahydrofuran (1mL), methanol (1mL), water (1mL) and lithium hydroxide monohydrate (66mg, 1.56mmol) into a single-necked flask successively, and stir the reaction solution at 20°C for 1 hour.
  • the mixture was diluted with water and extracted twice with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain off-white solid 45-3 (90 mg, yield: 93.8%).
  • Step 4 Add compound 45-3 (90 mg, 0.147 mmol), methanol (2.5 mL), and dioxane hydrochloride (1.0 mL, 4M) to a single-necked flask in sequence, and stir the reaction solution at 20° C. for 1 hour.
  • the mixture was diluted with water and extracted twice with ethyl acetate.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 5 Add compound 45-4 (50mg, 0.095mmol), tetrahydrofuran (1mL), methanol (1mL), water (1mL) and sodium hydroxide (60mg, 1.50mmol) into a single-necked flask successively, and the reaction solution was stirred at 20°C for 1 hour.
  • the mixture was concentrated to dryness, the residue was diluted with dichloromethane/methanol (10:1, 5 mL), and the resulting suspension was filtered. The filtrate was concentrated under reduced pressure to obtain off-white solid 45 (16 mg, yield: 30.8%).
  • Embodiment 12 the synthesis of compound 46
  • compound 46-1 was used instead of compound 45-4, and compound 46 was obtained by one-step reaction.
  • Embodiment 13 the synthesis of compound 47
  • Step 1 Add compound 44 (10mg, 0.019mmol), compound C1 (5mg, 0.029mmol), dichloromethane (1mL) and sodium triacetylborohydride (6mg, 0.029mmol) sequentially into a single-necked flask, and the reaction solution was stirred at 20°C for 2 hours.
  • the reaction solution was diluted with water and extracted twice with dichloromethane.
  • the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 2 sequentially add compound 47-1 (9 mg, 0.014 mmol), methanol (2.0 mL) and dioxane hydrochloride (1.0 mL, 4M) into a single-necked flask, and stir the reaction solution at 20° C. for 1 hour.
  • the reaction solution was concentrated under reduced pressure and lyophilized to obtain off-white solid 47 (5.5 mg, hydrochloride, yield: 67.9%).
  • Embodiment 14 the synthesis of compound 48
  • compound B5 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a three-step reaction to obtain compound 48.
  • Embodiment 15 the synthesis of compound 49
  • compound 49-1 was used instead of compound 41-2, and compound 49 was obtained by one-step reaction.
  • Embodiment 16 the synthesis of compound 50
  • compound B6 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a three-step reaction to obtain compound 50.
  • Embodiment 17 the synthesis of compound 51
  • compound 51-1 was used instead of compound 41-2, and compound 51 was obtained by one-step reaction.
  • Embodiment 18 the synthesis of compound 52
  • Step 1 Referring to the synthesis method of compound 45-3, compound B5-2 was used instead of compound B4, and a three-step reaction was carried out to obtain compound 52-3.
  • Step 4 Add compound 52-3 (18mg, 0.048mmol), dioxane (2.0mL) and dioxane hydrochloride (1.0mL, 4M) to a single-necked flask in turn, and stir the reaction solution at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure and lyophilized to give yellow solid 52 (14 mg, hydrochloride).
  • Embodiment nineteen the synthesis of compound 53
  • compound 53-1 was used instead of compound 52-2, and compound 53 was obtained by two-step reaction.
  • Embodiment 20 Synthesis of Compound 54
  • compound B7 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a three-step reaction to obtain compound 54.
  • Embodiment 21 Synthesis of Compound 55
  • compound 55-1 was used instead of compound 41-2, and compound 55 was obtained by one-step reaction.
  • Embodiment 22 Synthesis of Compound 56
  • compound B8 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a three-step reaction to obtain compound 56.
  • compound 57-1 was used instead of compound 41-2, and compound 57 was obtained by one-step reaction.
  • compound B9 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a three-step reaction to obtain compound 58.
  • compound 59-1 was used instead of compound 41-2, and compound 59 was obtained by one-step reaction.
  • Embodiment 26 the synthesis of compound 60
  • compound B10 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a three-step reaction to obtain compound 60.
  • Embodiment 27 Synthesis of Compound 61
  • compound 61-1 was used instead of compound 41-2, and compound 61 was obtained by one-step reaction.
  • Embodiment 28 Synthesis of Compound 62
  • compound B11 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a three-step reaction to obtain compound 62.
  • Embodiment 29 Synthesis of Compound 63
  • compound 63-1 was used instead of compound 41-2, and compound 63 was obtained by one-step reaction.
  • Embodiment 30 the synthesis of compound 64
  • Step 1 and Step 2 Referring to the synthesis method of compound 41-2, compound B14 was used instead of compound B20, and XantPhos was used instead of NiXantPhos to perform a two-step reaction to obtain compound 64-2 and compound 65-1.
  • Step 3 Add compound 64-2 (12 mg, 0.018 mmol), dichloromethane (2 mL) and trifluoroacetic acid (1 mL) to a one-necked flask in sequence, and stir the reaction solution at 20° C. for 2 hours. The reaction solution was concentrated under reduced pressure. A saturated sodium bicarbonate solution (6 mL) was added to the obtained residue, followed by extraction with ethyl acetate twice. The combined organic phases were concentrated under reduced pressure and lyophilized to afford white solid 64 (5 mg, yield: 58.1%).
  • Embodiment thirty-one the synthesis of compound 65
  • compound 65-1 was used instead of compound 64-2, and compound 65 was obtained by one-step reaction.
  • Embodiment thirty-two the synthesis of compound 66
  • Step 2 Referring to the synthesis method of compound A1, compound 66-2 was synthesized by using compound 66-1 instead of compound A1-11.
  • Step 3 to Step 5 Referring to the synthesis method of compound 41, using compound 66-2 instead of compound A20, a three-step reaction was carried out to obtain compound 66.
  • Embodiment thirty-four the synthesis of compound 68
  • compound 68-1 was used instead of compound A1-11, and compound 68 was obtained by four-step reaction.
  • compound 69-1 was used instead of compound 41-2, and compound 69 was obtained by one-step reaction.
  • Embodiment thirty-six the synthesis of compound 70
  • Step 1 Referring to the synthesis step 1 of compound 43, compound 72-1 (yellow solid, 20 mg, yield: 74.1%) was synthesized by using intermediate B12 instead of B2.
  • Step 3 Dissolve 72-2 (4 mg, 0.006 mmol, 1.0 eq) in dichloromethane (500 uL), cool to minus 70 degrees Celsius with a dry ice acetone bath, and then add boron tribromide (18 uL, 0.018 mmol, 3.0 eq). Stirred at low temperature for thirty minutes, LCMS showed product formation. The reaction was quenched by adding methanol (1 mL) at low temperature, concentrated under reduced pressure, and the residue was separated by preparative HPLC (formic acid system) to obtain crude compound 72 (1 mg, yield: 33.3%) as a white solid.
  • Step 1 Compounds 73-1 (yellow solid, 80 mg) and 73-2 (yellow solid, 80 mg) were synthesized by referring to the method of synthetic step 1 of compound 43.
  • Step 2 73-1 (80 mg, 0.11 mmol, 1.0 eq) was dissolved in tetrahydrofuran (500 uL), methanol (500 uL) and water (500 uL), and then lithium hydroxide monohydrate (14 mg, 0.33 mmol, 3.0 eq) was added.
  • the reaction solution was reacted at 25 degrees Celsius for 12 hours, and TLC showed that the reaction was complete.
  • the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure to give yellow solid 73-3 (90 mg, crude).
  • Step 3 Under 25 degrees Celsius conditions, add dichloromethane (10ml), 73-3 (33mg, 0.055 mmol, 1.0EQ), ethylamine hydrochloride (9mg, 0.11mmol, 2.0EQ), trio, 0.22mmmol, 4.0EQ), and TBTU (35mg, 0.11mmol, 2.0eq).
  • dichloromethane 10ml
  • 73-3 33mg, 0.055 mmol, 1.0EQ
  • ethylamine hydrochloride 9mg, 0.11mmol, 2.0EQ
  • trio 0.22mmmol, 4.0EQ
  • TBTU 35mg, 0.11mmol, 2.0eq
  • Step 4 Dissolve 73-4 (27mg, 0.043mmol, 1.0eq) in methanol (1mL) at 25°C, then add hydrochloric acid/dioxane solution (1mL, 4M) and stir for two hours. LCMS shows that the reaction is complete. The reaction solution was concentrated under reduced pressure to obtain white solid 73 (21 mg, yield: 87.5%).
  • Compound 74 (21 mg, yield: 87.5%) was obtained by referring to the synthesis method of compound 73 in three steps.
  • Compound 75 (22 mg, yield: 81.5%) was obtained by referring to the synthesis method of compound 73 in two steps.
  • Compound 76 (22 mg, yield: 81.5%) was obtained by referring to the synthetic method of compound 73 in two steps.
  • Step 1 Add 73-1 (30 mg, 0.56 mmol, 1.0 eq), hydrazine hydrate (1 mL) and ethanol (1 mL) into a 15 mL pressure bottle. The temperature was raised to 100°C and stirred for 12 hours. TLC showed that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a white solid 77-1 (30 mg, crude product).
  • Step 2 The white solid 77 (15 mg, yield: 66.1%) was synthesized by referring to the method of step 4 of compound 73.
  • Step 1 73-1 (30mg, 0.56mmol, 1.0eq) was dissolved in methanol (1mL), then added to hydrochloric acid/dioxane (1mL, 4M) solution, stirred at 25°C for 12 hours, LCMS showed that the product was formed. The reaction solution was concentrated under reduced pressure to obtain yellow solid 79-1 (24 mg, crude product).
  • Step 2 The white solid 79 (15 mg, yield: 50.0%) was synthesized by referring to the method of compound 73 synthesis step 2.
  • Compound 80 Refer to the synthetic method of compound 79 to synthesize white solid 80 (12 mg, yield: 52.9%) in two steps.
  • Step 1 Add anhydrous dichloromethane (1 mL) and 82 (15 mg, 0.026 mmol, 1.0 eq) to a 4 mL reaction flask in sequence at 25 degrees Celsius, then add boron tribromide (20 mg, 0.079 mmol, 3.0 eq) dropwise, and react for one hour.
  • LCMS showed that the product was formed, methanol (1 mL) was added to quench the reaction, filtered, and the filtrate was separated by preparative HPLC (formic acid system) to obtain a white solid 83 (4 mg, yield: 25%).
  • Embodiment fifty the synthesis of compound 84
  • Embodiment fifty-one the synthesis of compound 85
  • Embodiment fifty-two the synthesis of compound 86
  • Embodiment fifty-four Synthesis of compound 88
  • Embodiment fifty-five the synthesis of compound 89
  • Embodiment fifty-six the synthesis of compound 90
  • Step 2 Referring to the synthesis method of compound 41-2, using compound 90-1 instead of compound 41-1, one-step reaction was carried out to obtain compound 90-2 and compound 91-1.
  • Step 3 Referring to the synthesis method of compound 41, compound 90-2 was used instead of compound 41-2, and compound 90 was obtained by one-step reaction.
  • Embodiment fifty-seven the synthesis of compound 91
  • compound 91-1 was used instead of compound 41-2, and compound 91 was obtained by one-step reaction.
  • Test Example 1 YAP-TEAD protein interaction HTRF experiment
  • Inhibition % (1-(cpd signal -background signal )/(DMSO signal -background signal ))*100
  • the half-inhibitory concentration IC 50 value was calculated by GraphPad Prism software.
  • the IC 50 of each compound blocking the YAP-TEAD protein interaction is shown in Table 1, wherein, the letter A represents the IC 50 of less than 0.5uM; the letter B represents the IC 50 of 0.5uM to 5uM; the letter C represents the IC 50 of 5uM to 50uM, and the letter D represents the IC50 of greater than 50uM.
  • Compound 10 Compound 56 C Compound 11 C Compound 57 C Compound 12 C Compound 58 C Compound 13 C Compound 59 C Compound 14 C Compound 60 C Compound 15 C Compound 61 A Compound 16 C Compound 62 C Compound 17 C Compound 63 B Compound 18 C Compound 64 C Compound 19 C Compound 65 B Compound 20 C Compound 66 C Compound 21 C Compound 67 A Compound 22 C Compound 68 C Compound 23 C Compound 69 A Compound 24 C Compound 70 B Compound 25 C Compound 71 B Compound 26 C Compound 72 A Compound 27 C Compound 73 A Compound 28 C Compound 74 B Compound 29 C Compound 75 A Compound 30 C Compound 76 B Compound 31 B Compound 77 C Compound 32 B Compound 78 A Compound 33 B Compound 79 C Compound 34 C Compound 80 C Compound 35 C Compound 81 B Compound 36 B Compound 82 B Compound 37 B Compound 83 A Compound 38 B Compound 84 B Compound
  • Test Example 2 YAP/TEAD reporter gene suppression experiment
  • the inhibition of the compound on the target was detected by the signal of the reporter gene in the stable cell line SF268-YAP-Luc containing the YAP/TEAD reporter gene.
  • the sequence containing six tandem YAP/TEAD binding sites and a basic transcription promoter was constructed on the vector pGL4.76 of Promega Company.
  • the constructed reporter gene vector was transfected into SF268 cells (NCI DCTD tumor/cell line repository), and screened with 0.5 ⁇ g/ml hygromycin to obtain the SF268-YAP-Luc stable strain.
  • Inoculate SF268-YAP-Luc cells in a 96-well plate seed the cells into a 96-well plate at a density of 3000 cells per well, and have a volume of 100 ⁇ L per well (cell culture medium composition: RPMI1640 (Gibco-A10491-01) + 10% FBS (Gibco-10099-141C) + 1% Penicillin-Streptomycin (5,000 U/mL, Gibco -15070-063)), placed in a 37°C, 5% carbon dioxide incubator and cultured overnight.
  • cell culture medium composition RPMI1640 (Gibco-A10491-01) + 10% FBS (Gibco-10099-141C) + 1% Penicillin-Streptomycin (5,000 U/mL, Gibco -15070-063)
  • the compound to be tested was diluted 3-fold, and a total of 8 concentration gradients were set; a certain volume of DMSO (control group) or the compound to be tested (treatment group) was added to each well, and two replicates were set for each concentration, and the final concentration of DMSO was controlled at no higher than 0.5%. Place in a 37°C, 5% carbon dioxide incubator for 24 hours. Cell seeding and compound treatment were done in two identical parallel plates.
  • Renila-Glo Luciferase assay system kit (Promega, E2720) was used to detect reporter gene signals in control and treatment groups. Add 70ul Renila-Glo to each well, mix well, and incubate at room temperature for 10 minutes. use Signals were read with Multilabel Plate Reader (Perkin Elmer).
  • the CellTiter-Glo Luminescent Cell Viability Assay kit (Promega, G7570) was used to detect the cell viability of the control group and the treatment group. Add 50ul CellTiter-Glo to each well, mix well, and incubate at room temperature for 10 minutes. use Signals were read with Multilabel Plate Reader (Perkin Elmer).
  • Inhibition rate% (1-(Renila signal of compound-treated wells/Renila signal of DMSO-treated wells)/(CTG signal of compound-treated wells/CTG signal of DMSO-treated wells))*100
  • the IC 50 of the compounds blocking the expression of the YAP reporter gene is shown in Table 2.
  • the letter A indicates that the IC 50 is less than 0.5uM;
  • the letter B indicates that the IC 50 is from 0.5uM to 5uM;
  • the letter C indicates that the IC 50 is greater than 5uM.
  • the CellTiter-Glo Luminescent Cell Viability Detection Kit was used to quantitatively measure intracellular ATP and detect the number of living cells in the culture.
  • Step 1 Inoculate MSTO-211H (ATCC, CRL-2081 TM ) or NCI-H2052 (ATCC, CRL-5915 TM ) cells in a 96-well plate, inoculate the cells into the 96-well plate at a density of 1500 cells per well, with a volume of 100 ⁇ L per well, and culture overnight in a 37°C, 5% carbon dioxide incubator.
  • the medium is: RPMI1640 medium (GIBCO-A10491-01) + 10% FBS (GIBCO-10099141C) + 1% Pen/Strep (GIBCO-15070-063).
  • Second step compound treatment of cells.
  • the compound to be tested was diluted 3-fold, and a total of 9 concentration gradients were set; a certain volume of DMSO (control group) or the compound to be tested (treatment group) was added to each well, and two replicates were set for each concentration, and the final concentration of DMSO was controlled at no higher than 0.5%. Place in a 37°C, 5% carbon dioxide incubator for 96 hours.
  • Step 3 Use the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, G7570) to detect the cell viability of the control group and the treatment group. Add 50ul CellTiter-Glo to each well, mix well, and incubate at room temperature for 10 minutes. use Signals were read with Multilabel Plate Reader (Perkin Elmer).
  • Inhibition percentage (%) is calculated by the following formula:
  • Inhibition rate% (1-CTG signal of compound-treated wells/CTG signal of DMSO-treated wells)*100
  • Graphpad Prism software was used to calculate the IC50 value of the compound on the inhibition of CTG signal of cell proliferation activity.
  • the IC 50 of the compound's inhibitory activity on cell proliferation is shown in Table 3, wherein, the letter A indicates that the IC 50 is less than 1uM; the letter B indicates that the IC 50 is from 1uM to 5uM; the letter C indicates that the IC 50 is greater than 5uM.

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Abstract

La présente invention concerne un composé tricyclique tel que représenté dans la formule I suivante, sa préparation, une composition pharmaceutique et l'utilisation. Le composé selon la présente invention peut être utilisé en tant qu'inhibiteur de l'interaction entre YAP/TAZ et TEAD, et utilisé pour traiter ou prévenir des maladies médiées par l'interaction entre YAP/TAZ et TEAD.
PCT/CN2022/072781 2022-01-19 2022-01-19 Composé tricyclique, sa préparation, composition pharmaceutique et utilisation Ceased WO2023137634A1 (fr)

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CN202280089566.9A CN118574832A (zh) 2022-01-19 2022-01-19 三并环化合物、其制备、药物组合物及应用

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110691782A (zh) * 2016-12-01 2020-01-14 艾普托斯生物科学公司 作为brd4和jak2双重抑制剂的稠合的嘧啶化合物及其使用方法
WO2021186324A1 (fr) * 2020-03-16 2021-09-23 Novartis Ag Dérivés biaryle en tant qu'inhibiteurs d'interaction protéine-protéine yap/taz-tead
WO2022007866A1 (fr) * 2020-07-09 2022-01-13 深圳信立泰药业股份有限公司 Dérivé tricyclique condensé, son procédé de préparation et son application pharmaceutique

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0314967D0 (en) * 2003-06-26 2003-07-30 Hoffmann La Roche Piperazine derivatives
ES2754385T3 (es) * 2013-04-23 2020-04-17 Esteve Pharmaceuticals Sa Compuestos de pirazino-[1,2-a]indol, su preparación y uso en medicamentos
WO2014173903A1 (fr) * 2013-04-23 2014-10-30 Laboratorios Del Dr. Esteve, S.A. Composés de pyrazino[1,2-a]indole, leur préparation et leur utilisation dans des médicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110691782A (zh) * 2016-12-01 2020-01-14 艾普托斯生物科学公司 作为brd4和jak2双重抑制剂的稠合的嘧啶化合物及其使用方法
WO2021186324A1 (fr) * 2020-03-16 2021-09-23 Novartis Ag Dérivés biaryle en tant qu'inhibiteurs d'interaction protéine-protéine yap/taz-tead
WO2022007866A1 (fr) * 2020-07-09 2022-01-13 深圳信立泰药业股份有限公司 Dérivé tricyclique condensé, son procédé de préparation et son application pharmaceutique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RICHTER, H.G.F. ADAMS, D.R. BENARDEAU, A. BICKERDIKE, M.J. BENTLEY, J.M. BLENCH, T.J. CLIFFE, I.A. DOURISH, C. HEB: "Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT"2"C receptor agonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 16, no. 5, 1 March 2006 (2006-03-01), Amsterdam NL , pages 1207 - 1211, XP005263920, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2005.11.083 *
ROMAGNOLI ROMEO ET AL.: "Synthesis and Biological Effects of Novel 2-Amino-3-(4-chlorobenzoyl)-4-substituted Thiophenes as Allosteric Enhancers of the A1 Adenosine Receptor", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 67, 13 July 2013 (2013-07-13), XP028710095, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2013.07.002 *

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