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WO2025135855A1 - Nouveau composé hétérobicyclique pour inhiber l'interaction yap-tead et composition pharmaceutique le comprenant - Google Patents

Nouveau composé hétérobicyclique pour inhiber l'interaction yap-tead et composition pharmaceutique le comprenant Download PDF

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WO2025135855A1
WO2025135855A1 PCT/KR2024/020781 KR2024020781W WO2025135855A1 WO 2025135855 A1 WO2025135855 A1 WO 2025135855A1 KR 2024020781 W KR2024020781 W KR 2024020781W WO 2025135855 A1 WO2025135855 A1 WO 2025135855A1
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alkyl
substituted
compound
unsubstituted
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Korean (ko)
Inventor
김지숙
안영길
윤지희
정승현
한선영
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Hanmi Pharmaceutical Co Ltd
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Hanmi Pharmaceutical Co Ltd
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a heterobicyclic compound that inhibits Yes associated protein (YAP)-transcriptional enhancer associate domain (TEAD) binding, wherein the compound according to the present invention can directly inhibit YAP-TEAD binding in the Hippo pathway, which plays a key role in the process of cancer development.
  • YAP Yes associated protein
  • TEAD transcriptional enhancer associate domain
  • the Hippo signaling cascade is a key pathway for cancer development and tumor maintenance.
  • YAP and tafazzin (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inactivation of the Hippo signaling pathway promotes YAP/TAZ translocation to the nucleus, where YAP/TAZ interact with the enhancer-associated domain (TEAD) transcription factor to co-activate the expression of target genes and promote cell proliferation.
  • Target genes such as connective tissue growth factor (CTGF), Cyr61, AXL receptor tyrosine kinase, and MYC, which are closely related to tumorigenesis, are regulated by TEAD.
  • CTGF connective tissue growth factor
  • Cyr61 Cyr61
  • AXL receptor tyrosine kinase AXL receptor tyrosine kinase
  • MYC which are closely related to tumorigenesis
  • TEAD has been shown to be overexpressed in breast cancer stem cells and breast cancer, ovarian cancer, germ cell tumors, renal cell carcinoma, medullary blastoma, and gastric cancer.
  • Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been associated with numerous cancers.
  • EMT epithelial-mesenchymal transition
  • recent studies have reported that YAP overexpression or amplification, together with epithelial-mesenchymal transition (EMT) phenotype changes, are associated with resistance to the EGFR tyrosine kinase inhibitors Tarceva (erlotinib), Iressa (gefitinib), or Tagrisso (osimertinib).
  • the present inventors completed the present invention by developing a novel heterobicyclic compound for inhibiting YAP-TEAD protein interaction.
  • Patent Document 1 International Publication No. WO2019/040380
  • Patent Document 2 International Publication No. WO2020/243415
  • Non-patent literature 1 Semin. Cancer Biol. 2022 , 85 , 33
  • Non-patent document 6 Cells 2021 , 10, 2715
  • One object of the present invention is to provide a novel heterobicyclic compound having excellent inhibitory activity against YAP-TEAD binding in the Hippo pathway, which plays a key role in the development of cancer.
  • Another object of the present invention is to provide a pharmaceutical composition containing the compound as an active ingredient for treating or preventing a related disease caused by a dysregulation of the Hippo signaling pathway, specifically, TEAD activation.
  • a pharmaceutical composition for treating or preventing a disease related to a dysregulation of the Hippo signaling pathway, specifically, a disease caused by TEAD activation, comprising as an active ingredient a compound selected from the compound, an optical isomer, a diastereomer, a solvate, a hydrate and a pharmaceutically acceptable salt thereof.
  • novel heterobicyclic compound having the structure of chemical formula 1 in the present invention has excellent inhibitory activity against YAP-TEAD binding, and thus is effective against various diseases related to the Hippo pathway, which plays a key role in the development of cancer, and can be usefully used as a therapeutic agent therefor.
  • halogen in this specification may be F, Cl, Br, or I.
  • alkyl refers to a monovalent group derived from a saturated hydrocarbon by removing one hydrogen atom.
  • the alkyl includes a straight-chain, branched, or cyclic hydrocarbon residue which may be substituted or unsubstituted, and may be, for example, but not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or t -butyl.
  • alkenyl refers to a monovalent group derived from a hydrocarbon by the removal of one hydrogen atom, which contains one or more unsaturated regions, and at least one carbon-carbon double bond.
  • the alkenyl includes an alkyl group containing one or more double bonds, which may be substituted or unsubstituted, and examples thereof include, but are not limited to, prop-1-ene, but-1-ene, but-2-ene, 3-methylbut-1-ene, or pent-1-ene.
  • alkynyl refers to a monovalent group derived from a hydrocarbon by the removal of one hydrogen atom, and which contains one or more regions of unsaturation, i.e., at least one carbon-carbon triple bond.
  • the alkynyl may be, but is not limited to, -C ⁇ CH, -CH 2 C ⁇ CH, or -CH 2 CH 2 CH 2 C ⁇ C-.
  • alkylene refers to a straight-chain, branched, or cyclic saturated divalent hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Alkylene can also be represented as (-CH 2 -) p (where p is any integer) and can be, but is not limited to, methylene (-CH 2 -), 1,1-ethyl (-CH(CH 3 )-), 1,2-ethyl (-CH 2 CH 2 -), 1,1-propyl (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -).
  • alkenylene refers to a divalent group derived from an alkenyl by the removal of one hydrogen atom, i.e., a straight-chain, branched, or cyclic unsaturated divalent hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • alkynylene refers to a divalent group derived from an alkyne by the removal of one hydrogen atom, i.e., a straight-chain, branched, or cyclic unsaturated divalent hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • alkynylene can be, but is not limited to, -C ⁇ C-, -CH 2 C ⁇ C-, or -CH 2 CH 2 CH 2 C ⁇ C-.
  • cycloalkyl means, unless otherwise stated, a saturated monocyclic or polycyclic hydrocarbon ring having the specified number of carbon atoms, which ring may be substituted or unsubstituted.
  • the cycloalkyl group may be, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
  • heterocycloalkyl as used herein, unless otherwise stated, means a monocyclic, substituted or unsubstituted, cyclic alkyl group containing one or more heteroatoms selected from N, O, and S.
  • the heterocycloalkyl group can be, but is not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuranyl, or similar groups.
  • haloalkyl unless otherwise stated, is meant to include monohaloalkyl and polyhaloalkyl, which may be substituted or unsubstituted.
  • halogen and alkyl are as defined above.
  • alkoxy refers to a straight-chain or branched hydrocarbon moiety which may be substituted or unsubstituted, linked to oxygen.
  • the alkoxy may be, but is not limited to, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, or t -butoxy, for example.
  • alkoxyalkyl refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced with alkoxy.
  • alkoxyalkyl group include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, and isopropoxymethyl.
  • aryl refers to an aromatic group which may be substituted or unsubstituted, and may include, for example, C 3-10 aryl, C 3-8 aryl, or C 3-6 aryl, wherein the double bonds alternate (resonate) between adjacent carbon atoms or suitable heteroatoms. Examples thereof include, but are not limited to, phenyl, biphenyl, naphthyl, toluyl, or naphthalenyl.
  • heteroaryl as used herein may mean a monocyclic or bicyclic or more, substituted or unsubstituted, aromatic group containing one or more heteroatoms selected from N, O, and S, unless otherwise stated.
  • a monocyclic heteroaryl may be, but is not limited to, pyridinyl, imidazolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, or pyrazinyl.
  • the bicyclic heteroaryl can be, but is not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, isoquinolinyl, purinyl, or furopyridinyl.
  • carbocyclyl means a substituent comprising carbon ring atoms, unless otherwise stated, having the structure of a saturated carbocyclyl (e.g., a "cycloalkane” or “cycloalkyl”), a partially saturated carbocyclyl (e.g., a "cycloalkene” or “cycloalkenyl”), or a fully unsaturated carbocyclyl (e.g., an "aryl”).
  • the carbocyclyl may be a single ring (monocyclic) or a polycyclic ring structure.
  • a carbocyclyl comprises, for example, 3 to 14, or for example, 3 to 8 carbon ring atoms, and may be saturated, unsaturated or aromatized.
  • the ring atoms are atoms that are bonded together to form a ring or rings of a carbocyclyl substituent.
  • a saturated carbocyclyl group can be, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • an unsaturated carbocyclyl group can contain three or fewer double bonds.
  • an aromatic carbocyclyl group can be phenyl.
  • the carbocyclyl can include a fused combination of carbocyclyl groups, for example, but not limited to, naphthyl, phenanthryl, indanyl, and indenyl.
  • heterocyclyl means, unless otherwise stated, a substituent comprising at least one heteroatom as a ring atom, having the structure of a saturated heterocyclyl (e.g., "heterocycloalkyl"), a partially saturated heterocyclyl (e.g., “heterocycloalkenyl”), or a fully unsaturated heterocyclyl (e.g., "heteroaryl”).
  • the heterocyclyl can be a single ring (monocyclic) or a polycyclic ring structure.
  • the heterocyclyl comprises, for example, a total of 3 to 14, 6 to 14, or, for example, a total of 3 to 8 ring atoms, and can be saturated, unsaturated, or aromatized.
  • the ring atoms are atoms that are bonded together to form a ring or rings of a heterocyclyl substituent.
  • at least one of the ring atoms is nitrogen, oxygen, or sulfur, and the remaining ring atoms are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur.
  • the ring atoms of the heterocyclyl can have up to four heteroatoms such as N, O, and S, can include, for example, a total of 3 to 14 ring atoms, or, for example, a total of 5 to 7 ring atoms, and can be saturated, unsaturated, or aromatized.
  • the heterocyclyl can be, but is not limited to, imidazolyl, imidazolinyl, imidazolidinyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolaneyl, triazinyl, azepinyl, oxaze,
  • heterocyclyl may include fused heterocyclyl groups, such as, but not limited to, benzimidazolinyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, quinolinyl, quinazolinyl, quinoxazolinyl, dihydroquinazolinyl, benzothiazolyl, phthalimidyl, benzofuranyl, benzodiazepinyl, indolyl, or isoindolyl.
  • Heterocyclyl may be a carbon linking group or a heteroatom linking group.
  • N-linked heterocyclyl is , Including, but not limited to, the term "fused heteroaryl", as used herein, unless otherwise stated, refers to a substituted or unsubstituted ring system in which a heteroaryl group is linked in a fused manner to another aryl, heteroaryl, or heterocycloalkyl group.
  • a fused heteroaryl can form a 5+5-membered, 5+6-membered, 5+7-membered, 6+6-membered, or 6+7-membered fused ring system.
  • Any substituent herein can be, but is not limited to, any one substituent selected from among halogen, cyano, amino, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, C 1-6 alkoxy, and haloC 1-6 alkoxy.
  • a substituted alkyl, a substituted carbocyclyl, a substituted aryl, a substituted heterocyclyl, or a substituted heteroaryl can have one or more hydrogen atoms replaced by any one substituent selected from among halogen, cyano, amino, hydroxy, C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, C 1-6 alkoxy, and haloC 1-6 alkoxy.
  • stereoisomer as used herein may mean a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but being optically or stereoscopically different, and includes optical isomers or diastereoisomers.
  • optical isomers as used herein means two stereoisomers of a compound which are non-superimposable mirror images of each other.
  • diastereoisomer refers to a stereoisomer having two or more chiral centers, the molecules of which are not mirror images of each other.
  • the compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, such as diastereomers, optical isomers, and racemic mixtures, are considered to form part of the present invention. A 50:50 mixture of optical isomers is called a racemic mixture or racemate.
  • solvate as used herein may mean a compound of the present invention or a salt thereof, which comprises a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents for the purpose may be solvents that are volatile, non-toxic, and/or suitable for administration to humans.
  • the “solvate” may comprise a molecular complex comprising the compound and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • hydrate refers to a complex wherein the solvent molecule is water.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt, which can be prepared by any suitable method useful to those skilled in the art.
  • the desired pharmaceutically acceptable salt can be prepared by any suitable method useful to those skilled in the art, for example, by treating the free base with an inorganic acid or organic acid.
  • terapéuticaally effective amount means an amount of a compound of the present invention that treats or prevents a particular disease, condition or disorder, attenuates, improves or eliminates one or more symptoms of a particular disease, condition or disorder, or prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder.
  • treating refers to inhibiting a disease, condition or disorder in a subject experiencing or exhibiting the pathology or signs of the disease, condition or disorder, such as preventing or reversing further development of the pathology and/or signs, or ameliorating a disease, such as reducing the severity of the disease.
  • preventing refers to preventing a disease, condition or disorder, for example, in a subject who may be predisposed to the disease, condition or disorder but who does not yet experience or exhibit the pathology or signs of the disease.
  • subject or “individual” as used herein may be a vertebrate animal, such as a mammal, fish, bird, reptile, or amphibian.
  • the subject may be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent.
  • administering and “administration” as used herein refer to any method of providing the disclosed composition to a subject.
  • One embodiment of the present invention provides a compound selected from the compounds of the following formula 1, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof:
  • R 1 is hydrogen, halogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, cyano,
  • L 1 and L 2 is absent, bonded, C 1-6 alkylene, C 2-6 alkenylene, or C 1-3 alkylene substituted with halogen;
  • the bond is a single or double bond
  • W is -S(O) 2 -NR 4 R 5, -S(O)-NR 4 R 5, -C(O)-NR 4 R 5, , , , or and;
  • R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, cyano, C 1-6 alkyl, substituted or unsubstituted C 3-10 carbocyclyl, substituted or unsubstituted C 6-10 aryl, or substituted or unsubstituted C 4-10 heteroaryl;
  • X and Y are each independently -C- or -N-;
  • the compound may be a compound selected from compounds of the following formula 1A, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , , , X, Y, l, and m are defined as in Chemical Formula 1, respectively.
  • the compound may be a compound selected from compounds of the following formula 1B, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , , , X, Y, l, m, n, o, p, and q are defined as in Chemical Formula 1, respectively.
  • C 1-10 heteroaryl, C 6-14 fused heteroaryl, or C 1-10 heterocyclyl can be a compound containing 1 to 4 heteroatoms each independently selected from N, O, and S.
  • the compound comprises:
  • a phenyl group is a phenyl group, a pyridinyl group, a pyrazinyl group, a pyrazolyl group, an imidazolyl group, a thiophenyl group, a furanyl group, an oxazole group, an azetidinyl group, or It may be a compound of.
  • the compound comprises:
  • L 1 is a bond
  • Each R 2 and each R 3 can be a compound independently selected from the group consisting of hydrogen, halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, haloC 1-6 alkoxy, mono-(C 1-3 alkyl)-substituted carbamoyl (-(CO)-NH(C 1-3 alkyl)), di-(C 1-3 alkyl)-substituted carbamoyl (-(CO)-N(C 1-3 alkyl) 2 ), C 1-3 alkylsulfonyl (-SO 2 -(C 1-3 alkyl)), a substituted or unsubstituted C 3-6 cycloalkyl, a substituted or unsubstituted C 6-10 aryl, or a substituted or unsubstituted C 2-6 heterocycloalkyl.
  • the compound comprises:
  • C 3-6 cycloalkenyl may be a compound which is C 3-6 cycloalkenyl, C 3-6 cycloalkyl, C 4-6 heterocycloalkyl, or C 4-6 heterocycloalkenyl.
  • the compound comprises:
  • R 8 is hydrogen, halogen, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, or haloC 1-6 alkoxy;
  • the compound may be a compound selected from the following compounds, optical isomers, diastereomers, solvates, hydrates and pharmaceutically acceptable salts thereof:
  • the composition may be a pharmaceutical composition for treating a cancer or tumor that can be treated by exhibiting inhibitory activity against YAP-TEAD binding.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable additive in addition to the active ingredient.
  • the additive may be, but is not limited to, a diluent, a disintegrant, a binder, a lubricant, a surfactant, a suspending agent, or an emulsifier.
  • the pharmaceutical composition can be formulated according to a conventional method and can be prepared in various oral administration forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc., or parenteral administration forms such as intramuscular, intravenous, or subcutaneous administration.
  • the dosage, frequency of administration, or method of administration of the compound or pharmaceutical composition may vary depending on the subject being treated, the severity of the disease or condition, the rate of administration, and the judgment of the prescribing physician.
  • the physician may start at a level lower than that required to achieve the target therapeutic effect and gradually increase the dose of the compound or pharmaceutical composition of the present invention administered to the subject until the intended effect is achieved.
  • the compounds, compositions, and kits may be administered alone or concurrently, separately or sequentially with at least one other therapeutic agent.
  • the compound of chemical formula 1 according to the present invention can be prepared according to the synthetic method shown in Reaction Scheme 1 or Reaction Scheme 2.
  • R 1 , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , , , X, Y, l, and m are defined as defined in the chemical formula 1, respectively, but are not limited thereto and may be changed within a range understandable to those skilled in the art.
  • the starting material e.g., PG-indoline; 1 equivalent, reference equivalent
  • chlorosulfonic acid 7.5 equivalents
  • the reaction mixture is warmed to room temperature, heated, and reacted at 70°C.
  • the reaction solution is slowly added dropwise to water cooled to 0-5°C, and the formed solid is collected by filtration to obtain the target compound A.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 1 , L 2 , , , X, Y, l, m, n, o, p, and q are defined as defined in the chemical formula 1, respectively, but are not limited thereto and may be changed within a range understandable to those skilled in the art.
  • the reaction solution is stirred at 80°C for 3 hours.
  • the reaction solution is filtered through CELITE, washed with dichloromethane, water is added, and extracted with dichloromethane.
  • the organic layer is dried over anhydrous sodium sulfate, filtered under reduced pressure, the filtered organic layer is concentrated under reduced pressure, and the obtained residue is purified by MPLC to obtain the target compound E.
  • the compound of chemical formula 1 according to one embodiment of the present invention can be prepared according to the method illustrated in the above reaction scheme 1 or reaction scheme 2, but is not limited thereto.
  • a person having ordinary knowledge in the field of organic compounds can appropriately adjust the specific reaction path, reaction conditions, reaction amount, etc.
  • reaction solution was stirred at 100°C overnight, and after the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added, and extraction was performed three times with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtered organic layer was concentrated under reduced pressure.
  • Example 1 The procedure of Example 1 was repeated except that 2-(4,4-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (152 mg, 0.65 mmol) was used instead of 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane in [Step-8] of the above Example 1, to obtain 11 mg (5% yield) of the title compound.
  • Example 1 The procedure of Example 1 was repeated except that 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (622 mg, 1.96 mmol) was used instead of 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)cyclohex-1-en-1-yl)-1,3,2-dioxaborolane in [Step-8] of the above Example 1, to obtain 11 mg (2% yield) of the title compound.
  • the IC 50 value is less than 100 nM, it is indicated as A, when it is 100 nM or more but less than 500 nM, it is indicated as B, and when it is 500 nM or more, it is indicated as C.
  • NCI-H226 is a mesothelioma cancer cell line lacking the NF2 gene and was cultured in a medium containing 10% FBS and 1% Penicillin/Streptomycin in RPMI 1640. The cultured cells were dispensed at 0.7 x 10 3 /100 ⁇ l into a 96-well plate and cultured for 24 hours. Then, 100 ⁇ l of the test compound diluted to 2X the concentration was mixed into each well and cultured for 6 days. The SRB test method was used to measure cell growth inhibition, and the 50% inhibition value (GI 50 ) for cell growth by the compound was calculated using GraphPad Prism 9.
  • novel heterobicyclic compound having the structure of chemical formula 1 in the present invention has excellent inhibitory activity against YAP-TEAD binding, and thus is effective against various diseases related to the Hippo pathway, which plays a key role in the development of cancer, and can be usefully used as a therapeutic agent therefor.

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Abstract

La présente invention concerne : un composé choisi parmi un composé de formule chimique 1, et un isomère optique, un diastéréoisomère, un solvate et un hydrate de celui-ci, et un sel pharmaceutiquement acceptable de ceux-ci ; son procédé de préparation ; et son utilisation.
PCT/KR2024/020781 2023-12-21 2024-12-20 Nouveau composé hétérobicyclique pour inhiber l'interaction yap-tead et composition pharmaceutique le comprenant Pending WO2025135855A1 (fr)

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KR1020230188647A KR20250097400A (ko) 2023-12-21 2023-12-21 Yap-tead 상호작용 억제를 위한 신규한 헤테로비시클릭 화합물 및 이를 포함하는 약학적 조성물
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022457A1 (fr) * 1996-11-19 1998-05-28 Amgen Inc. Agents anti-inflammatoires a base de pyrrole condense a substitution aryle et heteroaryle
KR20080088609A (ko) * 2006-01-24 2008-10-02 일라이 릴리 앤드 캄파니 프로게스테론 수용체의 인돌 술폰아미드 조절제
WO2022117882A2 (fr) * 2020-12-03 2022-06-09 Domain Therapeutics Nouveaux inhibiteurs de par-2
KR20230053661A (ko) * 2020-08-17 2023-04-21 베타 파머수티컬 컴퍼니 리미티드 비사이클 화합물과 비사이클 화합물을 포함하는 조성물 및 이들의 용도
WO2023151560A1 (fr) * 2022-02-08 2023-08-17 Etern Biopharma (Shanghai) Co., Ltd. Composés hétéroaryle bicycliques et leurs utilisations

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111542315B (zh) 2017-08-21 2023-05-12 维瓦斯治疗公司 苯并磺酰基化合物
SG11202113129UA (en) 2019-05-31 2021-12-30 Ikena Oncology Inc Tead inhibitors and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022457A1 (fr) * 1996-11-19 1998-05-28 Amgen Inc. Agents anti-inflammatoires a base de pyrrole condense a substitution aryle et heteroaryle
KR20080088609A (ko) * 2006-01-24 2008-10-02 일라이 릴리 앤드 캄파니 프로게스테론 수용체의 인돌 술폰아미드 조절제
KR20230053661A (ko) * 2020-08-17 2023-04-21 베타 파머수티컬 컴퍼니 리미티드 비사이클 화합물과 비사이클 화합물을 포함하는 조성물 및 이들의 용도
WO2022117882A2 (fr) * 2020-12-03 2022-06-09 Domain Therapeutics Nouveaux inhibiteurs de par-2
WO2023151560A1 (fr) * 2022-02-08 2023-08-17 Etern Biopharma (Shanghai) Co., Ltd. Composés hétéroaryle bicycliques et leurs utilisations

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