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WO2018108064A1 - Composé spiro-aryl-phosphore-oxygène comme quatrième génération d'inhibiteur de kinase egfr - Google Patents

Composé spiro-aryl-phosphore-oxygène comme quatrième génération d'inhibiteur de kinase egfr Download PDF

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Publication number
WO2018108064A1
WO2018108064A1 PCT/CN2017/115577 CN2017115577W WO2018108064A1 WO 2018108064 A1 WO2018108064 A1 WO 2018108064A1 CN 2017115577 W CN2017115577 W CN 2017115577W WO 2018108064 A1 WO2018108064 A1 WO 2018108064A1
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group
compound
pharmaceutically acceptable
acceptable salt
compound according
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PCT/CN2017/115577
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English (en)
Chinese (zh)
Inventor
吴凌云
刘希乐
丁照中
陈曙辉
胡利红
赵乐乐
潘威
胡国平
黎健
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Medshine Discovery Inc
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Medshine Discovery Inc
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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
    • A61K31/66—Phosphorus compounds
    • 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
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides

Definitions

  • R 5 is selected from the group consisting of H, halogen, CN, C 1-3 alkyl, C 1-3 heteroalkyl, C 1-3 alkenyl, C 1-3 heteroalkenyl, C 3-6 cycloalkyl, 3 ⁇ a 6-membered heterocycloalkyl group, a phenyl group and a 5- to 6-membered heteroaryl group, said C 1-3 alkyl group, a C 1-3 heteroalkyl group, a C 1-3 alkenyl group, a C 1-3 heteroalkenyl group, C 3-6 cycloalkyl, 3-6-membered heterocycloalkyl, phenyl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 R;
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group means suitable A protecting group that is used to prevent side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-but
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • IC50 data was measured by Model 205in Activity Base (IDBS).
  • the compounds of the present invention showed potent anti-tumor activity in a subcutaneously implanted Ba/F3 (exon19del/T790m/C797S)-derived xenograft (CDX) BALB/c nude mouse resistance model.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une quatrième génération (mutation T790M/C797S) d'un inhibiteur de kinase EGFR, c'est-à-dire, un composé spiro-aryl-phosphore-oxygène, en particulier un composé tel que représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci, utilisé pour traiter des cancers.
PCT/CN2017/115577 2016-12-13 2017-12-12 Composé spiro-aryl-phosphore-oxygène comme quatrième génération d'inhibiteur de kinase egfr Ceased WO2018108064A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201611142656.2 2016-12-13
CN201611142656 2016-12-13

Publications (1)

Publication Number Publication Date
WO2018108064A1 true WO2018108064A1 (fr) 2018-06-21

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PCT/CN2017/115577 Ceased WO2018108064A1 (fr) 2016-12-13 2017-12-12 Composé spiro-aryl-phosphore-oxygène comme quatrième génération d'inhibiteur de kinase egfr

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WO (1) WO2018108064A1 (fr)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110305161A (zh) * 2018-03-20 2019-10-08 暨南大学 2-氨基嘧啶类化合物及其应用
WO2020147702A1 (fr) * 2019-01-17 2020-07-23 Betta Pharmaceuticals Co., Ltd Inhibiteurs d'egfr, compositions et procédés associés
WO2020147838A1 (fr) * 2019-01-18 2020-07-23 正大天晴药业集团股份有限公司 Sel d'un inhibiteur d'egfr, forme cristalline et procédé de préparation associé
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
WO2021018009A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant
WO2021018003A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant
CN112538072A (zh) * 2019-09-21 2021-03-23 齐鲁制药有限公司 新型氨基嘧啶类egfr抑制剂
WO2021057882A1 (fr) * 2019-09-26 2021-04-01 贝达药业股份有限公司 Inhibiteur d'egfr, composition et son procédé de préparation
WO2021073498A1 (fr) * 2019-10-17 2021-04-22 贝达药业股份有限公司 Inhibiteur d'egfr, composition et son procédé de préparation
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
CN112824420A (zh) * 2019-11-21 2021-05-21 浙江同源康医药股份有限公司 用作egfr激酶抑制剂的化合物及其应用
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2021160087A1 (fr) 2020-02-14 2021-08-19 贝达药业股份有限公司 Composé d'oxyde de quinolyle phosphine, et composition et application de celui-ci
CN113717156A (zh) * 2020-05-25 2021-11-30 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
CN115515949A (zh) * 2020-03-23 2022-12-23 齐鲁制药有限公司 新型氨基嘧啶类egfr抑制剂
CN115667226A (zh) * 2020-04-14 2023-01-31 齐鲁制药有限公司 作为egfr抑制剂的三环化合物
CN115697996A (zh) * 2020-06-08 2023-02-03 南京红云生物科技有限公司 烯基嘧啶类化合物、其制备方法与应用
WO2023138576A1 (fr) * 2022-01-18 2023-07-27 齐鲁制药有限公司 Combinaison pharmaceutique d'oxyde d'arylphosphore spirocyclique et d'anticorps anti-egfr
WO2023138574A1 (fr) * 2022-01-18 2023-07-27 齐鲁制药有限公司 Composition médicamenteuse d'oxyde de spiro aryl phosphine et d'anticorps anti-vegf
CN118852176A (zh) * 2023-04-26 2024-10-29 中国药科大学 螺环类化合物及其药物组合物和应用

Citations (3)

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Publication number Priority date Publication date Assignee Title
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
CN103501612A (zh) * 2011-05-04 2014-01-08 阿里亚德医药股份有限公司 抑制表皮生长因子受体导致的癌症中细胞增殖的化合物
CN104130265A (zh) * 2014-04-29 2014-11-05 苏州景泓生物技术有限公司 一种含有螺环或桥环的嘧啶类化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
CN103501612A (zh) * 2011-05-04 2014-01-08 阿里亚德医药股份有限公司 抑制表皮生长因子受体导致的癌症中细胞增殖的化合物
CN104130265A (zh) * 2014-04-29 2014-11-05 苏州景泓生物技术有限公司 一种含有螺环或桥环的嘧啶类化合物

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110305161A (zh) * 2018-03-20 2019-10-08 暨南大学 2-氨基嘧啶类化合物及其应用
WO2020147702A1 (fr) * 2019-01-17 2020-07-23 Betta Pharmaceuticals Co., Ltd Inhibiteurs d'egfr, compositions et procédés associés
WO2020147838A1 (fr) * 2019-01-18 2020-07-23 正大天晴药业集团股份有限公司 Sel d'un inhibiteur d'egfr, forme cristalline et procédé de préparation associé
JP2022517396A (ja) * 2019-01-18 2022-03-08 チア タイ ティエンチン ファーマシューティカル グループ カンパニー リミテッド Ｅｇｆｒ阻害剤の塩、結晶形及びその製造方法
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
CN114430740B (zh) * 2019-07-26 2023-12-29 贝达药业股份有限公司 Egfr抑制剂、组合物及其制备方法
WO2021018003A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant
CN114430739A (zh) * 2019-07-26 2022-05-03 贝达药业股份有限公司 Egfr抑制剂、组合物及其制备方法
CN114430740A (zh) * 2019-07-26 2022-05-03 贝达药业股份有限公司 Egfr抑制剂、组合物及其制备方法
WO2021018009A1 (fr) * 2019-07-26 2021-02-04 贝达药业股份有限公司 Inhibiteur d'egfr, composition et procédé de préparation correspondant
CN112538072A (zh) * 2019-09-21 2021-03-23 齐鲁制药有限公司 新型氨基嘧啶类egfr抑制剂
CN112538072B (zh) * 2019-09-21 2024-02-06 齐鲁制药有限公司 氨基嘧啶类egfr抑制剂
WO2021057882A1 (fr) * 2019-09-26 2021-04-01 贝达药业股份有限公司 Inhibiteur d'egfr, composition et son procédé de préparation
CN114502564A (zh) * 2019-09-26 2022-05-13 贝达药业股份有限公司 Egfr抑制剂、组合物及其制备方法
WO2021073498A1 (fr) * 2019-10-17 2021-04-22 贝达药业股份有限公司 Inhibiteur d'egfr, composition et son procédé de préparation
CN114430741A (zh) * 2019-10-17 2022-05-03 贝达药业股份有限公司 Egfr抑制剂、组合物及其制备方法
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
CN112824420B (zh) * 2019-11-21 2022-04-26 浙江同源康医药股份有限公司 用作egfr激酶抑制剂的化合物及其应用
CN112824420A (zh) * 2019-11-21 2021-05-21 浙江同源康医药股份有限公司 用作egfr激酶抑制剂的化合物及其应用
WO2021098883A1 (fr) * 2019-11-21 2021-05-27 浙江同源康医药股份有限公司 Composé utilisé en tant qu'inhibiteur de kinase egfr et son utilisation
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
JP2023513333A (ja) * 2020-02-14 2023-03-30 貝達薬業股▲ふん▼有限公司 キノリニル基ホスフィンオキシド化合物、並びにその組成物及び使用
WO2021160087A1 (fr) 2020-02-14 2021-08-19 贝达药业股份有限公司 Composé d'oxyde de quinolyle phosphine, et composition et application de celui-ci
CN114885607B (zh) * 2020-02-14 2024-05-14 贝达药业股份有限公司 喹啉基膦氧化合物及其组合物和用途
CN114885607A (zh) * 2020-02-14 2022-08-09 贝达药业股份有限公司 喹啉基膦氧化合物及其组合物和用途
CN115515949A (zh) * 2020-03-23 2022-12-23 齐鲁制药有限公司 新型氨基嘧啶类egfr抑制剂
EP4129996A4 (fr) * 2020-03-23 2023-07-12 Qilu Pharmaceutical Co., Ltd. Nouvel inhibiteur aminopyrimidine d'egfr
CN115667226A (zh) * 2020-04-14 2023-01-31 齐鲁制药有限公司 作为egfr抑制剂的三环化合物
WO2021238827A1 (fr) * 2020-05-25 2021-12-02 南京红云生物科技有限公司 Inhibiteur d'egfr, son procédé de préparation et son utilisation
CN113717156B (zh) * 2020-05-25 2023-05-09 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
CN113717156A (zh) * 2020-05-25 2021-11-30 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
JP2023528170A (ja) * 2020-06-08 2023-07-04 南京紅云生物科技有限公司 アルケニルピリミジン系化合物、その調製方法及び使用
CN115697996A (zh) * 2020-06-08 2023-02-03 南京红云生物科技有限公司 烯基嘧啶类化合物、其制备方法与应用
CN115697996B (zh) * 2020-06-08 2025-09-02 泰州红云制药有限公司 烯基嘧啶类化合物、其制备方法与应用
WO2023138574A1 (fr) * 2022-01-18 2023-07-27 齐鲁制药有限公司 Composition médicamenteuse d'oxyde de spiro aryl phosphine et d'anticorps anti-vegf
WO2023138576A1 (fr) * 2022-01-18 2023-07-27 齐鲁制药有限公司 Combinaison pharmaceutique d'oxyde d'arylphosphore spirocyclique et d'anticorps anti-egfr
CN118852176A (zh) * 2023-04-26 2024-10-29 中国药科大学 螺环类化合物及其药物组合物和应用

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