WO2021143729A1 - Composé, composition et molécule fonctionnelle ayant un effet inhibiteur multicible et leur utilisation - Google Patents

Composé, composition et molécule fonctionnelle ayant un effet inhibiteur multicible et leur utilisation Download PDF

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WO2021143729A1
WO2021143729A1 PCT/CN2021/071525 CN2021071525W WO2021143729A1 WO 2021143729 A1 WO2021143729 A1 WO 2021143729A1 CN 2021071525 W CN2021071525 W CN 2021071525W WO 2021143729 A1 WO2021143729 A1 WO 2021143729A1
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ring atoms
compound
group
substituted
alkyl
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PCT/CN2021/071525
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WO2021143729A9 (fr
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熊兵
沈竞康
缪泽鸿
陈丹琦
吕铠铠
曹丹燕
李艳莲
王昕�
陈驎
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中国科学院上海药物研究所
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    • 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
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 technical personnel of the present invention discovered that by designing BRD4-based multi-target inhibitors, specifically, the KAc binding group (K in formula (I), also called Kac pocket mimic) of the BET inhibitor was compared with a typical kinase inhibitor Binding group
  • the fusion design can realize the use of a small molecule to act on the different signal pathways of tumor cell growth at the same time, which can affect the occurrence and development of tumor cells from multiple aspects, achieve better therapeutic effects, and reduce drug resistance due to bypass activation. This possibility provides a new idea for drug research and development, especially the development of anti-tumor drugs.
  • R 1, R 2 and R 3 are each independently selected from: H, C 1 - 6 alkyl, C 1 - 6 alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, containing 3 heterocyclyl 8 ring atoms, aryl group containing 5-10 ring atoms, a heteroaryl group, halogen, cyano or isocyano 5 to 10 ring atoms; wherein, C 1 - 6 alkyl, C 1 - 6 alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, heterocyclic group containing 3-8 ring atoms, aryl group containing 5-10 ring atoms, containing 5 to 10 ring atoms heteroaryl optionally substituted with one or more of the following groups: C 1 - 6 alkyl, C 1 - 6 alkoxy group, a cycloalkyl group having 3 to 8 ring atoms, containing 3-8 ring atoms
  • R 1 , R 2 and R 3 is not H.
  • R 20 is each independently selected from: H, C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl containing 3-8 ring atoms, heterocyclic ring containing 3-8 ring atoms Group, aryl group containing 5-10 ring atoms, heteroaryl group containing 5-10 ring atoms, halogen, cyano, isocyano or -NR 10 R 11 ; the C 1-6 alkyl group, C 1-6 alkoxy groups, cycloalkyl groups containing 3-8 ring atoms, heterocyclic groups containing 3-8 ring atoms, aryl groups containing 5-10 ring atoms, those containing 5-10 ring atoms Heteroaryl groups are optionally substituted with one or more of the following groups: C 1-6 alkyl or 3-8 membered cycloalkyl.
  • R 20 is selected from: H, cyano, methoxy, methyl, ethyl, n-propyl, isopropyl, primary butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropyl Group substituted methyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorine, chlorine, phenyl, pyridyl, pyrimidinyl, triazinyl, Or -NR 10 R 11 .
  • the step of reacting the structural compound represented by formula (I-3) and the structural compound represented by formula (I-4) reacts with the structural compound represented by formula (I-3) and the structural compound represented by formula (I-5)
  • the steps are basically the same, and the difference lies in the positions of the substituents, which will not be repeated here.
  • Example 12 The compound of Example 12 was prepared in the same manner as in Example 1, except that 4-methylphenylboronic acid was used instead of phenylboronic acid in step (j) of Example 1.
  • Example 54 The compound of Example 54 was prepared in the same manner as in Example 49, except that cyclopentylformaldehyde was used instead of paraformaldehyde in step (a) of Example 49.
  • Example 97 The compound of Example 97 was prepared in the same manner as in Example 94 except that pyridine-4-boronic acid was used instead of phenylboronic acid in step (e) of Example 94.
  • Example 98 The compound of Example 98 was prepared in the same manner as in Example 94, except that pyridine-3-boronic acid was used instead of phenylboronic acid in step (e) of Example 94.
  • Example 105 The compound of Example 105 was prepared in the same manner as in Example 94, except that 3.5-dimethylisoxazole-4-boronic acid was used instead of phenylboronic acid in step (e) of Example 94.
  • step (c) of Example 1 Except that in step (c) of Example 1, cyclopentanone was used instead of acetone and in step (j), 3-cyclopropyl-1,5-dimethylpyrazole-4-boronic acid pinacol ester was used instead of phenylboronic acid. Otherwise, the compound of Example 118 was prepared by the same method as in Example 1.
  • Example 120 was prepared by the same method as in Example 1, except that boronic acid pinacol ester was substituted for phenylboronic acid.
  • Example 126 was prepared by the same method as in Example 1, except that 1,5-dimethylpyrazole-4-boronic acid pinacol ester was substituted for phenylboronic acid.
  • the fluorescent substrate is (+)-JQ1 linked to fluorescent molecules, and the working concentration is 5nM.
  • BRD4(I) protein working concentration is 10nM
  • total reaction system is 40uL
  • buffer is 50mM 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES) pH7.4, 150mM NaCl, 0.5mM3-[3-(cholamidopropyl )Dimethylamino]propanesulfonic acid inner salt (CHAPS).
  • the initial screening concentration of the compound is 1uM, and the ICs0 of the compound whose inhibition rate is greater than 60% under this condition is determined.
  • Echo 550 (manufacturer: Labcyte, model: Echo 550)

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

Abstract

La présente invention concerne un composé, une composition et une molécule fonctionnelle ayant un effet inhibiteur multicible et l'utilisation de ceux-ci. Le composé est un composé ayant une structure représentée par la formule (I). Spécifiquement, K est (II). Le composé possède un effet inhibiteur sur les deux cibles de BET et kinase, et peut agir simultanément sur différentes voies de signal pour la croissance de cellules tumorales pour obtenir de meilleurs effets thérapeutiques.
PCT/CN2021/071525 2020-01-15 2021-01-13 Composé, composition et molécule fonctionnelle ayant un effet inhibiteur multicible et leur utilisation WO2021143729A1 (fr)

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CN202010040040.4 2020-01-15

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CN114181237B (zh) * 2021-12-01 2024-02-23 上海凌凯医药科技有限公司 一种1-异丙基吡唑-5-硼酸频那醇酯的合成方法
CN115925686A (zh) * 2022-10-31 2023-04-07 贵州医科大学 Meridianin类衍生物及其路易斯酸促进的偶联合成方法和用途

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CN113121528A (zh) 2021-07-16
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