CA3109981A1 - Composes polycycliques et methodes pour la degradation ciblee de polypeptides du fibrosarcome rapidement accelere - Google Patents

Composes polycycliques et methodes pour la degradation ciblee de polypeptides du fibrosarcome rapidement accelere Download PDF

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Publication number
CA3109981A1
CA3109981A1 CA3109981A CA3109981A CA3109981A1 CA 3109981 A1 CA3109981 A1 CA 3109981A1 CA 3109981 A CA3109981 A CA 3109981A CA 3109981 A CA3109981 A CA 3109981A CA 3109981 A1 CA3109981 A1 CA 3109981A1
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Prior art keywords
optionally substituted
alkyl
group
ulm
aryl
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CA3109981A
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English (en)
Inventor
Andrew P. Crew
Keith R. Hornberger
Jing Wang
Craig M. Crews
Saul Jaime-Figueroa
Hanqing Dong
Yimin Qian
Kurt Zimmerman
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Yale University
Arvinas Operations Inc
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Yale University
Arvinas Operations Inc
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Publication of CA3109981A1 publication Critical patent/CA3109981A1/fr
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active 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
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N

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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)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne des composés bifonctionnels, ULM LPTM, qui s'avèrent utiles en tant que modulateurs du fibrosarcome rapidement accéléré (RAF, tel que c-RAF, A-RAF et/ou B-RAF ; la protéine cible). En particulier, la présente invention concerne des composés bifonctionnels, qui contiennent, au niveau d'une extrémité, un ligand de Von Hippel-Lindau, de céréblon, d'inhibiteurs de protéines d'apoptose ou d'homologue 2 double-minute de souris, qui se lie à l'ubiquitine ligase E3 respective, et, au niveau de l'autre extrémité, une fraction qui se lie à la protéine RAF cible, de sorte que la protéine cible se trouve à proximité de l'ubiquitine ligase pour effectuer la dégradation (et l'inhibition) de la protéine cible. La présente invention présente une large plage d'activités pharmacologiques associées à la dégradation/inhibition de la protéine cible. Les composés et les compositions selon la présente invention permettent de traiter ou de prévenir des maladies ou des troubles qui résultent de l'agrégation ou de l'accumulation de la protéine cible, ou de l'activation constitutive de la protéine cible.
CA3109981A 2018-09-07 2019-09-07 Composes polycycliques et methodes pour la degradation ciblee de polypeptides du fibrosarcome rapidement accelere Pending CA3109981A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201862728581P 2018-09-07 2018-09-07
US62/728,581 2018-09-07
PCT/US2019/050114 WO2020051564A1 (fr) 2018-09-07 2019-09-07 Composés polycycliques et méthodes pour la dégradation ciblée de polypeptides du fibrosarcome rapidement accéléré

Publications (1)

Publication Number Publication Date
CA3109981A1 true CA3109981A1 (fr) 2020-03-12

Family

ID=68051923

Family Applications (1)

Application Number Title Priority Date Filing Date
CA3109981A Pending CA3109981A1 (fr) 2018-09-07 2019-09-07 Composes polycycliques et methodes pour la degradation ciblee de polypeptides du fibrosarcome rapidement accelere

Country Status (9)

Country Link
EP (1) EP3846907A1 (fr)
JP (2) JP2022500368A (fr)
KR (2) KR102642203B1 (fr)
CN (1) CN113164775A (fr)
AU (2) AU2019335516B2 (fr)
CA (1) CA3109981A1 (fr)
IL (1) IL281188A (fr)
MX (1) MX2021002559A (fr)
WO (1) WO2020051564A1 (fr)

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CN111902141A (zh) 2018-03-26 2020-11-06 C4医药公司 用于ikaros降解的羟脑苷脂结合剂
EP3781156A4 (fr) 2018-04-16 2022-05-18 C4 Therapeutics, Inc. Composés spirocycliques
US20230099031A1 (en) * 2019-12-17 2023-03-30 Orionis Biosciences, Inc. Bifunctional agents for protein recruitment and/or degradation
WO2021201036A1 (fr) * 2020-03-31 2021-10-07 田辺三菱製薬株式会社 Dérivé d'hydroxypyrrolidine et son application médicinale
CN115996719A (zh) 2020-06-19 2023-04-21 C4医药公司 Braf降解剂
WO2021255213A1 (fr) * 2020-06-19 2021-12-23 F. Hoffmann-La Roche Ag Composés hétérobifonctionnels en tant qu'agents de dégradation de braf
JP2023539663A (ja) * 2020-08-28 2023-09-15 アルビナス・オペレーションズ・インコーポレイテッド 急速進行性線維肉腫タンパク質分解化合物及び関連する使用方法
EP4277901A1 (fr) 2021-01-13 2023-11-22 Monte Rosa Therapeutics, Inc. Composés d'isoindolinone
WO2022266206A1 (fr) * 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
CA3223447A1 (fr) 2021-06-25 2022-12-29 Korea Research Institute Of Chemical Technology Nouveau compose heterocyclique bifonctionnel ayant une fonction de degradation de btk par l'intermediaire d'une voie de proteasome d'ubiquitine, et son utilisation
WO2023023941A1 (fr) * 2021-08-24 2023-03-02 Biofront Ltd (Cayman) Agents de dégradation d'hpk1, compositions comprenant ces agents de dégradation d'hpk1 et leurs procédés d'utilisation
CA3235512A1 (fr) * 2021-10-22 2023-04-27 Xiaobao Yang Compose ligand de ligase e3 crbn, agent de degradation de proteine developpe sur la base d'un compose de ligand, et leurs utilisations
CN115894450B (zh) * 2021-11-30 2023-09-12 山东如至生物医药科技有限公司 一种新型多环类化合物及其组合物和用途
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US11957759B1 (en) 2022-09-07 2024-04-16 Arvinas Operations, Inc. Rapidly accelerated fibrosarcoma (RAF) degrading compounds and associated methods of use
WO2024089272A1 (fr) * 2022-10-28 2024-05-02 Institut National De La Sante Et De La Recherche Medicale Nouveaux inhibiteurs de la phosphatidylinositol 3-kinase
CN115806503A (zh) * 2022-12-02 2023-03-17 中国海洋大学 一种选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用

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Also Published As

Publication number Publication date
IL281188A (en) 2021-04-29
JP2023159166A (ja) 2023-10-31
AU2019335516A1 (en) 2021-03-11
JP2022500368A (ja) 2022-01-04
WO2020051564A1 (fr) 2020-03-12
EP3846907A1 (fr) 2021-07-14
KR102642203B1 (ko) 2024-03-04
AU2019335516B2 (en) 2022-06-16
KR20210073519A (ko) 2021-06-18
CN113164775A (zh) 2021-07-23
KR20240028539A (ko) 2024-03-05
AU2022228150A1 (en) 2022-09-29
MX2021002559A (es) 2021-07-21

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