WO2023119098A1 - Inhibiteurs de protéine kinase c thêta - Google Patents

Inhibiteurs de protéine kinase c thêta Download PDF

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Publication number
WO2023119098A1
WO2023119098A1 PCT/IB2022/062406 IB2022062406W WO2023119098A1 WO 2023119098 A1 WO2023119098 A1 WO 2023119098A1 IB 2022062406 W IB2022062406 W IB 2022062406W WO 2023119098 A1 WO2023119098 A1 WO 2023119098A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
group
halogen
mmol
Prior art date
Application number
PCT/IB2022/062406
Other languages
English (en)
Inventor
Claire Bouix-Peter
Sebastien Campos
Stefano Crosignani
Craig Steven Harris
John Maclean
Eric Talbot
Original Assignee
Galderma Holding SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Galderma Holding SA filed Critical Galderma Holding SA
Publication of WO2023119098A1 publication Critical patent/WO2023119098A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C07D487/22—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 four or more hetero rings

Definitions

  • a seventh aspect is directed to the compound of the first aspect or any of the first to thirty-first embodiments of the first aspect or the pharmaceutical composition of the second aspect, for use in medicine or any of the third to sixth aspects.
  • An eighth aspect is directed to the compound of the first aspect or any of the first to thirty-first embodiments of the first aspect or the pharmaceutical composition of the second aspect, for the preparation of a medicament for use in medicine or any of the third to sixth aspects.
  • Reference to “optionally substituted” indicates the compound is either not substituted or one or more hydrogens are replaced with an indicated group. The hydrogen(s) being replaced may be present at the same or different locations. The provided substitution(s) maintain stable compound valency.
  • a “C1-2 alkyl” refers to a saturated, monovalent, hydrocarbon chain, which may be methyl or ethyl.
  • a “OC1-2 alkyl” refers to a C1-2 alkyl connected to the oxy connecting atom.
  • a “C 1-2 haloalkyl” refers to a C 1-2 alkyl where one or more hydrogens is substituted with a halogen, where each halogen may be the same or different.
  • stereochemically pure isomeric forms of the compounds can be derived from corresponding stereochemically pure isomeric forms of the appropriate starting materials, intermediates, or reagents.
  • the compound can be synthesized by stereospecific methods of preparation, which typically employ stereochemically pure starting materials or intermediate compounds.
  • Pharmaceutically acceptable salts of compounds can be synthesized from the parent compound containing an acidic or basic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of a compound with a stoichiometric amount of the appropriate acid or base in water or in an organic solvent, or in a mixture of the two.
  • V is O
  • the obtained compound of formula (III-3) undergoes suitable deprotection reaction via one-step or two-step process to obtain a compound of formula (III-4), which has two terminal hydroxyl groups.
  • the compound of formula (III-4) is then subjected to Mitsunobo reaction to form the macrocycle under suitable conditions.
  • V is CH2
  • the deprotection step to obtain the compound of formula (III-4) may not be necessary, and the compound of formula (III-5) can be obtained under suitable ring formation conditions.
  • Conversion of the resulting compound of formula (III-5) to a compound of formula (III-6) depends on the R substituent.
  • a compound of formula (V-2) can be prepared from a compound of formula (V-1) by a nucleophilic aromatic substitution reaction (S N Ar) with a suitable aromatic compound bearing a leaving group, or by a Buchwald reaction with a suitable aryl halide, or by an Ullman type reaction with a suitable aryl halide.
  • S N Ar nucleophilic aromatic substitution reaction
  • a suitable aromatic compound bearing a leaving group or by a Buchwald reaction with a suitable aryl halide, or by an Ullman type reaction with a suitable aryl halide.
  • V is O
  • the resulting compound of formula (V-2) undergoes a suitable deprotection reaction via one-step or two-step process to obtain a compound of formula (V-3), which has two terminal hydroxyl groups.
  • 1,1'-bis(diphenylphosphino)ferrocene palladium(II)dichloride (78 mg, 0.09 mmol, 0.05 eq.) was finally added under nitrogen atmosphere and the resulting mixture was stirred at 100 °C overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by Flash Column Silica-CS (120 g, eluting with ethyl acetate in petroleum ether from 0% to 50%).

Abstract

La présente invention concerne des inhibiteurs de PKCθ de formule I, des sels pharmaceutiquement acceptables de ceux-ci et des utilisations de tels composés. Les utilisations du composé comprennent l'inhibition de l'activité de la PKCθ chez un sujet ayant besoin d'un tel traitement, le traitement de maladies ou de troubles à médiation par les lymphocytes T et le traitement de maladies ou de troubles auto-immuns ou inflammatoires. Des exemples de maladies ou de troubles particuliers ciblés par les composés décrits ici comprennent une maladie intestinale inflammatoire, l'asthme, l'arthrite, la colite, la sclérose en plaques, le rejet de greffe par l'hôte, l'encéphalomyélite auto-immune, le psoriasis et la dermatite.
PCT/IB2022/062406 2021-12-20 2022-12-16 Inhibiteurs de protéine kinase c thêta WO2023119098A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP21215840 2021-12-20
EP21215840.6 2021-12-20
EP22191529.1 2022-08-22
EP22191529 2022-08-22

Publications (1)

Publication Number Publication Date
WO2023119098A1 true WO2023119098A1 (fr) 2023-06-29

Family

ID=84767024

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2022/062406 WO2023119098A1 (fr) 2021-12-20 2022-12-16 Inhibiteurs de protéine kinase c thêta

Country Status (2)

Country Link
TW (1) TW202333677A (fr)
WO (1) WO2023119098A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014181813A1 (fr) 2013-05-10 2014-11-13 武田薬品工業株式会社 Composé hétérocyclique
US20170096422A1 (en) 2014-03-24 2017-04-06 Takeda Pharmaceutical Company Limited Heterocyclic compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014181813A1 (fr) 2013-05-10 2014-11-13 武田薬品工業株式会社 Composé hétérocyclique
US20170096422A1 (en) 2014-03-24 2017-04-06 Takeda Pharmaceutical Company Limited Heterocyclic compound

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
BREZAR ET AL., FRONTIERS IN IMMUNOLOGY, vol. 6, 2015, pages 6
CHAND ET AL., CURRENT PHARMACEUTICAL DESIGN, vol. 18, no. 00, 2012
COLLIER ET AL., ACDE MED CHEM. LETT, vol. 10, 2019, pages 1134
GEORGE ET AL., J. OF MEDICINAL CHEMISTRY, vol. 58, 2015, pages 222
HAGE-SLEIMAN ET AL., J. OF IMMUNOLOGY RESEARCH, vol. 2015, 2015
KATOH ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 27, 2017, pages 2497
KATOH TAISUKE ET AL: "Practical application of 3-substituted-2,6-difluoropyridines in drug discovery: Facile synthesis of novel protein kinase C theta inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 27, no. 11, 2 April 2017 (2017-04-02), pages 2497 - 2501, XP085002080, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2017.03.099 *
KATOH TAISUKE ET AL: "Supplementary data 1 for Practical application of 3-substituted-2,6-difluoropyridines in drug discovery: Facile synthesis of novel protein kinase C theta inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1 June 2017 (2017-06-01), pages 1S - S36, XP055914751, Retrieved from the Internet <URL:https://doi.org/10.1016/j.bmcl.2017.03.099> [retrieved on 20220422], DOI: 10.1016/j.bmcl.2017.03.099 *

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