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WO2025154017A1 - Inhibiteurs d'usp28 - Google Patents

Inhibiteurs d'usp28

Info

Publication number
WO2025154017A1
WO2025154017A1 PCT/IB2025/050526 IB2025050526W WO2025154017A1 WO 2025154017 A1 WO2025154017 A1 WO 2025154017A1 IB 2025050526 W IB2025050526 W IB 2025050526W WO 2025154017 A1 WO2025154017 A1 WO 2025154017A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
compound
formula
usp28
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/IB2025/050526
Other languages
English (en)
Inventor
Sara BUHRLAGE
Maria Tarazona GUZMAN
Cara Ann STARNBACH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dana Farber Cancer Institute Inc
Original Assignee
Dana Farber Cancer Institute Inc
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 Dana Farber Cancer Institute Inc filed Critical Dana Farber Cancer Institute Inc
Publication of WO2025154017A1 publication Critical patent/WO2025154017A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • Ubiquitin-specific protease 28 is a cysteine isopeptidase of the USP sub-family of DUBs that exerts its function through regulating the stability of a number of cellular proteins and has been characterized as a tumor-promoting factor found to stabilize many oncoproteins. Variations in USP28 have been identified in multiple cancer types, including breast cancer, acute myeloid leukemia (AML), ovarian cancer, and colorectal cancer. Additionally, USP28 overexpression has been correlated with poor prognosis in patients suffering from glioblastoma, non-small cell lung carcinoma, and bladder cancers.
  • An aspect of the invention is to provide USP28 inhibitors of Formula I:
  • R 1 is Ci - C 4 alkyl
  • R 2 is Cs - Cio heterocyclyl substituted with -C(O)R 3 ;
  • R 4 is C5 - Cio heterocyclyl; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is to provide USP28 inhibitors of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is propyl.
  • Another aspect of the invention is to provide USP28 inhibitors of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is propyl and R 2 is piperazin- 1-yl substituted with -C(O)R 3 .
  • Another aspect of the invention is to provide USP28 inhibitors of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is propyl and R 2 is piperazin- 1-yl substituted with -C(O)R 3 where R 3 is Ci - C4 alkoxy.
  • Another aspect of the invention is to provide USP28 inhibitors of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is propyl and R 2 is piperazin- 1-yl substituted with -C(O)R 3 where R 3 is C5 - Cio heterocyclyl.
  • Another aspect of the invention is to provide USP28 inhibitors of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is propyl and R 2 is piperazin- 1-yl substituted with -C(O)R 3 where R 3 is piperazin- 1-yl.
  • Another aspect of the invention is to provide USP28 inhibitors of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is propyl and R 2 is piperazin- 1-yl substituted with -C(O)R 3 where R 3 is -NHR 4 .
  • Another aspect of the invention is to provide USP28 inhibitors of Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is propyl and R 2 is piperazin- 1-yl substituted with -C(O)R 3 where R 3 is -NHR 4 and R 4 is piperidin-4-yl.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a USP28 inhibitor compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a further aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in therapy.
  • Another aspect of the present invention provides a method for treating cancer susceptible to inhibition of USP28 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a method for treating an autoimmune disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present invention provides a method for treating a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is to provide USP28 inhibitors of Formula where R 5 is piperidin-l-yl, piperidin-4-yl, morpholin-4-yl, piperazin- 1-yl, or 8- azabicyclo[3.2.1]octan-3-yl, or a pharmaceutically acceptable salt thereof.
  • Eliel and S. H. Wilen (Wiley 1994) and Enantiomers, Racemates, and Resolutions, J., Jacques, A Collet, and S. H. Wilen (Wiley 1991), including chromatography on chiral stationary phases, enzymatic resolutions, or fractional crystallization or chromatography of diastereomers formed for that purpose, such as diastereomeric salts.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) : (I) ou un sel pharmaceutiquement acceptable de ceux-ci utiles pour le traitement d'une maladie ou d'un trouble associé à USP28 et des méthodes d'inhibition d'USP28.
PCT/IB2025/050526 2024-01-19 2025-01-17 Inhibiteurs d'usp28 Pending WO2025154017A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463622919P 2024-01-19 2024-01-19
US63/622,919 2024-01-19

Publications (1)

Publication Number Publication Date
WO2025154017A1 true WO2025154017A1 (fr) 2025-07-24

Family

ID=96471016

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2025/050526 Pending WO2025154017A1 (fr) 2024-01-19 2025-01-17 Inhibiteurs d'usp28

Country Status (1)

Country Link
WO (1) WO2025154017A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200017525A1 (en) * 2016-02-12 2020-01-16 Forma Therapeutics, Inc. Thienopyridine Carboxamides as Ubiquitin-Specific Protease Inhibitors
US20230365583A1 (en) * 2020-08-10 2023-11-16 Dana-Farber Cancer Institute, Inc. Fused tricyclic pyrimidine-thieno-pyridine small molecule inhibitors of ubiquitin-specific protease 28

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200017525A1 (en) * 2016-02-12 2020-01-16 Forma Therapeutics, Inc. Thienopyridine Carboxamides as Ubiquitin-Specific Protease Inhibitors
US20230365583A1 (en) * 2020-08-10 2023-11-16 Dana-Farber Cancer Institute, Inc. Fused tricyclic pyrimidine-thieno-pyridine small molecule inhibitors of ubiquitin-specific protease 28

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