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WO2024148049A1 - Agents de dégradation d'irak4 et leurs utilisations - Google Patents

Agents de dégradation d'irak4 et leurs utilisations Download PDF

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Publication number
WO2024148049A1
WO2024148049A1 PCT/US2024/010124 US2024010124W WO2024148049A1 WO 2024148049 A1 WO2024148049 A1 WO 2024148049A1 US 2024010124 W US2024010124 W US 2024010124W WO 2024148049 A1 WO2024148049 A1 WO 2024148049A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
omannac
ogluc
mannac
gluc
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.)
Ceased
Application number
PCT/US2024/010124
Other languages
English (en)
Inventor
Vaishali DIXIT
Wei Lu
Irina SLOBODCHIKOV
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.)
Kymera Therapeutics Inc
Original Assignee
Kymera Therapeutics 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 Kymera Therapeutics Inc filed Critical Kymera Therapeutics Inc
Publication of WO2024148049A1 publication Critical patent/WO2024148049A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/08—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 two hetero rings linked by a carbon chain containing alicyclic 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

Definitions

  • IRAK4 DEGRADERS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Appl. No. 63/478,486, filed January 4, 2023, the contents of which are herein incorporated by reference.
  • TECHNICAL FIELD OF THE INVENTION [0002] The present invention provides compounds and methods useful for the modulation of interleukin- 1 receptor-associated kinase 4 (“IRAK4”) via ubiquitination and/or degradation by compounds according to the present invention.
  • the invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • IRAKIMiD degraders are subset of IRAK4 degraders with a unique profile that combines the activity of IRAK4 degradation and immunomodulatory imide drugs, or IMiDs, for the treatment of MYD88-mutant B-cell lymphomas.
  • Oncogenic mutations of MYD88 most commonly MYD88L265P, are common in several subsets of B-cell lymphomas.
  • MYD88 is estimated to be mutated in approximately 30-40% of ABC-DLBCL cases, 30-70% of primary CNS lymphoma cases, 45-75% of primary extranodal lymphomas cases, and more than 90% of Waldenström macroglobulinemia cases.
  • a provided compound degrades and/or inhibits IRAK4 and immunomodulatory imide drug (IMiD) substrates Ikaros and Aiolos.
  • the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: B 1 is B 2 is H, Gluc, or ManNAc; B 3 is H, Gluc, or ManNAc; B 4 is H, Gluc, or ManNAc; B 5 is H, Gluc, or ManNAc; B 6 is H, Gluc, or ManNAc; A 2 is H, Gluc, or ManNAc; A 3 is H, Gluc, ManNAc, or ; each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the present invention provides a compound of formula I-c: I-c or a pharmaceutically acceptable salt thereof, wherein: A 2 is H, Gluc, or ManNAc; B 3 is H, Gluc, or ManNAc; and each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , and R 44 is independently H, OH, OGluc, or OMan
  • the present invention provides a compound of formula I-r: I-r or a pharmaceutically acceptable salt thereof, wherein: A 2 is H, Gluc, or ManNAc; and each of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , and R 44 is independently H, OH, OGluc, or OManNAc; optionally provided that at least A 2 is Gluc or ManNAc or at least one of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16
  • R 9 is H.
  • R 10 is H.
  • R 11 is H.
  • R 12 is H.
  • R 13 is H.
  • R 14 is H.
  • R 15 is H.
  • R 16 is H.
  • R 17 is H.
  • R 18 is H.
  • R 19 is H.
  • R 20 is H.
  • R 21 is H. [0098]
  • R 1 is OH.
  • R 2 is OH.
  • R 3 is OH.
  • R 4 is OH.
  • R 5 is OH.
  • a compound of formula II is a metabolite of Compound A.
  • the metabolite is formed upon exposure of Compound A to a human, mouse, rat, monkey (e.g., cynomolgus monkey), or dog (e.g., beagle).
  • the metabolite is formed by hepatocytes.
  • the metabolite is formed during first-pass metabolism. 4.
  • Pharmaceutically acceptable compositions [0111] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the present invention provides a method for the treatment of adult patients with a relapsed and/or refractory B-cell non-Hodgkin lymphoma who have received one prior therapy. [0162] In some embodiments, the present invention provides a method for the treatment of adult patients with a relapsed and/or refractory B-cell non-Hodgkin lymphoma who have received two prior therapies. [0163] In some embodiments, the present invention provides a method for the treatment of adult patients with a relapsed and/or refractory B-cell non-Hodgkin lymphoma who have received three prior therapies.

Landscapes

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

Abstract

La présente invention concerne des composés, des compositions de ceux-ci, et des procédés d'utilisation de ceux-ci pour traiter un trouble, une maladie ou un état pathologique médié par IRAK4 chez un patient.
PCT/US2024/010124 2023-01-04 2024-01-03 Agents de dégradation d'irak4 et leurs utilisations Ceased WO2024148049A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363478486P 2023-01-04 2023-01-04
US63/478,486 2023-01-04

Publications (1)

Publication Number Publication Date
WO2024148049A1 true WO2024148049A1 (fr) 2024-07-11

Family

ID=91804345

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/010124 Ceased WO2024148049A1 (fr) 2023-01-04 2024-01-03 Agents de dégradation d'irak4 et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2024148049A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190092750A1 (en) * 2015-08-27 2019-03-28 Pfizer Inc. Bicyclic-fused heteroaryl or aryl compounds as irak4 modulators
US20210032250A1 (en) * 2017-05-23 2021-02-04 Theravance Biopharma R&D Ip, Llc Glucuronide prodrugs of janus kinase inhibitors
US20210228562A1 (en) * 2019-12-17 2021-07-29 Kymera Therapeutics, Inc. Irak degraders and uses thereof
US20220054453A1 (en) * 2020-07-30 2022-02-24 Kymera Therapeutics, Inc. Methods of treating mutant lymphomas
WO2022236339A1 (fr) * 2021-05-07 2022-11-10 Kymera Therapeutics, Inc. Agents de dégradation d'irak deutérés et leurs utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190092750A1 (en) * 2015-08-27 2019-03-28 Pfizer Inc. Bicyclic-fused heteroaryl or aryl compounds as irak4 modulators
US20210032250A1 (en) * 2017-05-23 2021-02-04 Theravance Biopharma R&D Ip, Llc Glucuronide prodrugs of janus kinase inhibitors
US20210228562A1 (en) * 2019-12-17 2021-07-29 Kymera Therapeutics, Inc. Irak degraders and uses thereof
US20220054453A1 (en) * 2020-07-30 2022-02-24 Kymera Therapeutics, Inc. Methods of treating mutant lymphomas
WO2022236339A1 (fr) * 2021-05-07 2022-11-10 Kymera Therapeutics, Inc. Agents de dégradation d'irak deutérés et leurs utilisations

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