Bi-heteroaryl substitute 1,4-benzodiazepines and uses thereof for the treatment of cancer
Inventors
Angibaud, Patrick Rene • BROGGINI, Diego Fernando Domenico • CUYCKENS, Filip Albert C • HOSTYN, Steven Anna • JONES, Russell Mark • Querolle, Olivier Alexis Georges • Vermeulen, Wim
Assignees
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Publication Number
US-11542247-B2
Publication Date
2023-01-03
Expiration Date
Abstract
The invention relates to new quinoline, pyridopyrazine, naphthyridine and quinazolinone derivative compounds, to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.
Core Innovation
The invention relates to pharmaceutical compositions comprising a compound of formula (1), including tautomeric or stereochemically isomeric forms, and pharmaceutically acceptable salts or solvates thereof. The disclosed structures are characterized by defined core positions X1, X2, X3 and X4, by a ring parameter n that is an integer equal to 1 or 2, and by variable substituents R1, R2a, R2b, R2c, R3 and R4 with defined options including fluoro or chloro, methoxy, hydroxyl, and alkyl substituted with —C(O)NHCH3 or —S(O)2-C1-4 alkyl.
The pharmaceutical compositions are described as tumor radiosensitizers and/or chemosensitizers for use in combination with ionizing radiation and/or anticancer therapy. Therapeutic use is described in the context of cancer treatment regimens, including combination regimens with other radiosensitizers and/or chemosensitizers and anticancer agents.
The compounds are associated with biological evaluation using enzymatic TR-FRET assays for FGFR1–FGFR4 and VEGFR2 (KDR), and cell-based assays using Ba/F3 proliferation systems including Ba/F3-FGFR1, Ba/F3-FGFR3, and Ba/F3-KDR. Binding affinity is supported by KinomeScan KINOMEscan data reported as pKd values for multiple compounds.
Claims Coverage
The independent claim coverage centers on compounds of formula (1) with specified X1–X4 patterns, n being 1 or 2, and defined substituent options for R1, R2a/R2b/R2c, R3 and R4. The claim set also includes tautomeric and stereochemically isomeric forms and pharmaceutically acceptable salts or solvates, giving four main inventive feature groups across the claims.
Formula (1) compound with defined X1–X4 and n
A compound of formula (1) or a tautomeric or stereochemically isomeric form thereof, wherein X1 is CH and X2 is CH and X3 is CH and X4 is C, or X1 is N and X2 is CH and X3 is N and X4 is C, or X1 is CH and X2 is CH and X3 is C(O) and X4 is N; and wherein n represents an integer equal to 1 or 2.
Defined substituent groups R1, R2a/R2b/R2c, R3, and R4
The compound further wherein R1 represents hydrogen, C1-6 alkyl, hydroxyC1-6 alkyl, C1-6 alkyl substituted with —C(O)NHCH3, or C1-6 alkyl substituted with —S(O)2-C1-4 alkyl; R2a represents hydrogen, fluoro or chloro; R2b represents methoxy or hydroxyl; R2c represents methoxy or hydroxyl; R3 represents hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or C1-2 alkyl substituted with C3-6 cycloalkyl; and R4 represents hydrogen, methyl or ethyl.
Pharmaceutically acceptable salts or solvates
The compound is further defined as a pharmaceutically acceptable salt or solvate thereof.
Overall claim coverage is anchored on a specifically defined formula (1) compound framework with constrained structural variables X1–X4 and n, and with defined substituent options R1, R2a/R2b/R2c, R3, and R4, optionally provided as pharmaceutically acceptable salts or solvates.
Stated Advantages
Used as tumor radiosensitizers and/or chemosensitizers.
Provides tumor radiosensitizing and/or chemosensitizing activity in connection with kinase targets involving FGFR1–FGFR4 and VEGFR2 (KDR).
Supported binding and activity assessment via enzymatic TR-FRET assays, cell-based Ba/F3 proliferation assays, and KinomeScan KINOMEscan pKd reporting.
Documented Applications
Tumor radiosensitizer use in cancer treatment in combination with ionizing radiation.
Tumor chemosensitizer use in cancer treatment in combination with anticancer agents.
Combination regimens with other radiosensitizers and/or chemosensitizers and anticancer agents.
Treatment of disease states mediated by an FGFR kinase by administering a compound as defined in claim 1.
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