Certain chemical entities, compositions, and methods
Inventors
Qian, Xiangping • Zhu, Yong-Liang
Assignees
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Publication Number
US-10759766-B2
Publication Date
2020-09-01
Expiration Date
Abstract
Chemical entities based on quinoxaline that are kinase inhibitors are described. Specifically, quinoxaline derivatives of Formula I, containing a diarylamide or diarylurea substructure that inhibit Braf mutant kinase activity, pharmaceutical compositions containing the inhibitor compounds and methods of treatment of cancer comprising administering an effective amount of the Braf inhibitor compound are described.
Core Innovation
The invention discloses substituted urea compounds and benzamide analogs that comprise quinoxaline-6-carbonyl substituents and substituted aryl moieties, including fluoro, chloro, and trifluoromethyl patterns. Representative members are provided as specific substituted urea compounds, and the content reports characterization by LRMS and 1H NMR with calculated versus found m/z agreement.
The patent states that Formula I compounds bind and inhibit multiple kinases, including B-Raf and KDR/VEGFR2, and emphasizes B-Raf in the context of B-Raf V600E. Cellular anti-proliferative activity is described for tumor cells expressing B-raf/V600E, and anti-tumor activity is described using xenograft models.
The disclosure includes pharmaceutical composition and formulation aspects, including routes of administration for using the compounds. General synthetic scheme descriptions are provided, and additional disclosure includes salt forms such as pharmaceutically acceptable salts, prodrugs, solvates, polymorphs, and isotopic/deuterated forms.
Claims Coverage
The claim coverage centers on a defined group of substituted urea compounds featuring quinoxaline-6-carbonyl substitution patterns and pharmaceutically acceptable salts. The provided claims also extend to therapeutic use features for Raf/KDR-mediated cancer and Raf-mediated disorders, including a biomarker-conditioned method based on determining BRAF mutation presence.
Defined substituted quinoxaline-6-carbonyl urea compounds
A compound selected from a defined group of substituted urea structures incorporating quinoxaline-6-carbonyl substitution patterns and specified aryl/heterocycle substitution patterns, or a pharmaceutically acceptable salt thereof.
Therapeutically effective administration for Raf/KDR-mediated cancer
A method of treating cancer mediated by Raf or KDR in a subject, comprising administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt of the compound.
Companion BRAF mutation determination for Raf-mediated disorder treatment
A method of treating a disorder mediated by Raf, comprising determining presence/absence of a BRAF mutation in a biological sample and, if present, administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt.
Across the provided claim content, coverage is anchored by the defined quinoxaline-6-carbonyl substituted urea scaffold and pharmaceutically acceptable salts, with additional claims to administration for Raf/KDR-mediated cancer and Raf-mediated disorders, including determination of BRAF mutation presence before administration.
Stated Advantages
Documented Applications
Treating cancer mediated by Raf or KDR in a subject by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt.
Treating a disorder mediated by Raf by determining presence/absence of a BRAF mutation in a biological sample and administering the compound or a pharmaceutically acceptable salt if the BRAF mutation is present.
Kinase inhibition measured with a Z′-LYTE® assay against BRAF and BRAF V600E.
Inhibition against KDR/VEGFR2.
Cell growth inhibition via an MTT assay in A375 cells and A549 cells.
In vivo tumor growth inhibition in a PLC/PRF/5 xenograft model.
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