Substituted quinazolines for inhibiting kinase activity
Inventors
Qian, Xiangping • Zhu, Yong-Liang
Assignees
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Publication Number
US-11304957-B2
Publication Date
2022-04-19
Expiration Date
Abstract
Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.
Core Innovation
The patent discloses substituted quinazoline kinase inhibitor scaffolds of Formula I, including variable ring fragments A and B and a linker Q. The linker Q includes an electrophilic group E capable of covalent bond formation, and the disclosure defines substituent and ring variables including X1, X2, X3, X4, X5, Z, R groups, n, and m.
Specific structural embodiments are provided for compounds of Formula Ia, Formula Ib, and Formula Ib'. The disclosures cover compounds and pharmaceutically acceptable salts within the Formula I scaffold framework, and the chemistry is presented in terms of the defined variable substituent patterns and the presence of the electrophilic group E for covalent bond formation.
The patent further relates to a process for preparing compounds having the structure of Formula Ib, Formula Ib', Formula Ib''', or Formula Ib'' by a two-step sequence from Formula F to Formula G to the final Formula Ib family product. In the broader disclosure, Formula I family compounds inhibit multiple protein kinases, with particular emphasis on EGFR, and are described as useful as kinase inhibitors for cancer treatment.
The document discloses pharmaceutical compositions containing the Formula I compounds and methods for cancer treatment involving administration of a therapeutically effective amount of the Formula I compounds. It particularly references EGFR and EGFR-mutant disorders, with EGFR mutation determination described in connection with treatment, and exemplary mutations including L858R, T790M, and exon 19 deletions (del E746-A750).
Claims Coverage
The consolidated claim coverage centers on one independent process claim for preparing Formula Ib family products via a two-step sequence from Formula F to Formula G to the final Formula product, together with independent compound coverage for Formula I scaffolds. The claim set repeatedly specifies palladium-catalyzed hydrogenation, acid-mediated conversion, and dependent refinements to catalyst, solvent, temperature, acid, and product selection, with one independent process claim and multiple dependent claims.
Two-step hydrogenation and acid-mediated conversion to Formula Ib family product
A process for preparing a compound having the structure of Formula Ib, Formula Ib', Formula Ib''', or Formula Ib'' by contacting a compound having the structure of Formula F with hydrogen in the presence of a palladium catalyst to provide Formula G, and contacting Formula G with Formula H in the presence of an acid to provide the final Formula Ib family product.
Defined substituent constraints for the Formula Ib family product
X1 is N or C4R2 or C4R2; each R1, R2, R4, and R5 is independently H or halo; R3 is optionally substituted heterocycloalkyl; and each R6, R12, R13, and R14 is independently H.
Substituted quinazoline kinase inhibitor scaffold with electrophilic group E
Compounds of Formula I include variable ring fragments A and B and a linker Q defined to include an electrophilic group E capable of covalent bond formation, with substituent variables X1, X2, X3, X4, X5, Z, R groups, n, and m.
Palladium on carbon catalyst
The palladium catalyst includes palladium on carbon.
Methanol solvent at room or ambient temperature for step (i)
Step (i) uses a solvent that includes methanol at room or ambient temperature.
Trifluoroacetic acid for step (ii)
The acid used in step (ii) is trifluoroacetic acid.
n-Butanol solvent with about 80°C to about 90°C for step (ii)
Step (ii) uses a solvent comprising n-butanol under conditions at a temperature from about 80°C to about 90°C.
Selected exemplified Formula Ib family compounds
The process narrows the Formula Ib family product to selected exemplified compounds from a listed group.
The claim coverage is dominated by a sequential hydrogenation and coupling process that converts Formula F to Formula G and then to a Formula Ib family product under acidic conditions, together with compound coverage for the Formula I scaffold. Dependent claims repeatedly add palladium on carbon, methanol at ambient conditions, trifluoroacetic acid, n-butanol with an 80°C to 90°C range, and selection of specific exemplified products.
Stated Advantages
Used as kinase inhibitors for cancer treatment.
Targets EGFR and EGFR-mutant disorders using compounds of Formula I.
Provides pharmaceutical compositions for administration as therapeutically effective amounts.
Inhibition of multiple protein kinases, with particular emphasis on EGFR, including EGFR mutants L858R, del E746-A750, T790M, and L858R/T790M.
Cellular anti-proliferation effects in EGFR-mutant tumor cell lines A549, A431, HCC827, and H1975.
Selectivity versus other kinases.
Reference to relevance in a xenograft mouse model context.
Documented Applications
Cancer treatment using kinase inhibitor compounds of Formula I, including contexts involving EGFR and EGFR-mutant disorders.
Treatment associated with EGFR mutation determination, including L858R, T790M, and exon 19 deletions (del E746-A750).
Treatment of melanoma.
Treatment of non-small cell lung cancer.
Treatment of colon cancer.
Inhibition of EGFR including EGFR mutants L858R, del E746-A750, T790M, and L858R/T790M for tumor cell proliferation settings.
Cellular anti-proliferation in EGFR-mutant tumor cell lines A549, A431, HCC827, and H1975.
Xenograft mouse model relevance and H1975 xenograft tumor growth inhibition study.
Therapeutic use of Formula I compounds through pharmaceutical compositions and routes of administration, including oral, intravenous, transdermal, inhalation, topical, and kits/articles of manufacture.
Kinase inhibition testing against BTK, EGFR and EGFR mutants, FGFR1/2, JAK2/3, and KDR/VEGFR2 using a Z-LYTE kinase assay.
Cell-growth inhibition testing using an MTT assay, including IC50 categories across cancer cell lines.
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