Tetrahydropyridopyrimidine pan-KRas inhibitors
Inventors
Wang, Xiaolun • Ivetac, Anthony • Kulyk, Svitlana • Lawson, John David • Marx, Matthew Arnold • Smith, Christopher Ronald
Assignees
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Publication Number
US-11999753-B2
Publication Date
2024-06-04
Expiration Date
Abstract
The present invention relates to compounds that inhibit at least one of KRas wild type, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H, pharmaceutical compositions comprising the compounds and methods of use therefor.
Core Innovation
The disclosure provides selected compounds defined by illustrated chemical structures, including tetrahydropyrido[3,4-d]pyrimidine derivatives and related heteroaromatic scaffolds, optionally as pharmaceutically acceptable salts. The examples share substituted naphthyl or naphthalene-linked groups and pyrrolizine or tetrahydro-1H-pyrrolizinyl methoxy linkers, with variations across amide, carbamoyl, triazole, imidazole, pyrazole, morpholinyl, piperidine-related, azepane, sulfone, hydroxyl, hydroxymethyl, and trifluoromethyl substituents.
The invention also provides anticancer compositions and methods that use compounds of Formula (I) and pharmaceutically acceptable salts and salt-containing pharmaceutical compositions. The compound of Formula (I) is used to treat wild-type KRas-associated cancer and specific KRas mutant-associated cancers, including KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H.
The disclosed compound set includes tetrahydropyridopyrimidine compounds and related pyrido[3,4-d]pyrimidine-based tetrahydropyridine/tetrahydropyrimidine derivatives, as well as substituted polycyclic nitrogen-containing small-molecule compounds with fluoro-, naphthalene-, spiro-, azepane-, piperidine-, pyrrolizine-, triazole-, pyrazine-, pyrazole-, piperazinyl-, and oxadiazole-containing motifs. The document further provides numerous specifically named examples, intermediates, salts, and characterization data supporting the described compound embodiments.
Claims Coverage
The consolidated claim coverage centers on selected compounds defined by illustrated chemical structures or Formula (I), with optional pharmaceutically acceptable salts. Across the provided claim descriptions, the coverage also extends to pharmaceutical compositions comprising a therapeutically effective amount with a pharmaceutically acceptable excipient.
Selected compound set with pharmaceutically acceptable salts
A compound selected from a set of chemical structures or Formula (I), together with a pharmaceutically acceptable salt thereof.
Particular illustrated compound or structure
The compound is a particular illustrated chemical compound or includes a particular compound structure shown in accompanying chemical images, optionally as a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with therapeutically effective amount and excipient
A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
Overall, the claims provide coverage to selected compound sets or Formula (I), optionally as pharmaceutically acceptable salts, with dependent narrowing to specific illustrated compounds and a pharmaceutical composition containing a therapeutically effective amount and a pharmaceutically acceptable excipient.
Stated Advantages
Treat wild-type KRas-associated cancer and KRas mutant-associated cancers, including the listed KRas mutations.
Inhibit KRas activity.
Inhibit cell proliferation.
Address resistance after KRas G12C covalent inhibitor failure.
Documented Applications
KRas binding displacement performance across KRas WT and KRas mutants is reported using a TR-FRET KRas binding displacement assay with KRas binding IC50 values.
KRas-mediated ERK phosphorylation inhibition is reported, including HTRF pERK readouts in KRas-mutant cell lines.
Anti-proliferative activity and viability effects are assessed in a 5-day viability assay against engineered 3T3 cells expressing adagrasib-resistance KRas mutations.
Treatment of wild-type KRas-associated cancer and KRas mutant-associated cancers, including KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D, and KRas Q61H associated cancers.
Treatment of lung cancer, including non-small cell lung cancer and small cell lung cancer.
Treatment of colorectal cancer, rectal cancer, and pancreatic cancer.
Patient-method using an FDA-approved assay or kit to determine KRas mutation status prior to administering the Formula (I) compound.
Treating KRas-associated cancers in contexts involving resistance after KRas G12C covalent inhibitor failure.
Inhibiting cell proliferation associated with KRas activity.
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