Heterocyclic derivatives, pharmaceutical compositions and their use in the treatment or amelioration of cancer
Inventors
Fabritius, Charles-Henry • Hekking, Koen • Gruber, Dorothea • FOLMER, Rutger • FLÜCKIGER-MANGUAL, Stefanie • Bohnacker, Thomas • Schwill, Martin • SCHMITZ-ROHMER, Debora
Assignees
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Publication Number
US-12595258-B2
Publication Date
2026-04-07
Expiration Date
Abstract
The present invention relates to compounds of formula (I) or salts, solvates, cocrystals, tautomers, or mixtures thereof. Furthermore, the present invention relates to pharmaceutical compositions comprising said compounds. Moreover, the present invention relates to the compounds of formula (I) or the salts, solvates, cocrystals, tautomers, or mixtures thereof or the pharmaceutical compositions for use as a medicament and to the compounds of formula (I) or the salts, solvates, cocrystals, tautomers, or mixtures thereof or the pharmaceutical compositions for use in the treatment or amelioration of cancer. Optionally, the compounds of formula (I) or the salts, solvates, cocrystals, tautomers, or mixtures thereof or the pharmaceutical compositions are administered in combination with a second therapeutic agent, in particular an anti-cancer agent.
Core Innovation
The invention relates to compounds of formula (I), including pharmaceutically acceptable salt, solvate, cocrystal, tautomer, or a mixture thereof. Preferred embodiments further include specific substituted examples and pharmaceutically acceptable salt forms, including a sodium salt.
The patent states that the compounds bind p300/CBP bromodomains and preferably inhibit multiple myeloma cell proliferation/survival by CBP/p300 bromodomain inhibition. The disclosure reports CBP/p300 bromodomain inhibition with OPM2 EC50 values at or below stated levels, and includes cellular efficacy assessment in multiple myeloma OPM-2 cells and a CBP bromodomain binding assay using TR-FRET.
The disclosed pharmacological use is extended to cancer indications, including multiple myeloma, melanoma, and NSCLC, and further includes combination therapy paradigms. The combinations described include EGFR inhibitor combinations for NSCLC defined by EGFR oncogenic alterations and/or resistance alterations, and KRAS inhibitor combinations for cancers with KRAS oncogenic alterations.
The disclosure also includes kit and dosage-form concepts and broad fibrotic disease use, including idiopathic pulmonary fibrosis and NASH. Co-administration of known anti-fibrotic/anti-inflammatory agents is described as an option, together with formulation and administration route options and general excipient concepts.
Claims Coverage
Two independent claims are identified, each directed to a compound having a specified formula, with coverage extending to pharmaceutically acceptable variants and, through dependent claims, to pharmaceutical compositions with formulation components. Across the independent claims, the inventive features focus on the chemical compound defined by a formula and the inclusion of pharmaceutically acceptable forms.
Formula-defined compound and pharmaceutically acceptable variants
A compound having the following formula, or a pharmaceutically acceptable salt, solvate, cocrystal tautomer, or a mixture thereof.
Formula-defined compound
A compound having the following formula.
The independent claim set covers compounds defined by specified formulas, including pharmaceutically acceptable salt, solvate, cocrystal, tautomer, or mixture variants, and dependent claims further direct coverage to pharmaceutical compositions containing a pharmaceutically effective amount formulated with a pharmaceutically acceptable carrier, diluent, or excipient.
Stated Advantages
Treating or ameliorating cancer.
Preventing resistance.
Anti-tumor effects via inhibiting p300/CBP bromodomains.
Improved durability, including resistance to EGFR/KRAS inhibitors.
Preferred selectivity, for example relative to the BET family.
Preferably inhibits multiple myeloma cell proliferation/survival via CBP/p300 bromodomain inhibition.
Binds p300/CBP bromodomains.
Documented Applications
Use as medicaments to treat or ameliorate cancer.
Use to prevent resistance, including resistance to EGFR/KRAS inhibitors.
Cancer indications explicitly mentioned include melanoma, NSCLC, prostate cancer, multiple myeloma, and acute myeloid leukemia.
Combination regimens explicitly described include regimens involving KRAS inhibitors and EGFR inhibitors.
Treating fibrotic diseases including idiopathic pulmonary fibrosis, non-alcoholic steatohepatitis, pulmonary fibrosis, radiation-induced pneumonitis/radiation fibrosis, interstitial lung disease, chronic fibrosing interstitial pneumonia, and non-specific interstitial pneumonia.
Combination therapy use with EGFR inhibitors for NSCLC defined by EGFR oncogenic alterations and/or resistance alterations.
Combination therapy use with KRAS inhibitors for cancers with KRAS oncogenic alterations.
Fibrotic disease use including idiopathic pulmonary fibrosis (IPF) and NASH, with optional co-administration of anti-fibrotic/anti-inflammatory agents.
Cellular efficacy evaluation in multiple myeloma OPM-2 (EC50 determination).
CBP bromodomain binding evaluation using TR-FRET.
Evaluation of a set of numbered compounds for efficacy/binding.
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