Pyrido-pyrimidinone and pteridinone compounds and methods of use
Inventors
Braun, Marie-Gabrielle • Castanedo, Georgette • Gibbons, Paul • Rudolph, Joachim • Vernier, William • Beveridge, Ramsay • Wu, Yao • Wu, Guosheng
Assignees
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Publication Number
US-12344603-B2
Publication Date
2025-07-01
Expiration Date
Abstract
Described herein are pyrido-pyrimidinone and pteridinone compounds or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods treating cancer, alone and in combination with other therapeutic agents.
Core Innovation
The disclosure concerns compounds having formula (Ic), (Id), (Ie), (Ie1), or (Ig), including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof. The structural definitions use variable substituents such as X1, R1, R2, R2A, R2B, R2C, and R3 through R10, with broad but explicit allowed sets including alkyl, cycloalkyl, heterocyclyl, halogen, cyano, hydroxyl, fluoroalkyl, sulfonamide-related groups, and ring-forming combinations.
The compounds are described with fluorinated heterocyclic and pteridine/pyrido[2,3-d]pyrimidinone-related scaffold features, and the examples include sulfonamide-bearing derivatives, including methanesulfonamide and trifluoropropane-1-sulfonamide motifs and related fluorinated sulfonamide series. The disclosed structures vary by stereochemistry, salt form, and substituent patterns on aryl, heterocyclic, and cyclohexyl or piperidine-linked side chains, with numbered compound examples, intermediates, and characterization data reported throughout the partial content.
The claim context links the compounds to IRE1-related disease or disorder, including IRE1-related cancer, and includes pharmaceutical composition and treatment method embodiments. In the examples, the compounds are characterized by reported yields, LCMS (ESI) [M+H]+ values, and measured HTRF IC50 values for IRE11a, and some entries include chiral separation or stereochemical assignment.
Claims Coverage
The independent claims are primarily structure-based and cover three recurring claim types: broad multi-parameter compound genera, a related genus with additional constraints including at least one specified R4/R5 motif, and selection of compounds from an enumerated list of numbered compounds. Across the consolidated record, the claims consistently use extensive substituent definitions for X1, R1, R2/R2A/R2B/R2C, and R3-R10, with stereoisomer, tautomer, and pharmaceutically acceptable salt coverage.
Multi-parameter compound genus with substituent constraints
A compound having formula (Ic), (Id), (Ie), (Ie1), or (Ig), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1 is —CRx or —N and Rx is hydrogen, C1-C4 alkyl, cyclopropyl, or halogen; R1 is C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 14-membered heterocyclyl; R2 is C1-C4 alkyl, C3-C6 cycloalkyl, or 4- to 10-membered heterocyclyl with defined R2A/R2B/R2C options and ring-forming combinations; and R3 through R10 are defined by enumerated allowed substituent sets.
Compound genus with at least one specified R4 or R5 motif
A compound having a formula, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R2A, R2B, R3, R4, and R5 are constrained by listed substituent sets, and wherein at least one of R4 and R5 is selected from —NR8A R9, —NR8C(O)R9, —NR8SO2R9, —C(O)NR8R9, or —SO2NR8R9, with additional constraints on R6, R7, R8, R8A, R8B, R8C, R9, R10, and R11.
Enumerated selection of numbered compounds
A compound or stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from a listed group of numbered compounds, including entries with lettered variants in the provided claim tables.
Overall, the claims are directed to defined chemical genera with extensive substituent and ring-forming restrictions, plus a separate enumerated-compound selection claim. The recurring inventive focus is a broad scaffold defined by explicit variable groups and optional substitution patterns, together with selection of specific numbered compounds in some claim families.
Stated Advantages
Potent and selective inhibitors/modulators of IRE11a activity are described.
Used as IRE1-related disease/cancer therapeutics via administration of an effective amount.
Supports pharmaceutical compositions and combination therapy for IRE1-mediated disorders and cancers.
Measured HTRF IC50 values for IRE11a are provided for multiple compounds.
Treat IRE1-related diseases.
Treat IRE1-mediated cancers, including cancers with increased IRE1 expression or increased IRE1 activity.
Extend treatment to diseases linked to abnormal IRE1 activity, including IRE1 deficiency and IRE1 hyperactivity.
Reduce macrophages in an atherosclerotic lesion.
Reduce IL-1β/CCL2/CCR2 production in atherosclerosis.
Documented Applications
Treating IRE1-related diseases, especially cancer, by administering an effective amount of the compound or a pharmaceutically acceptable salt.
IRE1-related disease/disorder and cancer therapeutics using the compounds of the disclosed tables or examples.
Pharmaceutical compositions comprising the compound with one or more pharmaceutically acceptable excipients.
Combination therapy with other anti-cancer agents or anti-inflammatory agents.
Measured HTRF IC50 evaluation for IRE11a inhibitory activity.
Treatment of IRE1-related diseases using IRE1-modulating compounds.
Treatment of IRE1-mediated cancer in a human patient, including cancers with increased IRE1 expression or increased IRE1 activity.
Treatment of diseases associated with abnormal IRE1 activity, including IRE1 deficiency and IRE1 hyperactivity; examples include neurodegenerative disorders and inflammatory/autoimmune diseases.
Treatment of atherosclerosis, including macrophage reduction and reduced IL-1β/CCL2/CCR2 production as described outcomes.
Combination regimens together with proteasome inhibitors, IMiDs, antibodies to CD38/VEGF-A/PD-1/PD-L1/IL-6, dexamethasone, and radiotherapy as described in the disclosure.
Treatment of an IRE1-related cancer in a subject by administering an effective amount of the compound or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition including the compound or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable excipients.
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