Pyridone compounds and methods of use
Inventors
Bannen, Lynne • Bui, Minna • Jiang, Faming • Maung, Jack • Raub, Andrew • Salvant, Justin • SPANGLER, Benjamin • Tso, Kin • Wang, Yong • Xu, Wei
Assignees
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Publication Number
US-12371428-B2
Publication Date
2025-07-29
Expiration Date
Abstract
The present disclosure relates generally to compounds and pharmaceutical compositions suitable as modulators of protein kinases, and methods for their use in treating disorders mediated, at least in part by, protein kinases.
Core Innovation
The invention is directed to substituted heteroaromatic carboxamides and related compounds, including pharmaceutically acceptable salts, tautomers, and stereoisomers. The compounds are characterized by a core scaffold in which X1 is N, X2 is N, CR3, or CH, X3 is N or CH, X4 is N or CR2, and X5 is N, CR3, or CH, with ring A attached to the phenyl ring and to the carbonyl of the amide linkage by the single and double wavy lines, respectively. Y is O or S, and ring-dependent Z1 to Z3 definitions are provided.
The compounds further include broad substitution at R1, R2, R10, and additional R groups such as R3, R7, R9, R18, R4, R15, R16, and R20, with optional substitution patterns and optional substitution by Rb. Selected pairs of R groups may form fused heterocycloalkyl or fused heteroaryl systems, and the ring nitrogen atom in the formula is optionally oxidized. Subscript values m, n, and p are constrained to defined ranges.
Specific embodiments include enumerated substituted heteroaromatic carboxamides with oxy-linked 6,7-dimethoxy-1,5-naphthyridin-4-yl or 6,7-dimethoxyquinolin-4-yl motifs, fluorinated aryl substituents, and related heteroaryl carboxamide cores. The examples vary in heterocycle type, aryl fluorination and halogenation patterns, and side-chain substitution patterns, and some members are explicitly identified as enantiomers or atropisomers.
Claims Coverage
The consolidated claim coverage includes a broad formula claim and selection claims directed to specific enumerated compounds. The inventive features center on the defined heteroaromatic carboxamide scaffold, extensive R-group variability, optional ring-nitrogen oxidation, ring-dependent Z definitions, and explicit selection of named compounds.
Substituted heteroaryl carboxamide scaffold of formula (I )
A compound of formula (I ), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein X1 is N; X2 is N, CR3, or CH; X3 is N or CH; X4 is N or CR2; X5 is N, CR3, or CH; ring A is attached to the phenyl ring and to the carbonyl of the amide linkage by the single and double wavy lines; Y is O or S; and Z1, Z2, and Z3 are defined based on the ring A structure.
Variable substituent framework with optional fused-ring formation
R1, R2, and R10 are each independently selected from broad substituent classes and optionally substituted with Rb; R3, R7, R9, R18, and additional R groups are also defined by broad substituent sets with optional substitution patterns; selected pairs of R groups may form fused heterocycloalkyl or fused heteroaryl systems; and the ring nitrogen atom is optionally oxidized, with m, n, and p constrained to stated integer ranges.
Selected dimethoxy naphthyridine and quinoline oxy-linked carboxamides
A compound selected from explicitly listed substituted heteroaromatic carboxamides, including members with 6,7-dimethoxy-1,5-naphthyridin-4-yl or 6,7-dimethoxyquinolin-4-yl oxy-linked motifs, fluorinated aryl substituents, and pyridine, pyridazine, pyrimidine, and related heteroaromatic carboxamide cores, including pharmaceutically acceptable salts or stereoisomers.
Compound selected from Compounds 21-824
A compound or a pharmaceutically acceptable salt or stereoisomer thereof, the compound selected from Compounds 21-824, where each listed member is defined by an explicit substituted heteroaromatic structure and IUPAC-style name, including stereochemical variants such as enantiomer and atropisomer entries where stated.
The claims cover a broad formula (I ) chemical class with defined heteroatom positions, ring A attachment points, broad substituent options, optional oxidation, and possible fused-ring formation, together with narrower selection claims for explicitly named substituted heteroaromatic carboxamides and Compounds 21-824.
Stated Advantages
Kinase potency is reported as IC50 values for AXL, KDR, Mer, and Met using radiometric 33P kinase assays and HTRF KinEase assays.
Cellular pathway inhibition is supported by autophosphorylation ELISA readouts for phospho-AXL, phospho-Met, phospho-KDR, and phospho-Mer, including ligand stimulation.
Activity binning is used to categorize IC50 performance (A: IC50 ≤100 nM; B: 100<IC50≤300 nM; C: IC50>300 nM; NT: not tested).
Documented Applications
Assessment of kinase inhibition potency against AXL, KDR, Mer, and Met using radiometric 33P kinase assays and HTRF KinEase assays.
Assessment of cellular pathway inhibition via autophosphorylation ELISAs measuring phospho-AXL in A-172 cells, phospho-Met in PC-3 cells, phospho-KDR in HUVEC cells, and phospho-Mer in transiently transfected 293A cells, including stimulation with Gas6, HGF, and VEGF165.
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