Inhibitors of fibroblast growth factor receptor kinases
Inventors
Kaldor, Stephen W. • Tyhonas, John • Murphy, Eric A. • Kanouni, Toufike • Arnold, Lee D. • Kania, Robert • Cox, Jason M.
Assignees
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Publication Number
US-11345681-B1
Publication Date
2022-05-31
Expiration Date
Abstract
Provided herein are heteroaryl inhibitors of fibroblast growth factor receptor kinases, pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.
Core Innovation
The invention relates to compounds, or pharmaceutically acceptable salts or solvates thereof, having the structure of Formula (I). The scaffold is defined by a Z group with t being 1 or 2, R1, R2, and R3 each independently selected from hydrogen, fluoro, or optionally substituted C1-C4 alkyl, and R4 defined as an optionally substituted benzimidazol-5-yl.
Within Formula (I), R is selected from hydrogen, optionally substituted C1-C6 alkyl optionally substituted C2-C7 alkenyl, —CO2R5, —CONHR5, or —CON(R5)2, where each R5 is optionally substituted C1-C6 alkyl, and R6 is an optionally substituted alkyl. The disclosed structures include pyrazole-4-carboxamide and ethynyl-linked heteroaryl examples, with benzimidazole, benzodiazole, benzothiazole, benzoxazole, indazole, imidazo[1,2-a]pyridine, imidazo[4,5-b]pyridine, quinoline, quinazoline, and related fused heteroaryl variants.
The examples provide specific compound structures with defined stereochemistry, including chiral pyrrolidine-containing motifs and (3S,5R) and related stereochemical assignments. The examples also show substitution patterns such as methoxymethyl, hydroxymethyl, hydroxyethyl, hydroxypropan-2-yl, methylamino, amino, cyclopropyl, cycloalkyl, halogen, fluoro, chloro, difluoro, difluoromethyl, trifluoroethyl, methyl, ethyl, cyano, trifluoromethyl, and methoxy-d3.
Claims Coverage
The independent claim coverage is centered on one Formula (I) compound family defined by Z, t, R1-R4, R, R5, and R6. The inventive features consistently recite the same core structural selectors, with dependent claims narrowing specific substituent choices and, in some instances, providing concrete examples such as R1 set to hydrogen, R = —CH2OCH3, and R6 = methyl.
Formula (I) compound with defined Z and t
A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I), wherein Z is selected from a group having the structure and t is 1 or 2.
Substituent pattern R1-R3 and benzimidazol-5-yl group R4
R1, R2, and R3 are each independently selected from hydrogen, fluoro, or optionally substituted C1-C4 alkyl, and R4 is an optionally substituted benzimidazol-5-yl.
Defined selection for R and carbonyl or alkenyl options
R is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C7 alkenyl, —CO2R5, —CONHR5, or —CON(R5)2, where each R5 is optionally substituted C1-C6 alkyl.
Optionally substituted alkyl for R6
R6 is an optionally substituted alkyl.
Dependent narrowing of benzimidazol substitution and specific embodiments
Dependent claims further narrow the benzimidazol-5-yl substitution pattern and include specific substitution examples such as R1 being hydrogen, R = —CH2OCH3, and R6 = methyl.
Overall, the claim coverage is defined by Formula (I) compounds with a Z/t framework, substituent selections for R1-R3, an optionally substituted benzimidazol-5-yl group at R4, and a defined set of alkyl, alkenyl, and carbonyl-containing options for R with R5, plus an optionally substituted alkyl R6. The dependent claims further narrow these selections and include specific substitution examples.
Stated Advantages
Not explicitly described in patent.
Documented Applications
FGFR kinase inhibitory compounds are exemplified as individual heteroaromatic chemical structures/names.
Therapeutic treatment of disease, including cancer.
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