Inhibitors of MET kinase
Inventors
OUYANG, Xiaohu S. • Kanouni, Toufike • Tyhonas, John S. • Cox, Jason M. • KANIA, Robert S.
Assignees
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Publication Number
US-11753395-B2
Publication Date
2023-09-12
Expiration Date
Abstract
Provided herein are inhibitors of MET receptor tyrosine kinase, pharmaceutical compositions comprising said inhibitory compounds, and methods for using said MET kinase inhibitory compounds for the treatment of disease.
Core Innovation
The invention relates to compounds, or pharmaceutically acceptable salts or solvates thereof, having the structure of Formula (II), with X as C-L1-R1 and L1 as O, and L as O. The structure defines multiple substituents, including R, R1, R6-R8, R9, R10, R11, and R12, and at least one of R6, R7, or R8 is not H. The disclosed examples include substituted quinoline, naphthyridine, and pyridine carboxamide derivatives, including 4-methoxypyridine-3-carboxamide analogs and fluorinated phenyl/heteroaryl variants.
The exemplified compounds vary the quinoline or naphthyridine ether substituent and the side-chain groups, including cyclopropoxy, hydroxyethoxy, hydroxypropoxy, methoxyethoxy, hydroxybutoxy, bis(2-methoxyethoxy), and methylaminoethoxy substituents. The disclosure also identifies stereochemical variants, including R and S enantiomeric examples and (2S) and (2R) examples, as well as additional fluoro and chloro substitution patterns. The examples are presented with structural depictions and analytical characterization such as MS ESI, LC-MS, 1H NMR, and 19F NMR, and in some cases TFA salt formation or reported isolated yields.
The disclosure also includes pharmaceutical compositions comprising the compounds together with pharmaceutically acceptable carriers or excipients, with dosage form categories such as tablets, capsules, and injectables. Use is described in connection with MET kinase inhibition, including contacting MET kinase and treatment contexts.
Claims Coverage
The document provides one independent claim directed to a Formula (II) compound, including pharmaceutically acceptable salts or solvates, with multiple structural variables and the requirement that at least one of R6, R7, or R8 is not H. Dependent claims refine the core structure by narrowing substituent options such as R6 and R9, and by adding a pharmaceutical composition embodiment with a pharmaceutically acceptable excipient.
Formula (II) compound scaffold with oxygen linkages
A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (II), wherein X is C-L1-R1 and L1 is O, and L is O.
Constrained substituent sets for R and R1
R and R1 are each selected from H, halogen, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl.
At least one of R6, R7, or R8 is not hydrogen
R6, R7, and R8 are each independently selected from H or halogen, provided that at least one of R6, R7, or R8 is not H.
Defined options for R9, R10, R11, and R12
R9 is selected from optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, and optionally substituted cycloalkylalkyl; R10 is H; R11 is H, halogen, NH2, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, NH(optionally substituted C1-C6 alkyl), or N(optionally substituted C1-C6 alkyl)2; and R12 is H, halogen, NH2, CN, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 alkoxy.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient.
Overall, the claim coverage centers on the Formula (II) scaffold with oxygen linkages and tightly constrained substituent choices across R, R1, R6-R8, R9, R10, R11, and R12, including the requirement that at least one of R6, R7, or R8 is not hydrogen. Dependent refinements narrow specific substituent embodiments and include a pharmaceutical composition variant with a pharmaceutically acceptable excipient.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Use in connection with MET kinase inhibition, including contacting MET kinase.
Methods of treatment using the MET kinase inhibitory compounds.
Pharmaceutical compositions formulated as tablets, capsules, or injectables with pharmaceutically acceptable carriers or excipients.
Therapeutic use for cancer/neoplastic disease via pharmaceutical compositions including oral or injection administration embodiments.
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