PKM2 modulators and methods for their use
Inventors
Ho, Koc-Kan • Xu, Yong • Saunders, Michael David • Liu, Xiaohui • Pearce, Scott Albert • Wright, Kevin Bret • Foulks, Jason Marc • Parnell, Kenneth Mark • Kanner, Steven Brian • Vollmer, David Lee • Liu, Jihua
Assignees
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Publication Number
US-10472328-B2
Publication Date
2019-11-12
Expiration Date
Abstract
Compounds having activity as PKM2 activators are disclosed. The compounds have the following structure (I): including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R1, R2, R3, R4, R5 and R6 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
Core Innovation
The disclosure provides chemical structure depictions and 1H-NMR data for multiple closely related structure-defined small-molecule candidates. The compounds share a common scaffold including amide or heteroaryl-amide features, multiple nitrogens, and CF3-substituted heteroaromatic or fluorinated aryl rings, with substituent variation including F, Cl, Br, CN, OH, OMe, NO2, and different side-chain or ring motifs.
The examples include substituted 1H-pyrazole-5-carboxamide derivatives and other substituted heteroaryl-amide compounds, together with disclosed intermediates and final compounds. The partial content also describes fused bicyclic heteroaryl systems, sulfonyl or sulfone-containing ring systems, and linked piperazine, azabicyclic-like, indolylmethyl, cyclobutylmethyl, azetidinylmethyl, and other amine side-chain motifs.
The invention further concerns pharmaceutical compositions and treatment methods using compounds selected from the depicted structures and pharmaceutically acceptable salts thereof. The compounds are also described as PKM2 modulator compounds that are PKM2 activators for modulating pyruvate kinase M2 activity, and as substituted 3-(trifluoromethyl)-1H-pyrazole-5-carboxamides with oxidized heteroaryl side-chain motifs.
Claims Coverage
The provided claim set includes three independent categories: compounds, pharmaceutical compositions, and methods for treating cancer. Across the claims, the coverage centers on selection of particular depicted compounds and pharmaceutically acceptable salts, formulation with a pharmaceutically acceptable carrier, diluent or excipient, and administration of an effective amount to treat specified cancers. The independent claims identify the inventive features as compound selection, composition formulation, and cancer treatment.
Selected compound and pharmaceutically acceptable salts
A compound selected from the depicted chemical structures, together with pharmaceutically acceptable salts thereof.
Pharmaceutical composition comprising selected compound and pharmaceutically acceptable carrier
A pharmaceutical composition comprising the selected compound and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
Cancer treatment by administering the selected compound
A method for treating cancer in a subject in need thereof by administering an effective amount of the selected compound or its pharmaceutically acceptable salt, with cancer types including lung cancer, pancreatic cancer, skin cancer, colon cancer, breast cancer, kidney cancer, ovarian cancer, and hematological malignancy.
The claims are directed to specific illustrated compounds and their pharmaceutically acceptable salts, corresponding pharmaceutical compositions with a carrier, diluent, or excipient, and methods of treating listed cancers by administering an effective amount of the selected compound or salt.
Stated Advantages
Documented Applications
Treating cancer in a subject in need thereof by administering an effective amount of the selected compound or a pharmaceutically acceptable salt.
The treated cancers explicitly include lung cancer, pancreatic cancer, skin cancer, colon cancer, breast cancer, kidney cancer, ovarian cancer, and a hematological malignancy.
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