Therapeutic compounds and compositions
Inventors
Salituro, Francesco G. • Saunders, Jeffrey O. • Yan, Shunqi
Assignees
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Publication Number
US-9199968-B2
Publication Date
2015-12-01
Expiration Date
Abstract
Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.
Core Innovation
The disclosed subject matter provides quinoline-8-sulfonamide compounds of formula (I), including subformula compounds of formulas Ic through Ii, or pharmaceutically acceptable salts thereof, that activate PKM2. These compounds incorporate variable ring atoms, linkers, and substituents, encompassing piperazine-benzamide-quinoline sulfonamide scaffolds, piperazine carboxylates, 3-oxopiperazine, and diazabicyclo[3.2.1]octane derivatives with aryl, heteroaryl, alkyl, cycloalkyl, gem-dialkyl, and deuterated variants. Characterized structural examples are supported by proton NMR, HPLC purity, and mass spectrometry data across the series.
The compounds and pharmaceutical compositions modulate PKM2 and glycolysis, inhibit cell proliferation, and treat conditions associated with reduced pyruvate kinase function. Reported screening results evaluate in vitro and ex vivo PKM2 activation, including enzyme-activity readouts and assay data across categories A through D. Documented applications include the treatment of cancer, obesity, autoimmune disorders, and metabolic or fat disorders. Because the background section is omitted in the provided content, the problem being solved is not explicitly described in patent.
Claims Coverage
The supplied claims identify one independent claim, claim 1, covering compounds of formula (I) and pharmaceutically acceptable salts thereof. Its coverage is summarized in three inventive features.
Formula (I) compound or pharmaceutically acceptable salt
Claim 1 recites a compound of formula (I), or a pharmaceutically acceptable salt thereof.
Variable ring atoms and linkers
W, X, Y, and Z are each independently selected from CH or N; Q and Q1 are independently selected from a bond or NRb; and L is selected from recited bond and chemical linker alternatives.
Substituent and numerical variable definitions
A is optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl; R1 is selected from alkyl, carbocycle, aryl, heteroaryl, and heterocyclyl; and remaining substituents and numerical variables including n, m, h, g, and p are defined as recited, including the proviso that the sum of g and h is at least 2.
Claim 1 covers the defined formula (I) compound genus and its pharmaceutically acceptable salts through specified ring atoms, linker alternatives, substituent groups, and numerical variables. The claims further encompass pharmaceutical compositions containing a pharmaceutically acceptable carrier, PKM2 activation, and the treatment of cancer associated with reduced PKM2 activity.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Activation of PKM2 and modulation of PKM2 and glycolysis, including PKM2 activation evaluation, combination therapy, and PKM2-based patient selection and monitoring.
Inhibition of cell proliferation.
Treatment of cancer, including cancer associated with reduced PKM2 activity, using a pharmaceutical composition comprising a formula (I) compound and a pharmaceutically acceptable carrier.
Treatment of conditions associated with reduced pyruvate kinase function, including diabetes, obesity, autoimmune disorders, benign prostatic hyperplasia, and metabolic or fat disorders.
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