Therapeutic compounds and compositions
Inventors
Salituro, Francesco G. • Saunders, Jeffrey O. • Yan, Shunqi
Assignees
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Publication Number
US-10029987-B2
Publication Date
2018-07-24
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 claimed invention relates to a compound of Formula I or a pharmaceutically acceptable salt thereof. Within Formula I, ring atoms W, X, Y, and Z are each independently selected from CH or N, and variables D and D1 are independently a bond or NRb. Group A represents an optionally substituted bicyclic heteroaryl, and the scaffold is further defined by linker L, substituents R1, R3, Ra, Rb, Rc, and Rd, and parameters n, m, g, and h.
Exemplary embodiments include quinoline-8-sulfonamide compounds bearing piperazine or homopiperazine groups, sulfonamide-reversed analogues, and amide derivatives with varied acyl, aryl, or heteroaryl substituents. The compounds modulate or activate PKM2, alter PKM2 allostery and FBP-related activity, and potentially redirect glycolytic metabolism to inhibit proliferation. Evaluated structural analogues are assigned categorical AC50 activity classifications.
Claims Coverage
The claims contain one independent claim, claim 1, which defines two inventive features covering a compound of Formula I or a pharmaceutically acceptable salt thereof.
Formula I compound scaffold
Claim 1 covers a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein W, X, Y, and Z are each independently selected from CH or N; D and D1 are independently selected from a bond or NRb; A is an optionally substituted bicyclic heteroaryl; and L is selected from a bond and recited carbonyl, carbon-chain, oxygen-containing, and nitrogen-containing linkers.
Substituent selections and structural parameters
The claim defines linker L as a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)—; specifies substituent selections for R1, R3, Ra, Rb, Rc, and Rd; and establishes structural parameters where n is 0, 1, or 2, m is 1, 2, or 3, and h is 1 and g is 2, or g is 1 and h is 2.
The claims cover a structurally defined genus of Formula I compounds and pharmaceutically acceptable salts defined by the specified core ring atoms, linkers, substituents, and structural parameters, with dependent claims addressing narrower subsets and pharmaceutical compositions.
Stated Advantages
The compounds are proposed to modulate, particularly activate, PKM2 and alter PKM2 allostery and FBP-related activity.
The compounds are described as potentially redirecting glycolytic metabolism and inhibiting proliferation.
Documented Applications
A pharmaceutical composition comprising a compound of claim 1 or its pharmaceutically acceptable salt, together with a pharmaceutically acceptable excipient.
Treatment of cancer and other PKM2-associated disorders, including obesity, diabetes, autoimmune disorders, and benign prostatic hyperplasia (BPH).
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