Heterobicyclic inhibitors of MAT2A and methods of use for treating cancer
Inventors
Konteatis, Zenon D. • LI, MINGZONG • Liu, Peng • MEDEIROS, MATTHEW • REZNIK, SAMUEL K. • Sui, Zhihua • Travins, Jeremy M. • Popovici-Muller, Janeta • ZHOU, SHUBAO • MA, GUANGNING
Assignees
PHARMARESOURCES (SHANGHAI) CO Ltd • Servier Pharmaceuticals LLC
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Publication Number
US-11524960-B2
Publication Date
2022-12-13
Expiration Date
Abstract
The present disclosure provides for compounds according to Formula I or Formula II and their pharmaceutically acceptable salts, stereoisomers, and/or tautomers thereof. Also provided are pharmaceutical compositions and the compounds of formulae I and II for use in methods of treating cancers, via inhibition of MAT2A, including some cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted and/or not fully functioning.
Core Innovation
The disclosed subject matter encompasses heterobicyclic compound genera of Formula I and Formula (II), or pharmaceutically acceptable salts thereof, featuring variable linkers, ring systems, and substituents. Representative examples include substituted pyrido[4,3-d]pyrimidin-7-one, 1,6-naphthyridin-7(6H)-one, and pyrido[3,4-b]pyrazin-7(6H)-one derivatives with optional spiro-fused rings. Structural characterizations are supported by LC-MS and 1H NMR across synthesized analogues with [procedural detail omitted for safety].
The compounds function as MAT2A inhibitors to reduce cellular S-adenosylmethionine synthesis and exhibit antiproliferative effects in MTAP-null and MTAP-positive cancer models. Several series demonstrate MAT2A inhibition below 100 nM for potential cancer therapy. Because the background section and abstract are omitted from the available content, the specific technical problem being solved is not explicitly described in patent.
Claims Coverage
The claims define two independent claims directed to distinct compound genera and pharmaceutically acceptable salts thereof across two inventive features.
Formula I compound genus
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein X is N or CR6, L is selected from O, S, NR, or a bond, and substituents R1, R2, R2a, R3, R4, and R5 encompass defined alkyl, carbocyclyl, aryl, heteroaryl, or heterocycloalkyl groups, with R2a and R2 optionally forming a spiro-fused ring.
Formula (II) compound genus
A compound of Formula (II), or a pharmaceutically acceptable salt thereof, comprising specified selections for linker L and substituent groups R1, R2, R3, R4, and R6, encompassing defined optionally substituted aryl, heteroaryl, and heterocycloalkyl moieties.
The independent claims cover the Formula I and Formula (II) compound genera and their pharmaceutically acceptable salts, with dependent claims addressing pharmaceutical compositions and therapeutic cancer applications.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I or Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Treatment of cancers, including MTAP-deficient or MTAP-null liver or colon cancers, and cancers harboring mutant KRAS or p53.
Inhibition of MAT2A and reduction of S-adenosylmethionine (SAM) synthesis in cancer.
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