US 2026/0217709 A1 · 2-OXOQUINAZOLINE DERIVATIVES AS METHIONINE ADENOSYLTRANSFERASE 2A INHIBITORS

Abstract

Disclosed herein are certain 2-oxoquinazoline derivatives of Formula (IA): that are methionine adenosyltransferase 2A (MAT2A) inhibitors. Also disclosed are pharmaceutical compositions comprising such compounds and methods of treating diseases treatable by inhibition of MAT2A such as cancer, including cancers characterized by reduced or absence of methylthioadenosine phosphorylase (MTAP) activity.

Claims25

Dependent claims

-54. (canceled)

A compound of Formula (IIId):

or a pharmaceutically acceptable salt thereof, wherein:
R3 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylsulfonyl, halo, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyloxy, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 dialkylaminocarbonyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, heteroaryl, heterocyclyl, or heterocyclyloxy, wherein heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or substituted with Ra, Rb, and/or Rc independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, hydroxy, halo, cyano, C1-6 alkoxycarbonyl, C1-6 hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, and C1-6 aminoalkyl;
R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylsulfonyl, halo, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, C1-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, C1-6 dialkylaminocarbonyl, C1-6 hydroxyalkyl, C1-6 hydroxyalkoxy, C1-6 hydroxyalkylamino, C1-6 alkoxy-C1-6 alkyl, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkoxy-C1-6 alkylamino, C1-6 aminoalkyl, C1-6 aminoalkoxy, C1-6 aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or substituted with Ra, Rb, and/or Rc independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C1-6 Preliminary Amendment A to Notice to File Missing Parts haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, hydroxy, halo, cyano, C1-6 hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, and C1-6 aminoalkyl;
R4 is hydrogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, halo, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, cyano, amino, C1-6 alkylamino, C1-6 dialkylamino, aminocarbonyl, C1-6 alkylaminocarbonyl, or C1-6 dialkylaminocarbonyl;
R1 is R7 wherein R7 is C3-6 cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, C6-10 aryl, heteroaryl, heterocyclyl selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, and morpholinyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl, heteroaryl, or heterocyclyl is unsubstituted or substituted with Rd, Re, and/or Rf;
R2 is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 aminoalkyl, aminocarbonyl-C1-6 alkyl, aminosulfonyl-C1-6 alkyl, —O—R8, —N9R10, or —Xb—R11 wherein:
R8 is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 aminoalkyl, C3-6 cycloalkyl, or C3-6 cycloalkyl substituted with one or two substituents independently selected from the group consisting of C1-6 alkyl, halo, and cyano;
R9 is hydrogen, C1-6 alkyl, C1-6 deuteroalkyl, or C3-6 cycloalkyl;
and
R10 is hydrogen, C1-6 alkyl, C1-6 deuteroalkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 haloalkoxy-C1-6 alkyl, C1-6 aminoalkyl, aminosulfonyl-C1-6 alkyl, C1-6 thioureidoalkyl, C1-6 alkylsulfonyl, C1-6 alkylsulfonyl-C1-6 alkyl, C1-6 cyanoalkyl, C1-6 alkylcarbonyl, C1-6 alkylaminocarbonyl, C1-6 dialkylaminocarbonyl, aminocarbonyl-C1-6 alkyl, C1-6 alkylaminocarbonyl-C1-6 alkyl, C1-6 dialkylaminocarbonyl-C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, substituted C3-6 cycloalkyl, substituted C3-6 cycloalkyl-C1-6 alkyl, bridged cycloalkyl, spirocycloalkyl, C6-10 aryl-C1-6 alkyl, heteroaryl, heteroaryl-C1-6 alkyl, heterocyclyl, heterocyclyl-C1-6 alkyl, or spiroheterocyclyl, wherein aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or substituted with Rj, Rk, and/or Rl;
Xb is a bond or C1-6 alkylene;
R11 is monocyclic heteroaryl or heterocyclyl selected from the group consisting of oxetanyl, azetidinyl, 2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, and morpholinyl, wherein heteroaryl or heterocyclyl is unsubstituted or substituted with Rm, Rn, and/or Ro;
Rd, Re, Rj, Rk, Rm, and Rn are independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, hydroxy, C1-6 alkylsulfonyl, halo, cyano, carboxy, C1-6 alkoxycarbonyl, C1-6 hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 aminoalkyl, aminosulfonyl, C1-6 alkylaminosulfonyl, C1-6 dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, C1-6 alkylaminocarbonyl, and C1-6 dialkylaminocarbonyl;
and
Rf, Rl, and Ro are independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, hydroxy, halo, amino, C1-6 alkylamino, C3-6 cycloalkylsulfonylamino, cyano, carboxy-C1-6 alkyl, and —Xc—R12 where Xc is bond or C1-6 alkylene;
and R12 is substituted or unsubstituted C6-10 aryl;
wherein
each heteroaryl has 5 to 10 ring members and from 1 to 3 heteroatoms ring vertices each independently N, O or S;
each heterocyclyl has 4 to 8 ring members and from 1 to 2 heteroatom ring vertices each independently N, O, or S(O)n, wherein n is 0, 1, or 2;
each bridged cycloalkyl has 5 to 7 ring members in which two non-adjacent ring atoms are linked by a (CRR′)q group, wherein q is 1 to 3 and R and R′ are each independently H or methyl;
each bridged heterocyclyl has 5 to 7 ring members in which two non-adjacent ring atoms are linked by a (CRR′)p group, wherein p is 1 to 3 and R and R′ are each independently H or methyl, each bridged heterocyclyl has from 1 to 3 heteroatom ring vertices each independently N, O, or S(O)m, wherein m is 0, 1, or 2;
each fused cycloalkyl is a saturated C3-6 cycloalkyl fused to phenyl or a five- or six-membered heteroaryl having 1-3 heteroatoms each independently N, O, or S;
each fused heterocyclyl is a heterocyclyl fused to C3-6 cycloalkyl, phenyl or a five- or six-membered heteroaryl having 1-3 heteroatoms each independently N, O, or S;
each spirocycloalkyl has 6 to 10 ring members wherein the rings are connected through only one atom;
and
each spiroheterocyclyl is a saturated bicyclic ring having 6 to 10 ring members and from 1 to 3 heteroatom ring vertices each independently N, O, or S(O)t, wherein t is 0, 1, or 2;
and the bicyclic ring is connected through only one atom.

24 more elements

Dependencies are inferred from the claim text.

Facts

Application

19/356,576Filed 13 Oct 2025

Priority

10 Dec 2018

Published

30 Jul 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification25 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61P 35/00
Antineoplastic agents
C07D 239/80
With hetero atoms directly attached in position 2: oxygen atoms
C07D 239/95
Quinazolines; Hydrogenated quinazolines: with hetero atoms directly attached in positions 2 and 4

Family

Application62/777,715Us provisional application · filed 10 Dec 2018

Application62/835,853Us provisional application · filed 18 Apr 2019

Application62/883,945Us provisional application · filed 7 Aug 2019

Application17/311,873Continuation · filed 9 Dec 2019

Application19/356,576Continuation

US 12,503,467 B2Related patent

US 2022/0106276 A1Published application

US 2026/0217709 A1This patent

From the US filing history. Foreign family members aren’t listed.

2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors

Life of this patent

Abstract

Claims25

2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors

Life of this patent

Abstract

Claims25