2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors
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.
1 . A compound of Formula (IIIa):
or a pharmaceutically acceptable salt thereof, wherein:
R 3 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyloxy, cyano, amino, C 1-6 alkylamino, C 1-6 dialkylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 dialkylaminocarbonyl, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, C 1-6 aminoalkoxy, heteroaryl, heterocyclyl, or heterocyclyloxy, wherein heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or substituted with R a , R b , and/or R c ; R a , R b , and R c are independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, hydroxy, halo, cyano, C 1-6 alkoxycarbonyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, and C 1-6 aminoalkyl;
R 5 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, cyano, amino, C 1-6 alkylamino, C 1-6 dialkylamino, C 1-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 dialkylaminocarbonyl, C 1-6 hydroxyalkyl, C 1-6 hydroxyalkoxy, C 1-6 hydroxyalkylamino, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkylamino, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 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 R a , R b , and/or R c ; R a , R b , and R c are independently selected from C 1-6 alkyl, C 1-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, hydroxy, halo, cyano, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, and C 1-6 aminoalkyl;
R 4 and R 6 are independently hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfonyl, halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, cyano, amino, C 1-6 alkylamino, C 1-6 dialkylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, or C 1-6 dialkylaminocarbonyl;
R 1 is R 7 ; R 7 is phenyl or 5- to 9-membered heteroaryl having from 1 to 3 heteroatoms ring vertices each independently N, O or S, wherein the phenyl or heteroaryl is unsubstituted or substituted with R d , R e , and/or R f ;
R 2 is NR 9 R 10 or —X b —R 11 ;
R 9 is hydrogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 3-6 cycloalkyl;
R 10 is hydrogen, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 haloalkoxy-C 1-6 alkyl, C 1-6 aminoalkyl, aminosulfonyl-C 1-6 alkyl, C 1-6 thioureidoalkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 alkylcarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 dialkylaminocarbonyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, C 1-6 dialkylaminocarbonyl-C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, substituted C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl-C 1-6 alkyl, bridged cycloalkyl, spirocycloalkyl, C 1-10 aryl-C 1-6 alkyl, heteroaryl, heteroaryl-C 1-6 alkyl, heterocyclyl, heterocyclyl-C 1-6 alkyl, or spiroheterocyclyl, wherein aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or substituted with R j , R k , and/or R l ;
X b is a bond or C 1-6 alkylene;
R 11 is monocyclic heteroaryl, or heterocyclyl selected from oxetanyl, azetidinyl, 2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, and morpholinyl, wherein heteroaryl or heterocyclyl is unsubstituted or substituted with R m , R n , and/or R o ; and
R d , R e , R j , R k , R m , and R n are independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, hydroxy, C 1-6 alkylsulfonyl, halo, cyano, carboxy, C 1-6 alkoxycarbonyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, C 1-6 dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, and C 1-6 dialkylaminocarbonyl; and
R f , R l , and R o are independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, hydroxy, halo, amino, C 1-6 alkylamino, C 3-6 cycloalkylsulfonylamino, cyano, carboxy-C 1-6 alkyl, and —X c —R 12 ; X c is a bond or C 1-6 alkylene; and R 12 is substituted or unsubstituted C 6-10 aryl;
wherein:
each heteroaryl has 5 to 10 ring members and from 1 to 3 heteroatoms ring vertices each independently N, O or S, unless otherwise specified;
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 C 3-6 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 C 3-6 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.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is methyl or ethyl.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkylcarbonyl, alkoxycarbonyl, C 1-6 alkylaminocarbonyl, C 1-6 dialkylaminocarbonyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, or C 1-6 dialkylaminocarbonyl C 1-6 alkyl.
5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is chloro, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl, or cyclopropyl.
7 . The compound of claim 1 , wherein R 5 is chloro, trifluoromethyl, or ethyl.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, fluoro, bromo, methyl, methoxy, or cyano; and R 6 is hydrogen.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 6 are hydrogen.
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, cyano, amino, C 1-6 alkylamino, C 1-6 dialkylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, or C 1-6 dialkylaminocarbonyl.
11 . The compound of 10 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is R 7 ; R 7 is phenyl which is unsubstituted or substituted with R d , R e , and/or R f ; R d and R e are independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, C 1-6 alkylsulfonyl, halo, cyano, carboxy, C 1-6 alkoxycarbonyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 aminoalkyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, C 1-6 dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl, and C 1-6 dialkylaminocarbonyl; and R f is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy, hydroxy, halo, and cyano.
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is R 7 ; R 7 is phenyl which is unsubstituted or substituted with R f ; R f is fluoro, chloro, bromo, or methyl, and R f is attached to a carbon atom on the phenyl ring that is ortho to the carbon atom of the phenyl ring attached to quinazolone nitrogen.
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is R 7 ; R 7 is pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which is unsubstituted or substituted with R d , R e , and/or R f ; R d and R e are independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, and 3-hydroxypropyl; and R f is selected from hydroxy, fluoro, chloro, cyano, and methyl.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is R 7 , R 7 is pyridinyl which is unsubstituted or substituted with R f ; R f is fluoro, chloro, bromo, or methyl; and R f is attached to a carbon atom on the pyridinyl ring that is ortho to the carbon atom of the pyridinyl ring attached to quinazolone nitrogen.
16 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
17 . A compound selected from the group consisting of:
Cpd
No.
Structure
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