2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors

A compound of Formula (IIIa):

• 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;
• Ra, Rb, and Rc are independently selected from 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 alkoxyC1-6 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;
• Ra, Rb, and Rc are independently selected from C1-6 alkyl, C1-6 cycloalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, hydroxy, halo, cyano, C1-6 hydroxyalkyl, C1-6 alkoxy-C1-6 alkyl, and C1-6 aminoalkyl;
• R4 and R6 are independently 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;
• R7 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 Rd, Re, and/or Rf;
• R2 is NR9R10 or —Xb—R11;
• R9 is hydrogen, C1-6 alkyl, C1-6 deuteroalkyl, or C3-6 cycloalkyl;
• 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, C1-10 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 oxetanyl, azetidinyl, 2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, and morpholinyl, wherein heteroaryl or heterocyclyl is unsubstituted or substituted with Rm, Rn, and/or Ro;
• and
• Rd, Re, Rj, Rk, Rm, and Rn are independently selected from 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 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;
• Xc is a 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, 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 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.