2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors

Abstract

To provide 2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors.SOLUTION: Disclosed herein are 2-oxoquinazoline derivatives of certain 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.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 777,715, filed December 10, 2018, U.S. Provisional Patent Application No. 62 / 835,853, filed April 18, 2019, and U.S. Provisional Patent Application No. 62 / 883,945, filed August 7, 2019, the contents of each of which applications are incorporated by reference in their entirety for all purposes.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable.

[0003] Reference to a "Sequence Listing," a table, or a computer program listing addendum submitted on a compact disc Not applicable. [Background technology]

[0004] Background of the Invention Cancer is a leading cause of death worldwide. A limitation in the widespread use of therapeutic approaches, such as chemotherapy and immunotherapy, is that their cytotoxic effects are not restricted to cancer cells and adverse side effects can occur in normal tissues. Consequently, novel strategies are needed to better target cancer cells.

[0005] Synthetic lethality occurs when the combined defects in the expression of two or more genes lead to cell death, but not when only one of these genes is deficient. The concept of synthetic lethality originates from studies in the Drosophila model system, where the combination of mutations in two or more individual genes leads to cell death (as opposed to viability, which occurs when only one of these genes is mutated or deleted). More recently, numerous studies have examined maladaptive genetic alterations in cancer cells that make them vulnerable to synthetic lethality approaches. These tumor-specific genetic defects have led to the use of targeted agents to induce the death of tumor cells while sparing normal cells.

[0006] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate S-adenosylmethionine (SAM). SAM is the major intracellular methyl donor used to methylate several substrates, including DNA, RNA, and proteins. One methylase that utilizes SAM as a methyl donor is protein arginine N-methyltransferase 5 (PRMT5). SAM is required for PRMT5 activity, but PRMT5 is competitively inhibited by 5'-methylthioadenosine (MTA). Because MTA is part of the methionine salvage pathway, cellular MTA levels remain low in a process initiated by methylthioadenosine phosphorylase (MTAP).

[0007] MTAP is located at a locus on chromosome 9 that is frequently deleted in cancer patient cells from several tissue origins, including the central nervous system, pancreatic cancer, esophagus, bladder, and lung (cBioPortal database). Loss of MTAP results in the accumulation of MTAP-deficient cells, which produce MTA more reliant on SAM generation and consequent MAT2A activity, compared with MTAP-expressing cells. In a screen of shRNA cell lines across approximately 400 cancer cell lines, MAT2A knockdown resulted in a greater loss of viability in a greater proportion of MTAP-deficient cells compared with MTAP-WT cells (see McDonald et al., 2017 Cell, 170, 577-592). Furthermore, inducible knockdown of MAT2A protein reduced tumor growth in vivo (see Marjon et al., 2016 Cell Reports, 15(3), 574-587). These results indicate that MAT2A inhibitors may offer a novel therapy for cancer patients, including those with MTAP-deficient tumors. Summary of the Invention

[0008] overview Disclosed herein are certain 2-oxoquinazoline derivatives that are methionine adenosyltransferase 2A (MAT2A) inhibitors. Also disclosed are pharmaceutical compositions containing such compounds and methods for treating diseases treatable by inhibition of MAT2A, such as cancer, including cancers characterized by reduced or absent methylthioadenosine phosphorylase (MTAP) activity.

[0009] In a first aspect, there is provided a compound of formula (IA'), or a pharmaceutically acceptable salt thereof: [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyloxy, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl.a , R b , and / or R c is replaced by; R 5 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N, and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 (In the formula, X a is a bond or alkylene, and R 7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f substituted by R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and R 10 is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl , fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heteroaryl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g, R h , R j , R k , R m , and R n is independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or -X c -R 12 (X in the formula c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; provided that R 1 is heterocyclyl and R d and R e If one of R is hydroxy, f is not hydroxy); however: (1) Formula: [ka] But the expression: [ka] where: (a) R 2is chloro, piperazin-1-yl, 2-methylpiperazin-1-yl, or 1H-benzo[d][1,2,3]triazol-1-yl, and R 3 and R 6 is hydrogen and R 4 is chloro, and R 5 is bromo or 5-methylindazol-4-yl, R 1 is not 2-isopropylphenyl; (b) R 2 is furan-2-yl, thien-2-yl, methyl, or butyl; R 3 , R 4 , and R 6 is hydrogen, and R 5 is methyl, R 1 is not isopropyl; (c) R 2 is hydrogen and R 3 , R 5 , and R 6 is hydrogen, and R 4 If is chloro, R 1 is not benzyl; (d) R 2 is hydrogen and R 3 , R 5 , and R 6 is hydrogen, and R 4 If is bromo, R 1 is not 2-morpholin-4-ylethyl; (e) R 2 is cyclopropyl, methyl, difluoromethyl, or pentafluoroethyl, and R 3 , R 5 , and R 6 is hydrogen, and R 4 When R is chloro or fluoro, 1 is not 4-methoxybenzyl; (f) R 2 is cyclohexyl, pyridin-2-yl, or furan-2-yl, and R 3 , R 5 , and R 6 is hydrogen, and R 4 If is chloro, R 1 is not cyclopropylmethyl; (g) R 2 is hydrogen or thien-2-yl, and R3 , R 5 , and R 6 is hydrogen, and R 4 is methoxy; or R 2 is thien-2-yl and R 3 , R 4 , and R 6 is hydrogen, and R 5 is methyl, R 1 is not cyclopropylmethyl or 2,2,2-trifluoroethyl; (h) R 2 and R 6 is methyl, and R 3 , R 4 , and R 5 is hydrogen; or R 2 and R 3 is methyl, and R 4 , R 5 , and R 6 is hydrogen, R 1 is not 2,5-, 2,6- or 2,8-dimethylquinolin-4-yl or 2-methyl-5-methoxy-, 2-methyl-6-methoxy- or 2-methyl-8-methoxyquinolin-4-yl; (i) R 2 is trifluoromethyl and R 3 is methoxy or methyl, and R 4 , R 5 , and R 6 is hydrogen; or R 2 is trifluoromethyl and R 3 is fluoro or hydrogen, and R 4 is halo, methyl, methoxy, isopropyl, or trifluoromethyl, and R 5 and R 6 is hydrogen, R 1 is not 4-methoxybenzyl or naphth-1-ylmethyl; (j) R 2 and R 3 is chloro, and R 4 , R 5 , and R 6 is hydrogen; or R 2 is trifluoromethyl and R 3is chloro, and R 4 , R 5 , and R 6 is hydrogen; or R 4 is amino and R 3 , R 5 and R 6 is hydrogen, and R 2 is 1-methyl-1-pyrimidin-2-ylethylamino, 1-cyclopropylethylamino, 1-pyrimidin-2-ylethylamino, 2-hydroxy-1-methylethylamino, or 3-hydroxy-1-methylpropylamino; or R 3 is methoxy and R 4 , R 5 and R 6 is hydrogen, and R 2 is 2-methyl-2-phenylpropylamino; or R 4 is chloro and R 3 , R 5 and R 6 is H and R 2 is 1-naphth-2-ylmethylpiperidin-4-ylamino, 1-ethoxycarbonylpiperidin-4-ylamino, or 1-quinolin-6-ylmethylpiperidin-4-ylamino, R 1 is not methyl;(k)R 2 is methyl and R 3 and R 6 is hydrogen, and R 4 and R 5 is methoxy, R 1 is not methyl, 2-pyridin-2-ylethyl or 3-phenylpropyl; (l) R 2 is trifluoromethyl and R 3 , R 5 , and R 6 is hydrogen, and R 4 is chloro, methoxy, or fluoro, R 1 is not benzyl, 4-methylbenzyl or 3,5-dimethylbenzyl; (m) R 2 is methyl and R 3 , R 5 , and R 6is hydrogen, and R 4 If is bromo, R 1 is not ethyl;(n)R 2 is 4-methoxycyclohexylamino, and R 3 , R 5 , and R 6 is hydrogen, and R 4 is iodine; or R 2 is methyl and R 3 and R 4 is methoxy, and R 5 and R 6 is hydrogen; R 1 is not methyl;(o)R 2 is amino or acetylamino, and R 4 is dimethylamino, and R 3 , R 5 , and R 6 is hydrogen, R 1 is not 4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (p)R 4 is chloro and R 3 , R 5 and R 6 is hydrogen, and R 1 is 2,2,2-trifluoroethyl, R 2 is not 1-ethoxycarbonylpiperidin-4-ylamino or 8-azabicyclo[3.2.1]oxy(ocy)-3ylamino; (q) R 5 is fluoro and R 3 , R 4 and R 6 is hydrogen, and R 2 is -4-aminocarbonylmethyl-2-methylphenylamino, R 1 is not 4-fluoro-2-(2-thiazol-2-ylmethoxy)phenyl, 4-fluoro-2-(2-pyridin-2-ylmethoxy)phenyl, or 4-chloro-2-methoxyphenyl; (r) R 6 is fluoro and R 3 , R 4 and R 5 is hydrogen, and R 2is 4-aminocarbonylmethyl-2-methylphenylamino, R 1 is not 4-fluoro-2-methoxyphenyl; (s) R 1 is 4-chloro-2-ethoxyphenyl, and R 5 is fluoro and R 3 , R 4 and R 6 is hydrogen, R 2 is not 3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino; and (t) R 4 is chloro and R 3 , R 5 and R 6 is hydrogen, and R 1 is pentyl, R 2 is not 1-naphth-1-ylmethylpiperidin-4-ylamino, 1-naphth-2-ylmethylpiperidin-4-ylamino, or 1-ethoxycarbonylpiperidin-4-ylamino, (2) Formula: [ka] But the expression: [ka] and (a) R 2 is hydrogen and R 3 and R 5 is methyl, and R 4 is hydrogen, R 1 is not 2-dimethylaminoethyl or 2-diisopropylaminoethyl; (b) R 2 is chloro and R 3 is 3-pentyloxy, and R 4 is hydrogen, and R 5 is methyl, R 1 is not 2,4,6-trimethylphenyl; (c) R 2 is cyclohexyl, 3-hydroxy- or 4-hydroxycyclohexyl, or 3-methylcyclohexyl, and R 3 and R 4is hydrogen, and R 5 is methyl, hydroxymethyl, or ethyl, R 1 is not ethyl; (d) R 2 and R 3 is hydrogen and R 4 is cyano, and R 5 is amino, R 1 is not allyl, benzyl, methyl, or ethyl; (3) Formula: [ka] But the expression: [ka] and (a) R 2 is hydrogen and R 3 is chloro, and R 5 is 1,3-dihydroxypropyl-2-ylamino, 3-diethylaminopropylamino, or 4-(4-methylpiperidin-1-yl)piperidin-1-yl, R 1 is not 2,4-difluorophenyl, 2,6-difluorophenyl or 4-trifluoromethylphenyl; (b) R 2 and R 3 is hydrogen, and R 5 is pyridin-4-ylamino, R 1 is not cyclopentyl; (c) R 1 is 4-hydroxy-5-hydroxymethylfuran-1-yl, and R 5 is amino, and R 3 is methoxy; or R 1 is 4-methoxybenzyl, and R 3 is methoxy, and R 5 is amino; R 2 is not Amino; Equation (4): [ka] But the expression: [ka] and (a) R 2 and R 5 is methoxy, and R 4 is hydrogen; or R 2 is hydrogen, amino or dimethylamino, and R 4 and R 5 is hydrogen, and R 4 and R 5 The other is methyl, or R 4 and R 5 is methyl; R 1 is not methyl; (b) R 1 is 4-hydroxy-5-hydroxymethylfuran-1-yl, and R 4 and R 5 is hydrogen, and R 4 and R 5 The other is methyl, or R 4 and R 5 If both R and R are methyl, 2 is not Amino; Equation (5): [ka] But the expression: [ka] and (a) R 2 is 4-hydroxycyclohexylamino, dimethylaminocarbonylmethylamino, or 4-(2-hydroxyethyl)piperazin-1-yl, and R 5 is chloro or 6-methoxypyridin-3-yl, and R 6 is hydrogen, R 1 is not 2-ethoxyethyl, and (b) R 2is 4-hydroxycyclohexylamino, 4-(2-hydroxyethyl)-piperazin-1-yl, 4-hydroxypiperidin-1-yl, 2-hydroxyethylamino, piperidin-4-ylamino, dimethylaminocarbonylmethylamino, or 2-morpholin-4-ylethylamino, and R 5 is chloro or 6-methoxypyridin-3-yl, and R 6 is hydrogen, R 1 is not 2-propyloxyethyl; Equation (6): [ka] But the expression: [ka] and R 2 is 4-(2-hydroxyethyl)piperazin-1-yl or 4-hydroxycyclohexylamino, and R 4 and R 6 is hydrogen, and R 5 is chloro or 6-methoxypyridin-3-yl, R 1 is not 2-propoxyethyl; and Equation (7): [ka] But the expression: [ka] and R 2 is 2-isopropyloxyethylamino, 4-hydroxy-cyclohexylamino, 4-(2-hydroxyethyl)piperazin-1-yl, 2-(morpholin-4-yl)ethylamino, and R 3 and R 6 is hydrogen, and R 5 is 6-methoxypyridin-3-yl, R 1 is not 2-propoxyethyl).

[0010] In one embodiment of the first aspect, there is provided a compound of formula (IA), or a pharmaceutically acceptable salt thereof: [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyloxy, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 5is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N, and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 (In the formula, X a is a bond or alkylene, and R7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f substituted by R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and R 10is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or -X c -R 12 (In the formula, X c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl, 1 is heterocyclyl, and R d and R e If one of R is hydroxy, f is not hydroxy).

[0011] In another embodiment of the first aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 and R 5is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N, and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 (In the formula, X a is a bond or alkylene, and R7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f substituted by R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl or cycloalkyl; and R 10is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or -X c -R 12 (In the formula, X c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.

[0012] In a second aspect, there is provided a pharmaceutical composition comprising the following compound, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient: (a) A compound of formula (IIA'): [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyloxy, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 5is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N, and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 (In the formula, X ais a bond or alkylene, and R 7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f substituted by R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and R 10is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl , fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heteroaryl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or -X c -R 12 (In the formula, X c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; provided that R 1 is heterocyclyl, and R d and R e If one of R is hydroxy, f is not hydroxy); or (b) A compound of formula (IIA): [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyloxy, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 5is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N; and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 (In the formula, X a is a bond or alkylene, and R7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f substituted by R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and R 10is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or -X c -R 12 (In the formula, X c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl); (c) a compound of formula (II): [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 and R 5is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N; and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 (In the formula, X a is a bond or alkylene, and R7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f substituted by R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl or cycloalkyl; and R 10is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyl(carbpnyl)alkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or -X c -R 12 (In the formula, X c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl); (d) A compound of formula (IVA): [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 and R 5is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N; (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen, and (iii) R 3 , R 4 , R 5 , and R 6 is hydrogen; R 1is a 5- to 8-membered cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are unsubstituted or d , R e , and / or R f where R d and R e is independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f is alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or -X c -R 12 (In the formula, X c is a bond, alkylene, or heteroalkylene, and R 12 is selected from optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl); or a tautomer thereof; or (e) a compound of formula (IA'), (IA), (I), or (IV); (or any embodiment thereof disclosed herein).

[0013] In a third aspect, there is provided a method of treating a disease mediated by MAT2A in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA), or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of this third aspect, the patient is in need of such treatment. In a second embodiment of this third aspect, and a first embodiment therein, the compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA), or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition. In a third embodiment of the third aspect, and a second embodiment therein, the disease is mediated by overexpression of MAT2A. In a fourth embodiment of the third aspect, and the first, second, and third embodiments therein, the disease is cancer.

[0014] In a fourth aspect, there is provided a method of treating an MTAP-null cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of the fourth aspect, the patient is in need of such treatment. In a second embodiment of the fourth aspect, and a first embodiment therein, the compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition.

[0015] In a fifth aspect, there is provided a method for inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in a cell, comprising contacting the cell with an effective amount of a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof.

[0016] In a sixth aspect, there is provided a method of treating cancer characterized by reduced or absent methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MTAP gene, or reduced function of the MTAP protein in a patient, comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

[0017] In a seventh aspect, there is provided a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, for inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in a cell.

[0018] In an eighth aspect, there is provided a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, for use in treating a disease mediated by overexpression of MAT2A in a patient.

[0019] In a ninth aspect, there is provided a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, for use in treating a cancer characterized by reduced or absent methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MTAP gene, or reduced function of the MTAP protein in a patient.

[0020] In a tenth aspect, there is provided a compound of formula (IV); or a tautomer thereof; or a pharmaceutically acceptable salt thereof: [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 and R 5 is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 , and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N; (ii) R 3 , R 4 , R 5 , and R 6is other than hydrogen, and (iii) R 3 , R 4 , R 5 , and R 6 is hydrogen; R 1 is a 5- to 8-membered cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are unsubstituted or d , R e , and / or R f where R d and R e is independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f is alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or -X c -R 12 (In the formula, X c is a bond, alkylene, or heteroalkylene, and R 12 is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl); with the proviso that the compound of formula (IV) is not: (1)R 1is not (a) 5-hydroxymethyltetrahydrofuran-2-yl or 5-hydroxymethyltetrahydro-furan-2-yl substituted by hydroxy or fluoro; (b) 3-hydroxy-4-hydroxymethylcyclopentyl; and (c) 5-aminomethyltetrahydrofuran-2-yl substituted by fluoro or hydroxy; (2) Formula: [ka] But the expression: [ka] If:(a) R 3 and R 5 is fluoro and R 4 and R 6 is hydrogen; or R 4 and R 5 is fluoro and R 3 and R 6 is hydrogen; or R 5 is fluoro and R 3 , R 4 and R 6 is hydrogen, R 1 is not cyclopentyl or tetrahydrofuran-3-yl; (b) R 5 is chloro, and R 3 , R 4 and R 6 is hydrogen, R 1 is not phenyl, 2-methoxyphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, 3-chlorophenyl, 4-methoxyphenyl, 3-methylphenyl, 2-ethoxyphenyl, or 4-ethoxyphenyl; (c) R 3 is fluoro and R 4 , R 5 and R 6 is hydrogen, R 1 is not 4-chlorophenyl; (d) R 4 is bromo, and R 3, R 5 and R 6 is hydrogen, R 1 is not 2,4-dibromophenyl or 2-bromo-4-methylphenyl; (e) R 4 is chloro and R 5 is bromo, and R 3 and R 6 is hydrogen, R 1 is not 3-cyanophenyl, 2-isopropylphenyl, 1-methylpropylphenyl, or 3-cyclopropylpyridin-4-yl; (f) R 4 is trifluoromethyl, and R 3 , R 5 and R 6 is hydrogen, R 1 is not 5-chloro-2-hydroxyphenyl or 5-chloro-2-methoxyphenyl; (g) R 4 is 2,2-difluoroethoxy, and R 3 , R 5 and R 6 is hydrogen, R 1 is not piperidin-4-yl; and (h) R 5 is methoxy, and R 3 , R 4 and R 6 is hydrogen; or R 4 and R 5 is fluoro and R 3 is hydrogen and R 6 is methyl, R 1 is not phenyl; (3) Formula: [ka] But the expression: [ka] If (a) R 3 and R 5 is methyl, and R 4 is hydrogen, R 1 is not 4-ethoxyphenyl; (b) R3 is 3-pentyloxy, and R 5 is methyl and R 4 is hydrogen, R 1 is not 2,4,6-trimethylphenyl; (c) R 4 and R 5 is chloro, and R 3 is hydrogen, R 1 is not 2-isopropyl-6-methylphenyl; (d) R 5 is trifluoromethyl, and R 3 and R 4 is hydrogen, R 1 is not phenyl, 4,6-dimethoxypyrimidin-2-yl, or 4-hydroxy-6-methoxypyrimidin-2-yl; (e) R 4 is amino, and R 3 and R 5 is hydrogen, R 1 is not phenyl, 2-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-, 3-, or 4-chlorophenyl, 4-ethylphenyl, cyclopentyl, cyclohexyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, or 2- or 4-methoxyphenyl; (f) R 4 is bromo, and R 3 and R 5 is hydrogen; or R 4 is hydrogen, and R 3 and R 5 is methyl, and R 3 and R 5 the other is hydrogen; or R 4 is hydrogen, and R 3 and R 5 is methyl; or R 5 is amino and R 3 and R 4 is hydrogen; R 5 is amino and R 3 is hydrogen, and R 4 is cyano; or R 4 is 2-hydroxyethyl, and R3 is hydrogen, and R 5 is methyl, R 1 is not phenyl; and (g) R 3 is furan-2-yl and R 4 and R 5 is hydrogen, R 1 is not cyclohexyl; Equation (4): [ka] But the expression: [ka] If (a) R 4 and R 5 is methyl, R 1 is not phenyl, 2-chlorophenyl, 3-chlorophenyl, 2-methoxyphenyl, 4-methylphenyl, or 4-methoxyphenyl; and Equation (5): [ka] But the expression: [ka] If R 3 and R 5 is ethylamino or chloro, R 1 is not phenyl).

[0021] In one embodiment of the tenth aspect, w, x, y, z, R of formula (IV) 1 , R 3 , R 4 , R 5 , and R 6 is as defined in embodiments 5, 21, 22, 23, 27 to 34, and in the subembodiments contained therein below.

[0022] Compounds of formula (IV) are useful as intermediates for the synthesis of compounds of formulas (IA), (I), (IIA), and (II), which also inhibit MAT2A. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein and that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0024] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this reference is intended to serve as a predicate underlying the use of such exclusive terminology as "solely," "only," and the like in conjunction with the recitation of claim elements or the use of a "negative" limitation.

[0025] When a range of values is provided, it is to be understood that each intervening value, to one-tenth of the unit of the lower limit, between that range and any other stated upper and lower limit, or intervening value within that stated range, unless the context clearly dictates otherwise, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of these limits, ranges excluding either or both of them are also included in the invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0026] Where necessary, any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is the one to which it is attached to the parent moiety. For example, the composite group alkoxyalkyl means that the alkoxy group is attached to the parent molecule via the alkyl group.

[0027] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed.

[0028] Definition: Unless otherwise stated, the following terms used in the specification and claims are defined for purposes of this application and have the following meanings:

[0029] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. It will be recognized by those skilled in the art that the term "alkyl" can include "alkylene" groups.

[0030] "Alkylene," unless otherwise specified, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0031] "Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a double bond, e.g., propenyl, butenyl, and the like.

[0032] "Alkynyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a triple bond, e.g., ethynyl, propynyl, butynyl, and the like.

[0033] "Alkoxy" means an --OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

[0034] "Alkoxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, as defined above, substituted with one alkoxy group, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0035] "Alkoxyalkoxy" means an --OR radical where R is alkoxyalkyl as defined above, e.g., methoxyethyloxy, ethyloxypropyloxy, and the like.

[0036] "Alkoxyalkylamino" means an --NRR' radical where R is hydrogen or alkyl and R' is alkoxyalkyl, each as defined above, eg, methoxyethylamino, methoxypropylamino, and the like.

[0037] "Alkylcarbonyl" means a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like.

[0038] "Alkoxycarbonyl" means a -C(O)OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

[0039] "Alkoxycarboxyalkyl" means an alkyl radical, as defined above, substituted by an alkoxycarboxy group, e.g., methylcarboxymethyl, ethylcarboxyethyl, and the like.

[0040] "Alkylthio" means an --SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.

[0041] "Alkylsulfonyl" means a -SO2R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

[0042] "Alkylsulfonylalkyl" means an -(alkylene)-SO2R radical where R is alkyl as defined above, e.g., methylsulfonylethyl, ethylsulfonylmethyl, and the like.

[0043] "Amino" means -NH2.

[0044] "Alkylamino" means an --NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and the like.

[0045] "Aminoalkyl" means a straight-chain monovalent hydrocarbon radical of one to six carbon atoms or a branched-chain monovalent hydrocarbon radical of three to six carbon atoms substituted by --NR'R", where R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl, each as defined herein, e.g., aminomethyl, aminoethyl, methylaminomethyl, and the like.

[0046] "Aminoalkoxy" means an --OR radical where R is aminoalkyl as defined above, e.g., aminoethyloxy, methylaminopropyloxy, dimethylaminoethyloxy, diethylaminopropyloxy, and the like.

[0047] "Aminoalkylamino" means an --NRR' radical where R is hydrogen or alkyl and R' is aminoalkyl, each as defined above, e.g., aminoethylamino, methylaminopropylamino, dimethylaminoethylamino, diethylaminopropylamino, and the like.

[0048] "Aminocarbonyl" means the -CONH2 radical.

[0049] "Alkylaminocarbonyl" means a -CONHR radical where R is alkyl as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, and the like.

[0050] "Aminosulfonyl" means the -SO2NH2 radical.

[0051] "Aminosulfonylalkyl" means an -(alkylene)SONR R radical, as defined above, where R is hydrogen or alkyl and R' is hydrogen, alkyl, or cycloalkyl, or R and R' together with the nitrogen atom to which they are attached form a heterocyclyl, e.g., methylaminosulfonylethyl, dimethylsulfonylethyl, and the like.

[0052] "Alkylaminosulfonyl" means a -SO2NHR radical where R is alkyl as defined above, e.g., methylaminosulfonyl, ethylaminosulfonyl, and the like.

[0053] "Aminocarbonylalkyl" means an -(alkylene)-CONRR' radical where R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, each as defined herein, e.g., aminocarbonylethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, and the like.

[0054] "Aminosulfonylalkyl" means an -(alkylene)-SONR R radical, where R and R are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, or alkoxyalkyl, each as defined herein, e.g., aminosulfonylethyl, methylaminosulfonylethyl, dimethylaminosulfonylethyl, and the like.

[0055] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

[0056] "Aralkyl" means a -(alkylene)-R radical where R is aryl as defined above, e.g., benzyl, phenethyl, and the like.

[0057] "Bridged cycloalkyl" means a saturated, monocyclic, 5- to 7-membered hydrocarbon radical in which two non-adjacent ring atoms are joined by a (CRR')n group, where n is 1 to 3, and each R is independently H or methyl (also referred to herein as a bridging group). A bridged cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples of bridged cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0058] "Bridged cycloalkylalkyl" means a -(alkylnene)-R radical where R is a bridged cycloalkyl as defined above. Examples include, but are not limited to, bicyclo[2.2.1]heptylmethyl, and the like.

[0059] A "bridged heterocyclyl" has 5 to 7 ring carbon atoms in which two non-adjacent ring atoms are joined by a (CRR')n group, where n is 1 to 3 and each R is independently H or methyl (also referred to herein as a bridging group), and wherein one or two ring carbon atoms, including the atoms of the bridging group, are N, O, or S(O) n (wherein n is an integer from 0 to 2). The bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octane, quinuclidine, 7-oxabicyclo[2.2.1]heptane, and the like.

[0060] "Bridged heterocyclylalkyl" means a -(alkylene)-R radical where R is a bridged heterocyclyl (including specific bridged heterocyclyl rings) as defined above.

[0061] "Cycloalkyl" means a monocyclic, monovalent hydrocarbon radical of 3 to 6 carbon atoms, which may be saturated or contain one double bond. Cycloalkyls may be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocycloprop-1-yl, 1-cyanomethylcycloprop-1-yl, 3-fluorocyclohexyl, and the like. When a cycloalkyl contains a double bond, it is referred to herein as a cycloalkenyl.

[0062] "Cycloalkylalkyl" means a -(alkylene)-R radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, and the like.

[0063] "Cycloalkylalkyloxy" means an --OR radical where R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyloxy, cyclobutylmethyloxy, and the like.

[0064] "Cycloalkyloxyalkyl" means a -(alkylene)-OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxyethyl, and the like.

[0065] "Cycloalkylsulfonylamino" means the radical -NRSO2-R' where R is hydrogen or alkyl and R' is cycloalkyl, each as defined above. Examples include, but are not limited to, cyclopropylsulfonylamino, N-cyclopropylsulfonylN(CH3), and the like.

[0066] "Cyanoalkyl" means an alkyl radical, as defined above, substituted with a cyano group, e.g., cyanomethyl, cyanoethyl, and the like.

[0067] "Carboxy" means the -COOH radical.

[0068] "Carboxyalkyl" means an alkyl radical, as defined above, substituted with a carboxy group, e.g., carboxymethyl, carboxyethyl, and the like.

[0069] "Deuteroalkyl" means an alkyl radical, as defined above, in which one to six hydrogen atoms in the alkyl chain have been replaced by deuterium atoms. Examples include, but are not limited to, -CD3, -CH2CHD2, and the like.

[0070] "Dialkylamino" means an --NRR' radical where R and R' are alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.

[0071] "Dialkylaminocarbonyl" means a --CONRR' radical where R and R' are alkyl as defined above, e.g., dimethylaminocarbonyl, diethylaminocarbonyl, and the like.

[0072] "Dialkylaminosulfonyl" means a -SO2NRR' radical where R and R' are alkyl as defined above, eg, dimethylaminosulfonyl, diethylaminosulfonyl, and the like.

[0073] "Fused cycloalkyl" means a saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms fused to a phenyl or 5- or 6-membered heteroaryl ring, as defined herein, and optionally substituted with 1, 2, or 3 substituents independently selected from alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, and cyano. Examples include, but are not limited to, tetrahydronaphthyl, 4,5,6,7-tetrahydro-1H-indolyl, 4,5,6,7-tetrahydrobenzoxazolyl, and the like.

[0074] "Fused heterocyclyl" means a heterocyclyl, as defined herein, fused to a cycloalkyl, phenyl, or 5- or 6-membered heteroaryl ring, as defined herein. The fused heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are not limited to, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydroquinolin-2(1H)-one, and the like.

[0075] "Fused heterocyclylalkyl" means a -(alkylene)-R radical where R is a fused heterocyclyloxy (including specific fused heterocyclyl rings) as defined above.

[0076] "Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

[0077] "Haloalkyl" means an alkyl radical as defined above substituted with one to five halogen atoms, such as fluorine or chlorine, including those substituted with various halogens, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl is substituted with only fluoro, it may be referred to in this application as a fluoroalkyl.

[0078] "Haloalkoxy" means an -OR radical where R is haloalkyl as defined above, e.g., -OCF, -OCHF, etc. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this application as fluoroalkoxy.

[0079] "Haloalkoxyalkyl" means an alkyl radical substituted with a haloalkoxy, each as defined above, e.g., trifluoromethoxyethyl, and the like.

[0080] "Heteroalkylene" means a linear saturated divalent hydrocarbon radical of 2 to 6 carbon atoms, or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms, in which one carbon atom is replaced by -O-, -NR-, -NR'CO-, -CONR'-, SONR'-, or -NR'SO-, where R and R' are independently H or alkyl as defined herein, unless otherwise specified, e.g., -CHO-, -OCH-, -(CH)O-, -O(CH)-, -(CH)NH-, -NH(CH)-, and the like.

[0081] "Hydroxyalkyl" means a straight-chain monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched-chain monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0082] "Hydroxyalkoxy" means an --OR radical where R is hydroxyalkyl as defined above, e.g., hydroxyethyloxy, hydroxypropyloxy, and the like.

[0083] "Hydroxyalkylamino" means an --NRR' radical where R is hydrogen or alkyl and R' is hydroxyalkyl, each as defined above, eg, hydroxyethylamino, hydroxypropylamino, and the like.

[0084] "Heteroaryl," unless otherwise specified, means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms in which one or more (in one embodiment, 1, 2, or 3) ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, and the like. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. When a heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaryl.

[0085] "Heteroaralkyl" means a -(alkylene)-R radical where R is heteroaryl (including the specified rings) as defined above.

[0086] "Heteroaryloxy" means -OR where R is heteroaryl (including the specified rings) as defined above.

[0087] "Heteroaralkyloxy" means an -O-(alkylene)-R radical where R is heteroaryl (including the specified rings) as defined above.

[0088] "Heteroarylcarbonyl" means -COR where R is heteroaryl (including specified rings) as defined above.

[0089] "Heteroarylamino" means --NRR', where R is hydrogen or alkyl and R' is heteroaryl (including the specified ring), as defined above.

[0090] "Heterocyclyl" refers to a heterocyclic group in which one or two ring atoms are N, O, or S(O). n (wherein n is an integer from 0 to 2), and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclyl ring can be optionally replaced by a -CO- group. More specifically, the term heterocyclyl includes, but is not limited to, azetidinyl, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated, it can contain one or two ring double bonds, provided that the ring is not aromatic. When the heterocyclyl contains at least one nitrogen atom, it may be referred to herein as heterocycloamino.

[0091] "Heterocyclylalkyl" means an -(alkylene)-R radical where R is heterocyclyl (including specific heterocyclyl rings) as defined above. For example, oxetanylethyl, piperidinylethyl, and the like.

[0092] "Heterocyclyloxy" means an -OR radical where R is heterocyclyl (including specific heterocyclyl rings) as defined above.

[0093] "Heterocyclylalkyloxy" means an -O-(alkylene)-R radical where R is heterocyclyl (including specific heterocyclyl rings) as defined above. E.g., oxetanylethyloxy, piperidinylethyloxy, and the like.

[0094] "Heterocyclylcarbonyl" means -COR where R is heterocyclyl (including specified rings) as defined above.

[0095] "Heterocyclylamino" means the radical --NRR' where R is hydrogen or alkyl and R' is heterocyclyl (including specific heterocyclyl rings) as defined above.

[0096] "Heterocyclyloxyalkyl" means an -(alkylene)-OR radical where R is heterocyclyl (including specific heterocyclyl rings) as defined above. E.g., oxetanyloxyethyl, piperidinyloxyethyl, and the like.

[0097] "Heterocyclyloxyalkoxy" means an -O-(alkylene)-R radical where R is heterocyclyloxy (including specific heterocyclyl rings) as defined above. E.g., oxetanyloxyethyloxy, piperidinyloxyethyloxy, and the like.

[0098] "Heterocyclyloxyalkylamino" means an -NR-(alkylene)-R' radical where R is hydrogen or alkyl and R' is heterocyclyloxy (including specific heterocyclyl rings) as defined above. For example, oxetanyloxyethylamino, piperidinyloxyethylamino, and the like.

[0099] The term "oxo" as used herein, alone or in combination, refers to =(O).

[0100] As used herein, "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carboxylic acid, monohydrogen carboxylic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydrogen iodide, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid and the like (see, e.g., Berge, SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0101] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise these salts are equivalent to the parent form of the compound for purposes of this invention.

[0102] The present disclosure also includes protected derivatives of the compounds of the present disclosure. For example, if the compounds of the present disclosure contain groups such as hydroxy, carboxy, thiol, or any group containing nitrogen atom(s), these groups can be protected with suitable protecting groups. A comprehensive list of suitable protecting groups can be found in T.W. Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the compounds of the present disclosure can be prepared by methods well known in the art.

[0103] The present disclosure also includes prodrugs of the compounds of Formulas (I), (IA), (II), (IIA), and (IVA), or pharmaceutically acceptable salts thereof. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. A non-limiting example of a prodrug would be a compound that is administered as an ester (the "prodrug"), but is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0104] Certain compounds of formulas (I), (IA), (II), (IIA), (IVA), and (IV) can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of formulas (I), (IA), (II), (IIA), (IVA), and (IV) may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of this disclosure.

[0105] Certain compounds of formulas (I), (IA), (II), (IIA), (IVA), and (IV) have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., individual enantiomers) are all intended to be encompassed within the scope of the present invention. When a stereochemical designation is given, it is meant to refer to a compound in which one of these isomers is present and the other isomer is substantially absent. The term "substantially absent" another isomer indicates that the two isomers are present in a ratio of at least 80 / 20, more preferably 90 / 10, or 95 / 5 or greater. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0106] Compounds of formula (I), (IA), (II), (IIA), and (IVA) and (IV) may also contain unnatural amounts of isotopes of one or more atoms that constitute such compounds. An unnatural amount of an isotope may be defined as a range from the amount found in nature of the atom in question, differing only in the presence of one or more isotopically enriched atoms, to 100% of the amount. Illustrative isotopes that can be incorporated into compounds of the invention, such as compounds of formula (I), (IA), (II), (IIA), and (IVA) and (IV) (and any embodiment thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, and 125 1, etc. Isotopically labeled compounds (e.g., 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds disclosed herein, included in Table 1 below, one or more hydrogen atoms is 2 H or 3 H or one or more carbon atoms are replaced by 13 C- or 14It is replaced by C-enriched carbon. 15 O. 13 N, 11 C, and 15 Positron-emitting isotopes, such as F, are useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared following procedures analogous to those illustrated in the schemes or examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0107] "Optionally substituted aryl" means aryl optionally substituted with one, two, or three substituents independently selected from alkyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.

[0108] "Optionally substituted heteroaryl" means heteroaryl as defined above optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

[0109] "Optionally substituted heterocyclyl" means, unless otherwise stated, a heterocyclyl as defined above optionally substituted by one, two, or three substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano.

[0110] A "pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable, that is useful in preparing pharmaceutical compositions, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0111] "Spirocycloalkyl" refers to a saturated bicyclic ring having 6 to 10 ring carbon atoms, where the rings are connected through only one atom, also referred to as a spiroatom, most often a quaternary carbon ("spirocarbon"). The spirocycloalkyl ring is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Representative examples include, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane (1:2:1:1), and the like.

[0112] "Spirocycloalkylalkyl" means a -(alkylene)-R radical where R is spirocycloalkyl (including specific spirocycloalkyl) as defined above.

[0113] "Spiroheterocyclyl" refers to a saturated bicyclic ring having 6 to 10 ring carbon atoms, where one, two, or three ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), and the remaining ring atoms are C; and the rings are connected through only one atom, also referred to as a spiroatom, most often a quaternary carbon ("spirocarbon"). The spiroheterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. Representative examples include, but are not limited to, 2,6-diazaspiro[3,3]heptane, 2,6-diazaspiro[3,4]octane, 2-azaspiro[3,4]octane, 2-azaspiro[3,5]nonane, 2,7-diazaspiro[4,4]nonane, and the like.

[0114] "Spiroheterocyclylalkyl" means an -(alkylene)-R radical where R is spiroheterocyclyl (including specific spiroheterocyclyl) as defined above.

[0115] "Sulfonylamino" means the radical -NRSO2R', where R is hydrogen or alkyl, and R' is alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, each group being defined herein.

[0116] "Substituted cycloalkyl" means a saturated, monocyclic, monovalent hydrocarbon radical of 3 to 6 carbon atoms substituted with one, two, or three substituents, where two of the three substituents are independently selected from alkyl, halo, alkoxy, hydroxy, haloalkyl, or haloalkoxy, and the third substituent is alkyl, halo, hydroxyalkyl, haloalkyl, haloalkoxy, or cyano. Examples include, but are not limited to, 3-hydroxy-3-trifluorocyclobutyl, 2,2-dimethyl-3-hydroxycyclobutyl, and the like.

[0117] "Substituted cycloalkylalkyl" means -(alkylene)-substituted cycloalkyl, each term being defined herein. Examples include, but are not limited to, 1-hydroxymethylcycloprop-1-ylmethyl, and the like.

[0118] As used herein, "about" is intended to qualify the numerical value it modifies, meaning a value that can vary within a range of error. If no specific error range is recited, such as a standard deviation for the mean value shown in a chart or data table, the term shall be understood to mean a range encompassing ±10%, preferably ±5%, of the recited value and range.

[0119] As used herein, "disease" is intended to be synonymous with, and used interchangeably with, the terms "disorder," "syndrome," and "pathology" (medical condition), in that it generally reflects an abnormal condition of the human or animal body or one of its parts that impairs normal function, is typically manifested by discernible signs and symptoms, and causes the human or animal to have a reduced length or quality of life.

[0120] "Patient" is generally synonymous with the term "subject" and, as used herein, includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0121] As used herein, "need for treatment" refers to the judgment by a physician or other practitioner that a subject needs or will benefit from treatment. This judgment is made based on a variety of factors that are within the physician's or practitioner's area of expertise.

[0122] "Administration," "administering," and the like, when applied to, e.g., a patient, cell, tissue, organ, or biological fluid, refer to the contact of, e.g., a compound of Formula (I), a pharmaceutical composition containing same, or a diagnostic agent with the subject, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact of a reagent with the cell (e.g., in vitro or ex vivo), as well as contact of a reagent with a fluid that is in contact with the cell.

[0123] As used herein, a "therapeutically effective amount" means the amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a subembodiment thereof described herein and / or a pharmaceutically acceptable salt thereof, which, when administered to a patient for treating a disease, either alone or as part of a pharmaceutical composition, and either in a single dose or as part of a series of doses, is sufficient to affect such treatment for the disease. A "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated. A therapeutically effective amount can be determined by measuring the relative physiological effect and can be adjusted in conjunction with, for example, dosing regimens and diagnostic analysis of the subject's condition. For example, measuring serum levels of a compound of Formula (I) (or, for example, a metabolite thereof) at a particular time point after administration can be an indicator of whether a therapeutically effective amount is being used.

[0124] "Treating" or "treatment" of a disease includes: (1) Prevention of disease, i.e., preventing the clinical manifestations of disease from occurring in a mammal that is exposed to or predisposed to the disease but that has not yet experienced or manifested symptoms of the disease; (2) Inhibition of the disease, i.e., arrest or reduction of the manifestation of the disease or its clinical symptoms; or (3) Relief of disease, i.e., causing regression of the disease or its clinical symptoms.

[0125] "Inhibit," "reduce," or any variation of these terms in relation to MAT2A includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more decrease in MAT2A activity compared to its normal activity, or any range of decrease derivable therein.

[0126] "Ureido" means the radical -NHCONRR' where R and R' are independently hydrogen or alkyl as defined above, e.g., -NHCONHmethyl, -NHCON(CH3)2, etc. "Thioureidoalkyl" means the radical -(alkylene)-NHSON2NRR' where R and R' are independently hydrogen or alkyl as defined above, e.g., -ethylene-NHSONHmethyl, -propylene-NHSON2NH2, etc.

[0127] Representative compounds of formula (I) are listed in Table 1 below: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-108

Table 1-109

[0128] Additional contemplated compounds of Formula (I) are set forth in Table 2 below: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20] [Table 2-21]

[0129] Implementation : In further embodiments 1 to 34 below, the present disclosure includes:

[0130] 1A. In embodiment 1A, a compound of formula (IA'), (IA), (IIA') or (IIA) or a pharmaceutically acceptable salt thereof (wherein w, x, y, z, R 1 and R 2 (described in the Summary above) are provided. In a first subembodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (IA). In a second subembodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (IIA). In a third subembodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (IA'). In a fourth subembodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (IIA').

[0131] 1. In embodiment 1, a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA') or a subembodiment described herein; or a pharmaceutically acceptable salt thereof (wherein w, x, y, z, R 1 and R 2 (described in the Summary above). In a first subembodiment of the first embodiment, the compound, or a pharmaceutically acceptable salt thereof, has structure (I). In a second subembodiment of the first embodiment, the compound, or a pharmaceutically acceptable salt thereof, has structure (II).

[0132] 2. In embodiment 2, there is provided a compound of any one of embodiments 1A or 1 and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is R 7 where R 7 is cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, phenyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where aryl, heteroaryl, and heterocyclyl are unsubstituted or d , R e , and / or R f is replaced by; and R 2 is alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 In a first subembodiment of embodiment 2, R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or R 11 is.

[0133] 3. In embodiment 3, there is provided a compound of any one of embodiments 1A or 1 and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, or aminosulfonylalkyl; and R 2 is alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 In a first subembodiment of embodiment 3, R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or R 11 is.

[0134] 4. In embodiment 4, any one of the compounds of embodiment 1A or 1 and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 1 is R 7 and R 7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f is replaced by

[0135] 5. In embodiment 5, the compound of any one of embodiments 1A and 1 through 4, and subembodiments therein, or a pharmaceutically acceptable salt thereof, has the structure of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or (IIIg): [ka]

[0136] In a first subembodiment of Embodiment 5, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula (IIIa). In a second subembodiment of Embodiment 5, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula (IIIb). In a third subembodiment of Embodiment 5, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula (IIIc). In a fourth subembodiment of Embodiment 5, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula (IIId). In a fifth subembodiment of Embodiment 5, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula (IIIe). In a sixth subembodiment of Embodiment 5, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula (IIIf). In a seventh subembodiment of Embodiment 5, the compound or a pharmaceutically acceptable salt thereof has the structure of Formula (IIIg).

[0137] 6. In embodiment 6, the compound of any one of embodiments 1A and 1 to 5 (e.g., compounds of formulae (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), and (IIIg)), and subembodiments therein, or pharmaceutically acceptable salts thereof, is 2 Ga-NR 9 R 10 It is what it is.

[0138] 7. In embodiment 7, the compound of any one of embodiments 1A and 1 through 5, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 2 -OR 8It is what it is.

[0139] 8. In embodiment 8, the compound of any one of embodiments 1A and 1 through 5, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 2 R 11 It is what it is.

[0140] 9. In embodiment 9, the compound of any one of embodiments 1A and 1 through 5, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 2 -(alkylene)-R 11 In a first subembodiment of embodiment 9, alkylene is methylene or ethylene. In a second subembodiment of embodiment 9, alkylene is methylene.

[0141] 10. In embodiment 10, the compound of any one of embodiments 1A and 1 through 6, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 9 In a first subembodiment of embodiment 10, R is hydrogen, methyl, ethyl, cyclopropyl, or trideuteromethyl. 9 is hydrogen, methyl, ethyl, or cyclopropyl. In a second subembodiment of embodiment 10, R 9 is hydrogen, methyl, or cyclopropyl. In a third subembodiment of embodiment 4, R 9 is hydrogen. In a fourth subembodiment of embodiment 10, R 9 In a fifth subembodiment of embodiment 10, R 9 In a sixth subembodiment of embodiment 10, R 9 is hydrogen or methyl. In a seventh subembodiment of embodiment 10, R 9 is trideuteromethyl.

[0142] 11. In embodiment 11, the compound of any one of embodiments 1A and 1 to 6 and 10, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 10 is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl, preferably R 10 In a first subembodiment of embodiment 11, R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl. 10 is hydrogen. In a second subembodiment of embodiment 11, R 10 is alkyl, preferably methyl, ethyl, isopropyl, isobutyl, or tert-butyl, preferably methyl. In a third subembodiment of embodiment 11, R 10 is haloalkyl, preferably 2,2-difluoroethyl or 2,2,2-trifluoroethyl. In a fourth subembodiment of embodiment 11, R 10 is hydroxyalkyl, preferably 2-hydroxyethyl, 3-hydroxypropyl, or dihydroxypropyl. In a fifth subembodiment of embodiment 5, R 10 is aminoalkyl, preferably aminoethyl, methylaminoethyl, dimethylaminoethyl, or diethylaminoethyl. In a sixth subembodiment of embodiment 11, R 10 In a seventh subembodiment of embodiment 11, R is alkoxyalkyl, preferably methoxyethyl, ethoxyethyl, methoxypropyl, or ethoxypropyl. 10is alkylcarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl, preferably acetyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, or diethylaminocarbonyl. In an eighth subembodiment of embodiment 11, R 10 In a ninth subembodiment of embodiment 11, R is alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, preferably methylaminocarbonylmethyl or dimethylaminocarbonylmethyl. 10 is trideuteromethyl.

[0143] 12. In embodiment 12, the compound of any one of embodiments 1A, 1 to 5, and 7, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 8 In a first subembodiment of embodiment 12, R is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. 8 is alkyl, preferably methyl, ethyl, isopropyl, isobutyl, or tert-butyl. In a second subembodiment of embodiment 12, R 8 is haloalkyl, preferably trifluoromethyl or 2,2,2-trifluoroethyl. In a third subembodiment of embodiment 12, R 8 is hydroxyalkyl, preferably 2-hydroxyethyl, hydroxypropyl, or dihydroxypropyl. In a fourth subembodiment of embodiment 12, R 8 is aminoalkyl, preferably aminoethyl, methylaminoethyl, dimethylaminoethyl, or diethylaminoethyl. In a fifth subembodiment of embodiment 12, R 8 is alkoxyalkyl, preferably methoxyethyl, ethoxyethyl, methoxypropyl, or ethoxypropyl.

[0144] 13. In embodiment 13, the compound of any one of embodiments 1A, 1 to 7, and 10, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 10 is independently cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, or spirocycloalkylalkyl. In a first subembodiment of embodiment 13, R 8 and R 10 is independently cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl, and each ring may independently be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. In a second subembodiment of embodiment 13, R 8 and R 10 is independently cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl, and each ring may independently be unsubstituted or substituted with one or two substituents independently selected from methyl, fluoro, or cyano. In a third subembodiment of embodiment 13, R 8 and R 10 is independently cycloalkylalkyl, preferably cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, or cyclohexylethyl, and the ring within each group may independently be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. In a fourth subembodiment of embodiment 13, R 8 and R 10is independently cycloalkyloxyalkyl, preferably cyclopropyloxyethyl, cyclobutyloxyethyl, cyclopentyloxyethyl, or cyclohexyloxyethyl, preferably cyclopropyloxyethyl, and the ring of each group may independently be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano. In a fifth subembodiment of embodiment 13, R 8 and R 10 is independently a bridged cycloalkyl or a bridged cycloalkylalkyl. In a sixth subembodiment of embodiment 13, R 8 and R 10 is independently spirocycloalkyl or spirocycloalkylalkyl. In a seventh subembodiment of embodiment 13, R 8 and R 10 is independently cycloalkyl or cycloalkylalkyl, preferably cyclopropyl or cyclopropylmethyl, and each ring may independently be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo, or cyano. In an eighth subembodiment of embodiment 13, R 8 and R 10 is independently cyclopropyl or cyclopropylmethyl, and each ring may independently be unsubstituted or substituted with one or two substituents independently selected from methyl, fluoro, or cyano. In a ninth subembodiment of embodiment 13, R 8 and R 10are independently cyclopropyl, cyclobutyl, 1-methylcyclopropyl, (cis)-3-hydroxy-3-methylcyclobutyl, (cis)-3-hydroxy-2,2-dimethylcyclobutyl, 1-cyanocyclobutyl, cyclopropylmethyl, 1-hydroxycyclopropmethyl, 1-fluorocyclopropmethyl, (trans)-3-hydroxy-1-methylcyclobutyl, (cis)-3-cyanocyclobutyl, 1-methylcyclobutyl, (cis)-3-hydroxycyclobutyl, (trans)-3-hydroxycyclobutyl, (trans) In a tenth subembodiment of embodiment 13, R is 1-3-cyanocyclobutyl, (2S,1R)-2-hydroxycyclobutyl, (1S,2S)-2-hydroxycyclobutyl, (1S,2R)-2-hydroxycyclobutyl, (1R,2R)-2-hydroxycyclobutyl, (1R,2R)-2-fluorocyclopropyl, 1-fluorocyclopropylmethyl, (1S,2R)-2-fluorocyclopropyl, (1R,2S)-2-fluorocyclopropyl, (1S,2S)-2-fluorocyclopropyl, 2,2-difluorocyclopropyl, (R)-1-cyclopropylethyl, or 2,2-difluorocyclopropylmethyl. 8 and R 10are independently cyclopropyl, cyclobutyl, 1-methylcyclopropyl, (cis)-3-hydroxy-3-methylcyclobutyl, (cis)-3-hydroxy-2,2-dimethylcyclobutyl, 1-cyanocyclobutyl, (trans)-3-hydroxy-1-methylcyclobutyl, (cis)-3-cyanocyclobutyl, 1-methylcyclobutyl, (cis)-3-hydroxycyclobutyl, (trans)-3-hydroxycyclobutyl, (trans)-3-cyanocyclobutyl, (2S,1R)-2-hydroxycyclobutyl, (1S,2S)-2-hydroxycyclobutyl, (1S,2R)-2-hydroxycyclobutyl, (1R,2R)-2-hydroxycyclobutyl, (1R,2R)-2-fluorocyclopropyl, (1S,2R)-2-fluorocyclopropyl, (1R,2S)-2-fluorocyclopropyl, (1S,2S)-2-fluorocyclopropyl, or 2,2-difluorocyclopropyl. In an eleventh subembodiment of embodiment 13, R 8 and R 10 is independently cyclopropylmethyl, 1-hydroxycyclopropamethyl, 1-fluorocyclopropamethyl, 1-fluorocyclopropylmethyl, (R)-1-cyclopropylethyl, or 2,2-difluorocyclopropylmethyl.

[0145] 14. In embodiment 14, the compound of any one of embodiments 1A, 1 to 7, and 10, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 8 and R 10 is independently phenyl or phenylalkyl (preferably benzyl or phenethyl), where phenyl by itself or as part of an aralkyl is unsubstituted or R j , R k , and / or R l is replaced by

[0146] 15. In embodiment 15, the compound of any one of embodiments 1 to 7 and 10, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is8 and R 10 is independently heteroaryl or heteroaralkyl, where heteroaryl, by itself or as part of a heteroaralkyl, is unsubstituted or R j , R k , and / or R l In a first subembodiment of embodiment 15, R 8 and R 10 is heteroaryl independently selected from pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, and indazolyl, preferably pyrazolyl, imidazolyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, and indazolyl, and each ring is unsubstituted or j , R k , and / or R l In a second subembodiment of embodiment 15, R 8 and R 10is heteroaralkyl independently selected from pyrazolylmethyl, pyrazolylethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolinylmethyl, quinolinylethyl, isoquinolinylmethyl, isoquinolinylethyl, indolylmethyl, indolylethyl, indazolylmethyl and indazolylethyl, or pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolinylmethyl, quinolinylethyl, isoquinolinylmethyl, isoquinolinylethyl, indolylmethyl, indolylethyl, indazolylmethyl and indazolylethyl, preferably pyrazolylmethyl or pyridinylmethyl, wherein each ring is unsubstituted or j , R k , and / or R l In a third subembodiment of embodiment 15, R 8 and R 10are 1-methyl-1H-pyrazol-5-yl, isoxazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 5-methylisoxazol-3-yl, 5-methylisoxazol-4-yl, 3-methoxyisoxazol-5-yl, 3,5-dimethylisoxazol-4-yl, 3-methylisoxazol-4-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-(difluoromethyl)pyridin-4-yl, 2-(difluoromethoxy)pyridin-4-yl, 5-methoxypyridin-3-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-cyanopyridin-4-yl, 3-methoxypyridin-4-yl, 3 3-fluoropyridin-4-yl, 3-chloropyridin-4-yl, 2-(trifluoromethyl)pyridin-4-yl, 2-methylpyridin-4-yl, pyrimidin-5-yl, 1-methyl-1H-imidazol-4-yl, 1-methylpyrazol-3-ylmethyl, 3-methoxyisoxazol-5-ylmethyl, oxazol-2-ylmethyl, oxazol-4-ylmethyl, oxazol-5-ylmethyl, isoxazol-3-ylmethyl, isoxazol-4-ylmethyl, isoxazol-5-ylmethyl, 1-methyl-1H-pyrazol-3-ylmethyl, 1-methyl-1H-pyrazol-4-ylmethyl, 1-methyl-1H-pyrazol-5-ylmethyl, pyridin-4-ylmethyl, pyridin-3-ylmethyl, or pyridin-2-ylmethyl.

[0147] 16. In embodiment 16, the compound of any one of embodiments 1A, 1 to 7, and 10, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 8 and R 10is independently heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where heterocyclyl, by itself or as part of another group, is unsubstituted or j , R k , and / or R l In a first subembodiment of embodiment 16, R 8 and R 10 is independently heterocyclyl, preferably oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and each ring is unsubstituted or j , R k , and / or R l In a second subembodiment of embodiment 16, R 8 and R 10 is independently heterocyclylalkyl, preferably oxetanylmethyl, oxetanylethyl, azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl, or morpholinylethyl, and each ring is unsubstituted or j , R k , and / or R l In a third subembodiment of embodiment 16, R 8 and R 10 are independently unsubstituted or R j , R k , and / or R l In a fourth subembodiment of embodiment 16, R 8 and R 10 is independently a bridged heterocyclyl, a bridged heterocyclylalkyl. In a fifth subembodiment of embodiment 16, R 8 and R 10is independently spiroheterocyclyl or spiroheterocyclylalkyl.

[0148] 17. In embodiment 17, the compound of any one of embodiments 1A, 1 to 5, 8, and 9, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 11 is unsubstituted, or R m , R n , and / or R o In a first subembodiment of embodiment 17, R 11 is oxetanyl, azetidinyl, 2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, preferably azetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, and each ring is unsubstituted or is selected from the group consisting of oxetanyl, azetidinyl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and morpholin-4-yl. m , R n , and / or R o In a second subembodiment of embodiment 17, R 11 is azetidin-1-yl, 4-hydroxyazetidin-1-yl, 4-methylaminocarbonylazetidin-1-yl, 4-dimethylaminocarbonylazetidin-1-yl, 2-hydromethylazetidin-1-yl, 2-methylazetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, piperidin-1-yl, 2-carboxypiperidin-1-yl, 2-aminocarbonylpiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, or morpholin-4-yl. 11 is 3-hydroxypyrrolidin-1-yl.

[0149] 18. In embodiment 18, the compound of any one of embodiments 1A, 1 to 5, 8, and 9, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 11 In a first subembodiment of embodiment 18, R 11 is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclopropyl, and each ring may independently be unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano.

[0150] 19. In embodiment 19, the compound of any one of embodiments 1A, 1 to 5, 8, and 9, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 11 is unsubstituted or R j , R k , and / or R l In a first subembodiment of embodiment 19, R 11 is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, and indazolyl, each ring being unsubstituted or j , R k , and / or R l In a second subembodiment of embodiment 19, R 11 is pyrazolyl, imidazolyl-2-yl, imidazolyl-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, or isothiazol-4-yl.

[0151] 20. In embodiment 20, the compound of any one of embodiments 1A, 1 through 5, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 2is a hydroxyalkyl, aminoalkyl, or aminocarbonylalkyl.

[0152] 21. In embodiment 21, the compound of any one of embodiments 1A, 1 to 20, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 4 and R 6 is independently selected from hydrogen, methyl, chloro, fluoro, bromo, methoxy, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, or dimethylaminocarbonyl. 4 is hydrogen, fluoro, methoxy, cyano, and R 6 is hydrogen. In a second subembodiment of embodiment 21, R 4 and R 6 is hydrogen. In a second subembodiment of embodiment 21, R 4 and R 6 is hydrogen. In a third subembodiment of embodiment 21, R 4 and R 6 is independently selected from hydrogen, methyl, chloro, fluoro, methoxy, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, or dimethylaminocarbonyl. 4 is hydrogen, fluoro, bromo, methyl, methoxy, or cyano, and R 6 is hydrogen.

[0153] 22. In embodiment 22, the compound of any one of embodiments 1A, 1 to 21, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 5is alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, heterocyclyloxyalkylamino, and preferably R 5 is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl, heteroaryl, heterocyclyl, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; a , R b , and / or R c In a first subembodiment of embodiment 22, R 5 is methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclopentyl, cyano, methylsulfonyl, methylamino, or dimethylamino. 5 is hydroxymethyloxy, hydroxyethyloxy, hydroxymethylamino, hydroxyethylamino, aminoethyloxy, methylaminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, aminoethylamino, methylaminoethylamino, dimethylaminoethylamino, or diethylaminoethylamino. In a third subembodiment of embodiment 22, R 5R is each unsubstituted or independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; a , R b , and / or R c In a fourth subembodiment of embodiment 22, R is a 5- or 6-membered heteroaryl substituted by 5 is a group in which each ring is unsubstituted or R a and / or R b In a fifth subembodiment of embodiment 22, R is a 4- or 6-membered heterocyclyl substituted by 5 In a sixth subembodiment of embodiment 22, R is halo, alkyl, haloalkyl, or cycloalkyl. 5 In a seventh subembodiment of embodiment 22, R is chloro, methyl, ethyl, trifluoromethyl, or cyclopropyl. 5 In an eighth subembodiment of embodiment 22, R is trifluoromethyl, 1,1-difluoroethyl, or cyclopropyl. 5 is chloro, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl, or cyclopropyl.

[0154] 23. In embodiment 23, the compound of any one of embodiments 1A, 1 to 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 3is hydrogen, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; a , R b , and / or R c In a first subembodiment of embodiment 23, R 3 is hydrogen. In a second subembodiment of embodiment 23, R 3 is methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano, methylsulfonyl, aminocarbonyl, methylamino, or dimethylamino. 3 is hydroxymethyloxy, hydroxyethyloxy, hydroxymethylamino, hydroxyethylamino, aminoethyloxy, methylaminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, aminoethylamino, methylaminoethylamino, dimethylaminoethylamino, or diethylaminoethylamino. In a fourth subembodiment of embodiment 23, R 3 is a group in which each ring is unsubstituted or R a , R b , and / or R cIn a fifth subembodiment of embodiment 23, R is a heteroaryl, preferably a 5- or 6-membered heteroaryl, such as pyrazolyl, imidazolyl, triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, or pyrimidinyl, either substituted by 3 is heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or a , R b , and / or R c In a sixth subembodiment of embodiment 3, R 3 In a fifth subembodiment of embodiment 23, R is oxopyrrolidinyl, morpholin-4-yl, or 2-morpholin-4-ylethyloxy. 3 is hydrogen or methoxy. In an eighth subembodiment of embodiment 23, R 3 is a group of the second, third, fourth, fifth or sixth subembodiment, R 2 is amino or methylamino, R 4 and R 6 is hydrogen, and R 5 is other than hydrogen.

[0155] 24. In embodiment 24, the compound of any one of embodiments 1A, 1, 3, 5 to 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 1 is alkyl, preferably methyl, ethyl, or isopropyl.

[0156] 25. In embodiment 25, the compound of any one of embodiments 1A, 1, 3, 5 to 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 1 is haloalkyl, preferably trifluoromethyl.

[0157] 26. In embodiment 26, the compound of any one of embodiments 1A, 1, 3, 5 to 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 1 is a hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, or aminosulfonylalkyl.

[0158] 27. In embodiment 27, the compound of any one of embodiments 1A, 1, 2, 4 to 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 1 But R 7 where R 7 In a first subembodiment of embodiment 27, R is cycloalkyl, bridged cycloalkyl, fused cycloalkyl, or spirocycloalkyl. 7 is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, unsubstituted or substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, cyano, or halo. In a first subembodiment of embodiment 27, R 7 is a cycloalkenyl, cyclopentenyl, or cyclohexenyl that is unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, hydroxy, alkoxy, cyano, or halo.

[0159] 28. In embodiment 28, the compound of any one of embodiments 1A, 1, 2, 4 to 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 1 But R 7 where R 7 is unsubstituted or R d , R e , and / or R f aryl, substituted by fIn a first subembodiment of embodiment 28, R is selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. 7 is unsubstituted or R d、 R e , and / or R f In a second subembodiment of embodiment 28, R 7 is unsubstituted or R d , R e , and / or R f phenyl, substituted by d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f In a third subembodiment of embodiment 28, R is selected from hydroxy, fluoro, chloro, cyano, or methyl. 7 is R d , R e , and / or R f phenyl, substituted by d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f is selected from hydroxy, fluoro, chloro, cyano, or methyl, and wherein R d , R e , and / or R f is attached to a carbon atom on the phenyl ring that is ortho or meta to the carbon atom on the phenyl ring that is attached to the quinazolone nitrogen. 7 is unsubstituted or R e and / or Rf phenyl, substituted by e is methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f is fluoro, chloro, cyano or methyl, and where R f is attached to a carbon atom on the phenyl ring that is ortho to the carbon atom on the phenyl ring that is attached to the quinazolone nitrogen. 7 is unsubstituted or R f phenyl, substituted by f is fluoro, chloro, bromo, or methyl, and where R f is attached to a carbon atom on the phenyl ring that is ortho to the carbon atom on the phenyl ring attached to the quinazolone nitrogen.

[0160] 29. In embodiment 28, the compound of any one of embodiments 1A, 1, 2, and 4 through 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 1 But R 7 where R 7 is unsubstituted, or R d , R e , and / or R f heteroaryl, substituted by f is selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In a first subembodiment of embodiment 29, R 7 is unsubstituted or R d , R e , and / or R fIn a second subembodiment of embodiment 29, R is a 5- or 6-membered heteroaryl ring substituted by, for example, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f is selected from hydroxy, fluoro, chloro, cyano, or methyl. In a third subembodiment of embodiment 29, R d , R e , and / or R f where R d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f is selected from hydroxy, fluoro, chloro, cyano, or methyl, and wherein R d , R e , and / or R f is attached to a carbon atom on the heteroaryl ring that is ortho or meta to the carbon atom on the heteroaryl ring attached to the quinazolone nitrogen. 7 is unsubstituted or R e and / or R f pyridinyl or pyrimidinyl, preferably pyridin-3-yl or pyrimidin-4-yl, substituted by e is methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f is fluoro, chloro, cyano or methyl, and where R fis attached to a carbon atom on the pyridinyl or pyrimidinyl ring that is ortho to the carbon atom on the phenyl ring that is attached to the quinazolone nitrogen. 7 is unsubstituted or R f pyridinyl, preferably pyridin-2-yl or pyridin-3-yl, substituted by f is fluoro, chloro, or methyl, and where R f is attached to a carbon atom on the pyridinyl ring that is ortho to the carbon atom on the phenyl ring that is attached to the quinazolone nitrogen.

[0161] 30. In embodiment 30, the compound of any one of embodiments 1A, 1, 2, and 4 through 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 1 But R 7 where R 7 is heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heterocyclyl is unsubstituted or R d , R e , and / or R f where R f is selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. 7 is pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, or morpholinyl, and each ring is independently unsubstituted or d , R e , and / or R f In a second subembodiment of embodiment 30, R 7 is pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, or morpholinyl, and each ring is independently unsubstituted or d , Re and / or wherein R d , R e , and / or R f are independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, hydroxy, methylsulfonyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl.

[0162] 31. In embodiment 31, the compound of any one of embodiments 1A, 1, 2, and 4 to 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 1 But R 7 where R 7 But R d , R e , and / or R f aryl substituted by f But -X c -R 12 where X c is alkylene or heteroalkylene, and R 12 In a first subembodiment of embodiment 28, R is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. 7 is R d , R e , and / or R f In a second subembodiment of embodiment 28, R 7 is unsubstituted or R d , R e , and / or R f and phenyl substituted by R d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R fis selected from 2-phenyloxyethyl, 2-phenylaminoethyl, 2-phenylethyloxy, or 2-phenylaminoethyl, wherein phenyl is optionally substituted with one or two substituents independently selected from methyl, fluoro, chloro, methoxy, hydroxy, trifluoromethyl, or trifluoromethoxy. In a third subembodiment of embodiment 31, R f is attached to a carbon atom on the phenyl ring that is ortho or meta to the carbon atom on the phenyl ring attached to the quinazolone nitrogen.

[0163] 32. In embodiment 32, the compound of any one of embodiments 1A, 1, 2, and 4 to 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, is 1 But R 7 where R 7 But R d , R e , and / or R f heteroaryl substituted by f But -X c -R 12 where X c is alkylene or heteroalkylene, and R 12 In a first subembodiment of embodiment 32, R is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. 7 is unsubstituted or R d , R e , and / or R f In a second subembodiment of embodiment 32, R d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and Rf is selected from 2-phenyloxyethyl, 2-phenylaminoethyl, 2-phenylethyloxy, or 2-phenylaminoethyl, wherein phenyl is optionally substituted with one or two substituents independently selected from methyl, fluoro, chloro, methoxy, hydroxy, trifluoromethyl, or trifluoromethoxy. In a third subembodiment of embodiment 32, R f is attached to an atom of the heteroaryl ring that is ortho or meta to the carbon atom of the heteroaryl ring attached to the quinazolone nitrogen.

[0164] 33. In embodiment 33, the compound of any one of embodiments 1A, 1, 2, and 4 through 23, and subembodiments therein, or a pharmaceutically acceptable salt thereof, wherein R 1 But -X a -R 7 where X a is alkylene, and R 7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f is replaced by

[0165] It is understood that the embodiments set forth above include all combinations of the embodiments and subembodiments listed therein. For example, the R listed in embodiment 30 and / or its first and / or second subembodiments. 1 Groups can be independently combined with one or more of embodiments 1-28 and 31 to 33 and / or subembodiments contained therein.

[0166] The present disclosure includes the following additional embodiments 35 to 90.

[0167] 35. A compound of formula (IA) or a pharmaceutically acceptable salt thereof: [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyloxy, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 5is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N, and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is R 7 where R 7is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f is replaced by; R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and R 10is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or -X c -R 12 (X in the formula c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; however: (1) Formula: [ka] But the expression: [ka] where: (a) R 2 is piperazin-1-yl, 2-methylpiperazin-1-yl, or 1H-benzo[d][1,2,3]triazol-1-yl, and R 3 and R 6 is hydrogen and R 4 is chloro, and R 5 is bromo or 5-methylindazol-4-yl, R 1 is not 2-isopropylphenyl; (b) R 2 and R 6 is methyl, and R3 , R 4 , and R 5 is hydrogen; or R 2 and R 3 is methyl, and R 4 , R 5 , and R 6 is hydrogen, R 1 is not 2,5-, 2,6- or 2,8-dimethylquinolin-4-yl or 2-methyl-5-methoxy-, 2-methyl-6-methoxy- or 2-methyl-8-methoxyquinolin-4-yl; (c) R 2 is amino or acetylamino, and R 4 is dimethylamino, and R 3 , R 5 , and R 6 is hydrogen, R 1 is not 4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (d) R 5 is fluoro and R 3 , R 4 and R 6 is hydrogen, and R 2 is 4-aminocarbonylmethyl-2-methylphenylamino, R 1 is not 4-fluoro-2-(2-thiazol-2-ylmethoxy)phenyl, 4-fluoro-2-(2-pyridin-2-ylmethoxy)phenyl, or 4-chloro-2-methoxyphenyl; (e) R 6 is fluoro and R 3 , R 4 and R 5 is hydrogen, and R 2 is 4-aminocarbonylmethyl-2-methylphenylamino, R 1 is not 4-fluoro-2-methoxyphenyl; (f) R 1 is 4-chloro-2-ethoxyphenyl, and R 5 is fluoro and R 3 , R 4 and R 6 is hydrogen, R 2 is not 3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino; (2) Formula: [ka] But the expression: [ka] and R 1 is 4-hydroxy-5-hydroxymethylfuran-1-yl, and R 5 is amino, and R 3 When R is methoxy; 2 is not an amino; and (3) Formula: [ka] But the expression: [ka] and R 1 is 4-hydroxy-5-hydroxymethylfuran-1-yl, and R 4 and R 5 is hydrogen, and R 4 and R 5 The other is methyl, or R 4 and R 5 If both R and R are methyl, 2 is not an amino).

[0168] 36. The compound of embodiment 35, wherein the compound has the structure of formula (I): [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 and R 5is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N, and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is R 7 where R 7is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, phenyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f is replaced by; R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl, or cycloalkyl; and R 10is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or -X c -R 12 (X in the formula c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.

[0169] 37. The compound of embodiment 35 or 36, having the structure of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIg): or a pharmaceutically acceptable salt thereof: [ka]

[0170] 38. The compound of embodiment 35 or 36, having the structure of Formula (IIIa), or a pharmaceutically acceptable salt thereof.

[0171] 39. The compound of embodiment 35 or 36, having the structure of Formula (IIIb), or a pharmaceutically acceptable salt thereof.

[0172] 40. The compound of embodiment 35 or 36, having the structure of Formula (IIIc), or a pharmaceutically acceptable salt thereof.

[0173] 41. The compound of embodiment 35 or 36, having the structure of formula (IIId), or a pharmaceutically acceptable salt thereof.

[0174] 42. The compound of embodiment 35 or 36, having the structure of Formula (IIIe), or a pharmaceutically acceptable salt thereof.

[0175] 43. The compound of embodiment 35 or 36, having the structure of formula (IIIf), or a pharmaceutically acceptable salt thereof.

[0176] 44. The compound of embodiment 35 or 36, having the structure of formula (IIIg), or a pharmaceutically acceptable salt thereof.

[0177] 45. R 2 Ga-NR 9 R 10 45. The compound of any one of embodiments 35 to 44, wherein

[0178] 46. R 2 -OR 8 45. The compound of any one of embodiments 35 to 44, wherein

[0179] 47. R 2 But R 11 45. The compound of any one of embodiments 35 to 44, wherein

[0180] 48. R 9 Embodiment 46. The compound of any one of embodiments 35 to 45, wherein is deuteroalkyl, preferably trideuteromethyl.

[0181] 49. R 9 46. The compound of any one of embodiments 35 to 45, wherein is hydrogen.

[0182] 50. R 9 46. The compound of any one of embodiments 35 to 45, wherein is alkyl, preferably methyl or ethyl.

[0183] 51. R 946. The compound of any one of embodiments 35 to 45, wherein is cycloalkyl, preferably cyclopropyl.

[0184] 52. R 10 The compound of any one of embodiments 35 to 45 and 49 to 51, wherein is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl.

[0185] 53. R 10 53. The compound of embodiment 52, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0186] 54. R 8 and R 10 53. The compound of embodiment 46 or 52, or a pharmaceutically acceptable salt thereof, wherein is alkyl, preferably methyl.

[0187] 55. R 10 53. The compound of embodiment 52, or a pharmaceutically acceptable salt thereof, wherein is alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl, preferably methylaminocarbonyl-methyl or dimethylaminocarbonylmethyl.

[0188] 56. R 8 and R 10 is independently phenyl or phenylalkyl, preferably benzyl or phenethyl, where phenyl, by itself or as part of benzyl and phenethyl, is unsubstituted or R j , R k , and / or R l or a pharmaceutically acceptable salt thereof.

[0189] 57. R 8 and R 10is independently cycloalkyl or cycloalkylalkyl, and each ring may independently be unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, halo, or cyano; or a pharmaceutically acceptable salt thereof.

[0190] 58. R 8 and R 10 is independently heteroaryl or heteroaralkyl, where heteroaryl, by itself or as part of a heteroaralkyl, is unsubstituted or j , R k , and / or R l or a pharmaceutically acceptable salt thereof.

[0191] 59. R 8 and R 10 is heteroaryl independently selected from pyrazolyl, imidazolyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, and indazolyl, and each ring is unsubstituted or j , R k , and / or R l or a pharmaceutically acceptable salt thereof.

[0192] 60. R 8 and R 10is heteroaralkyl independently selected from pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolinylmethyl, quinolinylethyl, isoquinolinylmethyl, isoquinolinylethyl, indolylmethyl, indolylethyl, indazolylmethyl, and indazolylethyl, and each ring is unsubstituted or j , R k , and / or R l or a pharmaceutically acceptable salt thereof.

[0193] 61. R 8 and R 10 is independently heterocyclyl, preferably oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and each ring is unsubstituted or j , R k , and / or R l or a pharmaceutically acceptable salt thereof.

[0194] 62. R 8 and R 10 is independently heterocyclylalkyl, preferably oxetanylmethyl, oxetanylethyl, azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl, or morpholinylethyl, and each ring is unsubstituted or j , R k , and / or R l or a pharmaceutically acceptable salt thereof.

[0195] 63. R 2is R 11 where R 11 is unsubstituted or R m , R n , and / or R o 48. The compound of any one of embodiments 35 to 44 and 47, wherein R is heterocyclyl substituted by:

[0196] 64. R 11 is oxetanyl, azetidinyl, 2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, preferably azetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, and each ring is unsubstituted or is selected from the group consisting of oxetanyl, azetidinyl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, and morpholin-4-yl. m , R n , and / or R o and preferably R 11 64. The compound of embodiment 63, wherein R is azetidin-1-yl, 4-hydroxyazetidin-1-yl, 4-methylaminocarbonylazetidin-1-yl, 4-dimethylaminocarbonylazetidin-1-yl, 2-hydromethyl-azetidin-1-yl, 2-methylazetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, piperidin-1-yl, 2-carboxypiperidin-1-yl, 2-aminocarbonylpiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl, or morpholin-4-yl; or a pharmaceutically acceptable salt thereof.

[0197] 65. R 2 is R 11 where R 11 is unsubstituted or R m , R n , and / or R oheteroaryl, preferably R 11 is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, and indazolyl, each ring being unsubstituted or m , R n , and / or R o 48. The compound of any one of embodiments 35 to 44 and 47, or a pharmaceutically acceptable salt thereof, substituted by:

[0198] 66. R 2 45. The compound of any one of embodiments 35 to 44, or a pharmaceutically acceptable salt thereof, wherein is hydroxyalkyl, aminoalkyl, or aminocarbonylalkyl.

[0199] 67. R 5 R is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl, heteroaryl, heterocyclyl, where heterocyclyl or heteroaryl is unsubstituted or independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c 67. The compound of any one of embodiments 35 to 66, substituted by:

[0200] 68. R 5is methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclopentyl, cyano, pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, oxetan-3-yl, pyrrolidin-1-yl, tetrahydrofuranyl, 2-oxoazetidin-1-yl, or 2-oxopyrrolidin-1-yl, where the heterocyclyl or heteroaryl ring is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c or a pharmaceutically acceptable salt thereof.

[0201] 69. R 5 68. The compound of embodiment 67, or a pharmaceutically acceptable salt thereof, wherein is chloro, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl, or cyclopropyl.

[0202] 70. R 5 69. The compound of embodiment 68, wherein is chloro, trifluoromethyl, or ethyl.

[0203] 71. R 4 and R 6 is independently selected from hydrogen, methyl, chloro, fluoro, methoxy, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, or dimethylaminocarbonyl; or a pharmaceutically acceptable salt thereof.

[0204] 72. R 4 is hydrogen, fluoro, methoxy, cyano, and R 671. The compound of any one of embodiments 35 to 70, or a pharmaceutically acceptable salt thereof, wherein:

[0205] 73. R 4 is hydrogen or bromo, and R 6 71. The compound of any one of embodiments 35 to 70, or a pharmaceutically acceptable salt thereof, wherein:

[0206] 74. R 4 and R 6 71. The compound of any one of embodiments 35 to 70, or a pharmaceutically acceptable salt thereof, wherein:

[0207] 75. R 3

[0082] Embodiment 75. The compound of any one of embodiments 35 to 74, or a pharmaceutically acceptable salt thereof, wherein: is hydrogen, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl.

[0208] 76. R 3 76. The compound of embodiment 75, or a pharmaceutically acceptable salt thereof, wherein:

[0209] 77. R 3 is methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano, methylsulfonyl, aminocarbonyl, methylamino, or dimethylamino; or a pharmaceutically acceptable salt thereof.

[0210] 78. R 3 is heteroaryl, preferably 5- or 6-membered heteroaryl such as pyrazolyl, imidazolyl, triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, or pyrimidinyl, and each ring is unsubstituted or a , Rb , and / or R c 75. The compound of any one of embodiments 35 to 74, or a pharmaceutically acceptable salt thereof, wherein

[0211] 79. R 3 75. The compound of any one of embodiments 35 to 74, or a pharmaceutically acceptable salt thereof, wherein is heterocyclyl, preferably oxopyrrolidinyl, morpholin-4-yl, or 2-morpholin-4-ylethyloxy.

[0212] 80. R 1 is R 7 where R 7

[0047] Embodiment 79. The compound of any one of embodiments 35 to 79, or a pharmaceutically acceptable salt thereof, wherein R is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and each ring is either unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, hydroxy, alkoxy, cyano, or halo.

[0213] 81. R 1 is R 7 where R 7 is unsubstituted or R d , R e , and / or R f phenyl, substituted by d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f 80. The compound of any one of embodiments 35 to 79, or a pharmaceutically acceptable salt thereof, wherein is selected from hydroxy, fluoro, chloro, cyano, and methyl.

[0214] 82. R 1 is R 7 where R7 is unsubstituted or R f phenyl, substituted by f is fluoro, chloro, bromo, or methyl, and where R f 80. The compound of any one of embodiments 35 to 79, wherein is attached to a carbon atom on the phenyl ring that is ortho to the carbon atom of the phenyl ring attached to the quinazolone nitrogen; or a pharmaceutically acceptable salt thereof.

[0215] 83. R 1 is R 7 where R 7 is unsubstituted or independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl; d and / or R e and / or R selected from hydroxy, fluoro, chloro, cyano, and methyl f or a pharmaceutically acceptable salt thereof.

[0216] 84. R 1 is R 7 where R 7 is R d , R e , and / or R f phenyl, substituted by d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f -X c R 12 (where Xc is selected from alkylene or heteroalkylene, preferably heteroalkylene; or a pharmaceutically acceptable salt thereof.

[0217] 85. R 1 is R 7 where R 7 is R d , R e , and / or R f and 5- or 6-membered heteroaryl rings, such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, substituted by d and R e is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl, and R f -X c R 12 (where X c is selected from alkylene or heteroalkylene, preferably heteroalkylene; or a pharmaceutically acceptable salt thereof.

[0218] 86. A pharmaceutical composition comprising a compound of any one of embodiments 35 to 85, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0219] 87. A method of treating a disease mediated by MAT2A in a patient, comprising administering to the patient a therapeutically effective amount of the following compound, or a pharmaceutically acceptable salt thereof: (a) A compound of formula (IIA): [ka] (In the formula: w is CR 3 or N; x is CR 4or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyloxy, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 5is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N; and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is R 7 where R 7is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f is replaced by; R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and R 10is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or -X c -R 12 (X in the formula c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl); (b) a compound of formula (II): [ka] (In the formula: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; and z is CR 6 or N, where: R 3 and R 5is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. a , R b , and / or R c is replaced by; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z can be N; and (ii) R 3 , R 4 , R 5 , and R 6 is other than hydrogen; R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 (In the formula, X ais a bond or alkylene, and R 7 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the aryl, heteroaryl, or heterocyclyl is unsubstituted or d , R e , and / or R f substituted by R 2 is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 , -NR 9 R 10 , or -X b -R 11 where: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, spiroheterocyclyl, and spiroheterocyclylalkyl. g , R h , and / or R i is replaced by; R 9 is hydrogen, alkyl, or cycloalkyl; and R 10is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or is selected from the group consisting of aryl, heteroaryl, heterocyclyl, heteroaryl, heterocyclyl, heterocyclyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl. j , R k , and / or R l is replaced by; X b is a bond or alkylene; and R 11 is a cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, where the heteroaryl or heterocyclyl is unsubstituted or m , R n , and / or R o is substituted by; and R d , R e , R g , R h , R j , R k , R m , and R nis independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R f , R i , R l , and R o is alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or -X c -R 12 (X in the formula c is a bond, alkylene, or heteroalkylene, and R 12 are independently selected from optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl); or (c) A compound according to any one of embodiments 35 to 85, or a pharmaceutically acceptable salt thereof.

[0220] 88. The method of embodiment 87, wherein the disease is cancer.

[0221] 89. A compound of formula (IIA) or (II) as defined in embodiment 87, or a pharmaceutically acceptable salt thereof; or A method of treating MTAP-null cancer in a patient, comprising administering to the patient a therapeutically effective amount of: a compound of any one of embodiments 35 to 85, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

[0222] 90. A compound of formula (IIA) or (II) as defined in claim 87, or a pharmaceutically acceptable salt thereof; or A method for treating cancer in a patient characterized by reduced or absent MTAP gene expression, absence of the MTAP gene, or reduced function of the MTAP protein, comprising administering to the subject a therapeutically effective amount of any one of the compounds of embodiments 35 to 85 or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

[0223] General Synthesis The compounds of the present disclosure can be made by the methods depicted in the reaction schemes shown below.

[0224] The starting materials and reagents used in the preparation of these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or are prepared by methods known to those skilled in the art according to procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the methods by which the compounds of the present disclosure may be synthesized, and various modifications to these schemes may be implemented and will be suggested to those of skill in the art upon reading this disclosure. The starting materials and intermediates of the reactions, as well as the final products, may be isolated and purified, if desired, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0225] Unless otherwise specified, reactions described herein are carried out at atmospheric pressure and over a temperature range of about −78° C. to about 150° C., such as about 0° C. to about 125° C., and also, for example, at about room (or ambient) temperature, such as about 20° C.

[0226] The compounds and subembodiments of formula (I) and (II) described herein, wherein w, x, y, and z are not nitrogen and R2 is other than hydrogen, and other groups are as defined in the Summary), can be prepared by the method illustrated and described in Scheme 1 below. [ka]

[0227] A 2,4-dioxoquinazoline compound of formula 1, wherein R 1 , R 3 , R 4 , R 5 and R 6 is one of those outlined above or a precursor group thereof) can be prepared by methods well known in the art to give compounds of formula (I) 2 For example, treatment of compound 1 with POCl in the presence of an organic base such as triethylamine in an inert organic solvent provides compounds of formula (I) where R 2 is chloro), which can then be converted by methods well known in the art to a compound of formula (I), 2 is other than halo). For example, a compound of formula (I) 2 is -NR 9 R 10 , heterocyclyl containing at least a nitrogen atom, or heteroaryl with a basic nitrogen) can be reacted with the corresponding compound of formula (I), where R 2 is chloro) to the formula -NR 9 R 10 The compounds of formula -NR 9 R 10Amines or heterocyclyls containing at least a nitrogen atom are commercially available. For example, methylamine, dimethylamine, ethylamine, dimethylamine, cyclopropylamine, 2-aminooxetane, tetrahydrofuran-2-amine, benzylamine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyrazole, 2-pyridinamine, 3-pyridinamine, 3-pyridinamine, and cyclopropylmethylamine are commercially available.

[0228] Or, -NR9R 10 can be prepared by alkylating or arylating compounds of formula (I), where R 2 is —NH2).

[0229] A compound of formula (I) 2 is R 11 where R 11 is heteroaryl) can be converted under Suzuki reaction conditions to a compound of formula (I), 2 is halo).

[0230] Compounds of formula 1 can be prepared by methods known in the art, some of which are exemplified and described below. Synthesis from 2-halobenzamides: Method (a) [ka]

[0231]

[0033] The reaction of a compound of formula 2 (wherein X is halo, such as chloro, and other groups are as defined in the Summary or precursor groups thereof) with a compound of formula R in the presence of an inorganic base, such as potassium carbonate, cesium carbonate, and copper. 1 NH2 amine (wherein R 1is as defined in the Summary or a precursor group thereof) provides compounds of formula 3. Compounds of formula 2 are either commercially available or can be made by methods well known in the art. Compounds of formula 2 are converted to compounds of formula 1 by treatment with a base such as sodium hydride in the presence of N,N-carbonyldiimidazole under conditions well known in the art.

[0232] Alternatively, compounds of formula 1 from compound 2 can be prepared as shown in method b below. Method (b) [ka]

[0233] of a compound of formula 2 (wherein X is halo, preferably chloro, and the other groups are those defined in the Summary and their precursor groups) in a chlorinated organic solvent, such as oxalyl chloride or a compound of formula R 1 NCO isocyanate (wherein R 1 is as defined in the Summary or a precursor group thereof) of formula R 1 Treatment of NH with an amine provides the acylurea compound of formula 4, which is then cyclized under conditions well known in the art in the presence of a base such as sodium hydride or KHMDS to provide the compound of formula 1.

[0234] Synthesis from 2-halobenzoic acids: Method(c) [ka] by reacting a benzoic acid compound of formula 5 (wherein X is halo, preferably chloro, and the other groups are those defined in the summary or precursor groups thereof) with a benzoic acid compound of formula R 1 NH2 amine (wherein R 1is as defined in the Summary or a precursor group thereof) provides compounds of formula 6. Alternatively, the amination reaction can be carried out in the presence of LDA in THF at -78°C. Compounds of formula 5 are either commercially available or can be made by methods well known in the art. Compounds of formula 6 are converted to compounds of formula 1 by treatment with urea under conditions well known in the art.

[0235] Alternatively, compounds of formula 6 can be converted to amide compounds of formula 3 by treatment of compound 6 with HATU or EDCI / HOBt and ammonium chloride in the presence of an organic base such as diisopropylethylamine in an organic solvent such as THF. Compound 6 can then be prepared as shown in "Methods" or method b above and converted to compound 1.

[0236] Synthesis from 2-aminobenzoic acid: Method (d) [ka] 2-aminobenzoic acid compounds of formula 7, where R 3 From R 6 groups are those defined in the Summary or precursor groups thereof) in the presence of copper acetate and a base such as triethylamine, pyridine, etc., by reacting R 1 Br halide (wherein R 1 is as defined in the Summary or a precursor group thereof) to provide compound 6, which can then be converted to a compound of formula 1 as previously described.

[0237] Synthesis from 2-aminobenzamide: Method(e) [ka] 2-aminobenzamide compounds of formula 8, where R 3 From R 6groups are those defined in the Summary or precursor groups thereof) in the presence of a base such as triethylamine, pyridine, etc., in the presence of copper(I) chloride, to form a compound of formula R 1 Boronic acid of B(OH) 1 is as defined in the Summary or a precursor group thereof) to provide compounds of formula 3, which can then be converted to compounds of formula 1 as previously described.

[0238] Compounds of formula (I) and (II) and subembodiments described herein can be converted to other compounds of formula (I) and (II), respectively, by methods well known in the art. For example, compounds of formula (I) or (II) (wherein R 5 is a halo (precursor group)) can be converted to the corresponding compound of formula (I) or (II), respectively, by treating it with sodium methoxide in the presence of CuI in DMF. 5 is methoxy). Compounds of formula (I) or (II) 5 is a halo (precursor group)) can be converted to the corresponding compound of formula (I) or (II), respectively, by treating it with zinc cyanide in the presence of a Pd catalyst, such as Pd(PH3)4, in DMF. 5 is cyano). 5 is a halo (precursor group) can be converted to the corresponding compound of formula (I) by treating it with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of CuI in DMF. 5 is trifluoromethyl).

[0239] utility Overexpression of the enzyme MAT2A has been shown to mediate certain cancers. In embodiments, the cancers include neuroblastoma, intestinal cancer (e.g., rectal cancer, colon cancer, familial adenomatous polyposis carcinoma, and hereditary nonpolyposis colorectal cancer), esophageal cancer, labial cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors). These include Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0240] In another embodiment, the cancer is lung cancer, non-small cell lung (NSLC) cancer, bronchioloalveolar carcinoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial cancer, vaginal cancer, vulva cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer. , prostate cancer, bladder cancer, cancer of the kidney or ureter, renal cell carcinoma, renal pelvic carcinoma, mesothelioma, hepatocellular carcinoma, bile duct cancer, chronic or acute leukemia, lymphocytic lymphoma, neoplasms of the central nervous system (CNS), intramedullary tumors of the spinal cord, brain stem glioma, glioblastoma multiforme, astrocytoma, schwannoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, pituitary adenocarcinoma, including refractory forms of any of the foregoing cancers, or a combination of one or more of the foregoing cancers.

[0241] Methylthioadenosine phosphorylase (MTAP) is an enzyme found in all normal tissues that catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Adenine is salvaged to produce adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Because of this salvage pathway, MTA can serve as an alternative purine source when de novo purine synthesis is blocked, for example, by antimetabolites such as L-alanosine.

[0242] Many human and mouse malignant cells lack MTAP activity. MTAP deficiency is not only observed in tissue culture cells; it is also present in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, and mesothelioma. K. Marjon et al. (Cell Reports 15 (2016) 574-587), incorporated herein by reference, reported that the growth of MTAP-null cancer cells was inhibited by knockdown of MAT2A expression with shRNA. MTAP-null cancers are cancers in which the MTAP gene is deleted, lost, or otherwise inactivated, or in which the MTAP protein has reduced or impaired function.

[0243] Thus, in one embodiment of the present disclosure, there is provided a method of treating an MTAP-null cancer in a patient, wherein the cancer is characterized by reduced or absent MTAP expression, or the absence of the MTAP gene, or reduced function of the MTAP protein, compared to cancers in which the MTAP gene is present and fully functional, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), or (IIA'), or a subembodiment described herein or a pharmaceutically acceptable salt thereof. In another embodiment, there is provided a method of treating an MTAP-null cancer in a patient in need thereof, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), or (IIA'), or a subembodiment described herein or a pharmaceutically acceptable salt thereof. In certain embodiments, the MTAP null cancer is leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, or mesothelioma. In another embodiment, the MTAP null cancer is pancreatic cancer. In yet another embodiment, the MTAP null cancer is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B-cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), or mantle cell lymphoma (MCL). In yet another embodiment, the MTAP null cancer is gastric cancer. In yet another embodiment, the cancer is colon cancer. In yet another embodiment, the MTAP null cancer is liver cancer. In yet another embodiment, the MTAP null cancer is glioblastoma multiforme (GBM). In yet another embodiment, the MTAP null cancer is bladder cancer. In yet another embodiment, the MTAP null cancer is esophageal cancer. In yet another embodiment, the MTAP null cancer is breast cancer. In yet another embodiment, the MTAP null cancer is NSLCC. In yet another embodiment, the MTAP null cancer is MCL. In yet another embodiment, the MTAP null cancer is DLBCL. In yet another embodiment, the MTAP null cancer is ALL.

[0244] Genomic analysis of MTAP-null cell lines indicates that cell lines that also incorporate KRAS or p53 mutations are sensitive to MAT2A inhibition. Accordingly, methods of treating cancer in a patient characterized by reduced or absent MTAP expression, or the absence of the MTAP gene, or reduced function of the MTAP protein (i.e., MTAP-null), and further characterized by the presence of mutant KRAS and / or mutant p53, are also provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), or (IIA'), or a subembodiment described herein. In one embodiment, the cancer is MTAP-null and KRAS-mutant. In another embodiment, the cancer is MTAP-null and p53-mutant. In yet another embodiment, the cancer is MTAP-null, KRAS-mutant, and p53-mutant.

[0245] The term "mutant KRAS" or "KRAS mutation" refers to a KRAS protein (or a gene encoding the protein) that incorporates an activating mutation that alters its normal function. For example, a mutant KRAS protein may incorporate a single amino acid substitution at position 12 or 13. In certain embodiments, the KRAS mutant incorporates a G12X or G13X substitution, where X represents any amino acid change at the designated position. In certain embodiments, the substitution is G12V, G12R, G12C, or G13D. In another embodiment, the substitution is G13D. By "mutant p53" or "p53 mutation" is meant a p53 protein (or a gene encoding the protein) that incorporates a mutation that inhibits or eliminates its tumor suppressor function. In certain embodiments, the p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R282W, A159V, or R280K. In certain embodiments, the cancer is non-small cell lung cancer (NSLCC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer.

[0246] Assay The ability of compounds of the present disclosure to inhibit MAT2A can be measured as described in Biological Example 1 below.

[0247] Pharmaceutical Composition A compound of Formula (I), (IA), (IA'), (II), (IIA), or (IIA'), or a subembodiment thereof described herein, or a pharmaceutically acceptable salt thereof, may be in the form of a composition suitable for administration to a subject. Generally, such a composition is a pharmaceutical composition containing a compound of Formula (I), (IA), (IA'), (II), (IIA), or (IIA'), or a subembodiment thereof described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, the compound of Formula (I), (IA), (IA'), (II), (IIA), or (IIA'), or a subembodiment thereof described herein, or a pharmaceutically acceptable salt thereof, is present in a therapeutically effective amount. The pharmaceutical composition may be used in the methods disclosed herein; thus, for example, the pharmaceutical composition can be administered to a subject ex vivo or in vivo to practice the therapeutic methods and uses described herein.

[0248] The pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; examples of routes of administration are described herein. Furthermore, the pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds, such as those described herein, to treat the diseases, disorders, and conditions contemplated by the present disclosure.

[0249] Pharmaceutical compositions containing the active ingredient (e.g., a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a pharmaceutically acceptable salt thereof) may be in a form suitable for oral use, such as a tablet, capsule, troche, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup, liquid, microbead, or elixir. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more substances, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide pharmaceutically elegant and palatable preparations. Tablets, capsules, and the like contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets, capsules, and the like. These excipients may be, by way of example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin or gum acacia, and lubricants, such as magnesium stearate, stearic acid or talc.

[0250] Tablets, capsules, and the like suitable for oral administration may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Tablets may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional materials for controlling delivery of the administered composition include biodegradable or biocompatible particles or polymeric materials, such as polyesters, polyamic acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide and glycolide copolymers, polylactide and glycolide copolymers, or ethylene-vinyl acetate copolymers. For example, oral substances can be entrapped in microcapsules prepared by coacervation techniques or by interfacial polymerization using hydroxymethylcellulose or gelatin microcapsules or poly(ethyl methacrylate) microcapsules, respectively, or in colloidal drug delivery systems. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the aforementioned formulations are known in the art.

[0251] Tablets for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as, for example, peanut oil, liquid paraffin, or olive oil.

[0252] Aqueous suspensions contain the active substance in admixture with excipients suitable for its manufacture. Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents, such as natural phosphatides (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptodecaethyleneoxycetanol), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyethylene sorbitan monooleate). These aqueous suspensions can also contain one or more preservatives.

[0253] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.

[0254] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0255] The pharmaceutical composition may also be in the form of an oil-in-water emulsion.The oil phase may be, for example, a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof.Suitable emulsifiers may be natural gums, such as gum acacia or gum tragacanth; natural phosphatides, such as soybean, lecithin, and fatty acid-derived esters or partial esters; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0256] The pharmaceutical compositions typically contain a therapeutically effective amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), or (IIA'), or a subembodiment thereof described herein, or a salt thereof, and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl or n-propyl p-hydroxybenzoic acid esters), emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle is normal saline or citrate-buffered saline, which can be supplemented with other substances commonly found in pharmaceutical compositions for parenteral administration. Neutral buffered saline or serum albumin-containing saline are further examples of vehicles. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Representative buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. By way of example, buffer components can be water-soluble substances such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0257] After the pharmaceutical composition is formulated, it may be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an auto-injector (e.g., similar to an EpiPen®)), while in other embodiments, a multi-use container (e.g., a multi-use vial) is provided.

[0258] Formulations, such as controlled-release formulations, including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems, can also contain carriers to protect the compositions from rapid degradation or elimination from the body. For example, time-retardants such as glyceryl monostearate or glyceryl stearate, alone or in combination with a wax, may be used. Any drug delivery device, including implants (e.g., implantable pumps) and catheter systems, slow-infusion pumps and devices, may be used to deliver the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, all of which are well known to those skilled in the art.

[0259] Time-release injections, generally administered subcutaneously or intramuscularly, may also be used to release a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, over a defined period of time. Time-release injections are typically either solid- or oil-based and generally contain at least one of the formulation ingredients set forth herein. Those skilled in the art are familiar with the possible formulations and uses of time-release injections.

[0260] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally-acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable diluents, solvents, and dispersion media that may be employed include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland, fixed oil may be employed, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are permitted for use in injectable preparations. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0261] The compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, may also be administered in the form of suppositories for rectal administration or sprays for nasal or inhalation use. Suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0262] Administration route Compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, and compositions containing same, may be administered in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracapsular, intraarticular, intraperitoneal, intracerebral (intraparenchymal), and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Time-release injections, generally administered subcutaneously or intramuscularly, may also be utilized to administer compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, over a defined period of time. Certain embodiments of the present invention contemplate oral administration.

[0263] Combination therapy The present invention contemplates the use of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents often have different, complementary mechanisms of action. Such combination therapy is particularly advantageous by allowing for reduced dosage of one or more of the agents, thereby reducing or eliminating adverse effects associated with the one or more agents. Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect against the underlying disease, disorder, or condition.

[0264] As used herein, "combination" is meant to include therapies that can be administered separately, e.g., that are formulated separately for separate administration (e.g., that can be provided in a kit), and therapies that can be administered together in a single formulation (i.e., "co-formulation").

[0265] In some embodiments, compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, are administered or applied sequentially, e.g., where one substance is administered before one or more other substances. In other embodiments, compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, are administered simultaneously, e.g., where two or more substances are administered simultaneously or near simultaneously; these two or more substances may be present in two or more separate formulations or combined in a single formulation (i.e., co-formulation). Regardless of whether two or more substances are administered sequentially or simultaneously, they are considered to be administered concomitantly for purposes of this disclosure.

[0266] A compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, may be combined with at least one other (active) agent in any manner appropriate under the circumstances. In one embodiment, treatment with at least one active agent and at least one compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, is maintained for a period of time. In another embodiment, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable), while treatment with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, is maintained at a constant dosing regimen. In further embodiments, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable), while treatment with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, is reduced (e.g., a lower dosage, less frequent dosing, or a shorter treatment regimen). In yet other embodiments, treatment with at least one active agent is reduced or discontinued (e.g., if the subject is stable), and treatment with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, is increased (e.g., a higher dosage, more frequent dosing, or a longer treatment regimen). In yet another embodiment, treatment with at least one active agent is maintained and treatment with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, is reduced or discontinued (e.g., a lower dosage, less frequent dosing, or a shorter treatment regimen). In yet another embodiment, treatment with at least one active agent and treatment with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, are reduced or discontinued (e.g., a lower dosage, less frequent dosing, or a shorter treatment regimen).

[0267] The present disclosure provides methods of treating cancer with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, and at least one additional therapeutic or diagnostic agent.

[0268] In some embodiments, the compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, is administered orally with or without administra- tion of temozolomide, pemetrexed, pegylated liposomal doxorubicin (Doxil), eribulin (Halaven), ixabepilone (Ixempra), protein-bound paclitaxel (Abraxane), oxaliplatin, irinotecan, vena cava, or benzodiazepine. It is administered in combination with at least one additional therapeutic agent selected from toclax (a bcl2 inhibitor), 5-azacytidine, anti-CD20 therapeutic agents such as rituximab and obinutuzumab, hormones (anastrozole, exemestane, letrozole, zoladex, luponeligard), CDK4 / 6 inhibitors, palvocisirubin, abemacisirubin, CPI (avelumab), cemiplimab-rwlc, and bevacizumab.

[0269] In some embodiments, the present disclosure provides a method of treating cancer comprising administering a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, in combination with a signal transduction inhibitor (STI) to achieve additive or synergistic inhibition of tumor growth. As used herein, the term "signal transduction inhibitor" refers to a substance that selectively inhibits one or more steps in a signal transduction pathway. Examples of signal transduction inhibitors (STIs) useful in the methods described herein include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., Gleevec); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) her-2 / neu receptor inhibitors (e.g., Herceptin); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidylinositol kinase inhibitors. Agents involved in immune modulation may also be used in combination with one or more compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, to suppress tumor growth in cancer patients.

[0270] In some embodiments, the present disclosure provides a method of treating cancer comprising administering a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, in combination with a chemotherapeutic agent. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, mesuredopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; quiolambucil, chloram ... Nitrogen mustards such as lornafazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; aclacinomycin, actinomycin, and australamycin cin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, Antibiotics such as puromycin, chelamycin, rhodrubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine;Pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and 5-FU; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; Seglaton; Aldophosphamide glycoside; Aminolevulinic acid; Amsacrine; Bestravcil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquone; Elformitin; Elliptinium acetate; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procaine Rubadine; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacitocin; Arabinoside (Ara-C); Cyclophosphamide; Thiotepa; Taxoids, such as paclitaxel and doxetaxel; Chlorambucil; Gemcitabine; 6-Thioguanine; Mercaptopurine; Methotrexate; platinum and platinum coordination complexes, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine;and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. In certain embodiments, the compounds of the present disclosure are co-administered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere, and mitomycin C. In certain embodiments, the cytostatic compound is doxorubicin.

[0271] Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as estrogen antagonists, including, for example, tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, onapristone, and toremifene; and androgen antagonists, such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing. In some embodiments, the combination therapy includes the administration of hormones or related hormonal agents.

[0272] The present disclosure also contemplates the combination of a compound of Formula (I), (IA), (IA'), (II), (IIA), or (IIA'), or a subembodiment described herein, or a salt thereof, with an immune checkpoint inhibitor. The vast array of genetic and epigenetic alterations characteristic of all cancers provides a diverse set of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the ultimate magnitude (e.g., level of cytokine production or proliferation) and quality (e.g., type of resulting immune response, such as the pattern of cytokine production) of the response initiated through antigen recognition by the T cell receptor (TCR) are regulated by the balance between costimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are important for preventing autoimmunity (i.e., maintaining self-tolerance) and for protecting tissues from damage when the immune system responds to pathogen infection. Expression of immune checkpoint proteins is dysregulated by tumors as an important mechanism of immune resistance. Examples of immune checkpoint inhibitors include, but are not limited to, CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFβ, CD73, CD39, A2AR, A2BR, IDO1, TDO2, arginase, B7-H3, and B7-H4. Cell-based modulators of anti-cancer immunity are also contemplated. Examples of such modulators include, but are not limited to, chimeric antigen receptor T cells, tumor-infiltrating T cells, and dendritic cells.

[0273] The present disclosure contemplates the use of compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, in combination with inhibitors of the aforementioned immune checkpoint receptors and ligands, such as ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, and durvalumab.

[0274] Additional therapeutic modalities that may be used in combination with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, include radiation therapy, monoclonal antibodies against tumor antigens, conjugates of monoclonal antibodies and toxins, T-cell adjuvants, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy).

[0275] The present disclosure contemplates the use of compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, either alone or in combination with radiation and / or temozolomide (TMZ), avastin, or lomustine, for the treatment of glioblastoma.

[0276] The present disclosure includes pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0277] dosage A compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, may be administered to a subject in an amount that depends, for example, on the purpose of administration (e.g., the desired degree of resolution); the age, weight, sex, and health and physiological condition of the subject to whom the formulation is being administered; the route of administration; and the nature of the disease, disorder, condition, or symptoms thereof. The dosing regimen may also take into account the existence, nature, and extent of any adverse effects associated with the administered substance(s). Effective dosages and dosing regimens can be readily determined, for example, from safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0278] Generally, dosing parameters dictate that the dosage be below an amount that may be irreversibly toxic to the subject (the maximum tolerated dose (MTD)) and above the amount required to produce a measurable effect in the subject, such amount being determined by pharmacokinetic and pharmacodynamic parameters, e.g., relevant to ADME, taking into account the route of administration and other factors.

[0279] An effective dose (ED) is the dosage or amount of a substance that produces a therapeutic response or desired effect in a proportion of subjects who take it. 50 ED is the dose or amount of a substance that produces a therapeutic response or desired effect in 50% of the population to which it is administered. 50 Although the ED is commonly used as a reasonable predictor of a substance's effectiveness, the dosage that a clinician would consider reasonable does not necessarily take into account all relevant factors. Therefore, in some situations, the effective dose may be greater than the calculated ED. 50 In other situations, an effective dose is greater than the calculated ED 50 In still other situations, the effective dose is less than the calculated ED 50 is the same as

[0280] Additionally, an effective amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, can be an amount that, when administered to a subject in one or more doses, produces a desired result compared to a healthy subject. For example, with respect to a subject experiencing a particular disorder, an effective amount can be one that improves a diagnostic parameter, measurement, marker, etc. of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90%, where 100% is defined as the diagnostic parameter, measurement, marker, etc. exhibited by a healthy subject.

[0281] In some embodiments, a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, may be administered (e.g., orally) at a dosage level of from about 0.01 mg / kg to about 50 mg / kg, or from about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times per day to achieve the desired therapeutic effect.

[0282] For oral administration, the compositions may be provided in the form of tablets, capsules, and the like containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient.

[0283] In some embodiments, a dose of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, is contained in a "unit dosage form." The phrase "unit dosage form" refers to a physically discrete unit, each unit containing a predetermined amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, either alone or in combination with one or more additional substances, sufficient to produce a desired effect. It will be understood that the parameters of the unit dosage form will depend on the particular substances and the effect to be achieved.

[0284] kit The present invention also contemplates kits comprising compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, as well as pharmaceutical compositions thereof. These kits are generally in the form of physical structures housing various components, as described below, that are used, for example, in practicing the methods described above.

[0285] The kit can include one or more compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subembodiments described herein, or salts thereof, can be provided in a ready-to-use form (e.g., a tablet or capsule) or in a form that requires reconstitution or dilution, for example, prior to administration (e.g., a powder). When the compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof, is in a form that requires reconstitution or dilution by the user, the kit may also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, or the like, packaged together with or separately from the compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subembodiment described herein, or a salt thereof. When combination therapy is contemplated, the kit may contain several substances individually, or they may be already combined in the kit. Each component of the kit may be enclosed in a separate container, and the various containers may all be in a single package. The kits of the present invention may be designed for the conditions required to properly maintain the components contained therein (e.g., refrigeration or freezing).

[0286] The kit may include a label or package insert defining information about the components therein and instructions for their use (e.g., dosing parameters, mechanism of action, clinical pharmacology of the active ingredient(s), including pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert may include manufacturer information, such as lot number and expiration date. The label or package insert may, for example, be integral with the physical structure that houses the component, be contained separately within the physical structure, or be affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0287] The label or package insert may additionally comprise or be incorporated into a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), electronic storage medium such as CD- or DVD-ROM / RAM, DVD, optical disk such as MP3, magnetic tape, or RAM and ROM, or hybrids thereof such as magnetic / optical storage media, FLASH media, or memory type cards, etc. In some embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, for example, via the internet, are provided. [Example]

[0288] Example The following examples and reference examples (intermediates) are presented to provide those skilled in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the experiments described below have been performed or that they are all that may be performed. It should be understood that the illustrative descriptions set forth herein are not necessarily performed, but rather, these descriptions may be performed to generate data of the nature described therein, etc. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0289] Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (° C.), and pressure is at or near atmospheric. Standard abbreviations are used, including: μg = microgram; μl or μL = microliter; mM = millimole; μM = micromole; aa = amino acid(s); AcO = acetic anhydride; AcCl = acetyl chloride; ACN = acetonitrile; AIBN = 2,2'-azobis(2-methylpropionitrile); BID = twice daily; BINAP = 2,2'-bis(diphenylphosphino)-1,1'binaphthyl; BocO or (Boc)O = di-tert-butyl dicarbonate; bp = base pair(s); BSA = bovine serum albumin; BW = body weight; d = doublet; dd = double doublet; DEAD = diethyl azodicarboxylate; DIBAL = diisobutylaluminum hydride; DIEA = N,N-diisopropylethylamine; DIPEA = N,N-diisopropylethylamine; dl or dL = deciliter; DMA = dimethyl Acetamide; DMAP = dimethylaminopyridine; DME = 1,2-dimethoxyethane; DMEM = Dulbecco's modified Eagle's medium; DMF = N,N-dimethylformamide; DMSO = dimethyl sulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; DTT = dithiothreitol; EDTA = ethylenediaminetetraacetic acid; ES = electrospray; EtOAc = ethyl acetate; EtOH = ethanol; g = grams; h or hr = hours; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HOAc = acetic acid; HPLC = high performance liquid chromatography; HPLC = high performance liquid chromatography; im = intramuscular (into muscle); ip= intraperitoneal (into the peritoneal cavity); IHC = immunohistochemistry; IPA = isopropyl alcohol; kb = kilobases; kDa = kilodaltons; kg = kilogram; l or L = liter; LC = liquid chromatography; LCMS = liquid chromatography and mass spectrometry; m / z = mass to charge ratio; M = mole; m = multiplet; MeCN = acetonitrile; MeOH = methanol; MeSO2Cl = methanesulfonyl chloride; mg = milligram; min = minutes; min = minutes; ml or mL = milliliter; mM = millimole; MS = mass spectrometry; MsCl = methanesulfonyl chloride; N = normal; NADPH = nicotinamide adenine dinucleotide phosphate; NBS = N-bromosuccinimide; ng = nanogram; nm = nanometer; nM = nanomole; NMP = N-methylpyrrolidone; NMR = nuclear magnetic resonance; ns = statistics not scientifically significant; nt = nucleotide(s); PBS = phosphate-buffered saline; Pd / C = palladium on carbon; Pd2(dba)3 = tris(debenzylideneacetone)dipalladium; Pd(dppf)Cl2 = 1,1'-bis(diphenylphosphino)ferrocene-palladium(ll) dichloride; PE = petroleum ether; QD = daily; QM = monthly; QW = weekly; rac = racemic; Rt = retention time; s = singlet; s or sec = seconds; sat. = saturated; SC or SQ = subcutaneous (subcutaneously); t = triplet; TBAB = tetra-n-butylammonium bromide; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin-layer chromatography; TMSCl = trimethylsilyl chloride; TsOH = p-toluenesulfonic acid; U = units; wt = wild-type.

[0290] Synthesis Example Reference Example 1 Synthesis of 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one [ka] Process 1 Synthesis of 4-chloro-2-(phenylamino)benzoic acid [ka] To a stirred solution of 2,4-dichlorobenzoic acid (1 equiv.) in DMF (0.5 M) was added aniline (1.5 equiv.), copper(0) powder (0.5 equiv.), and potassium carbonate (2 equiv.), and the reaction mixture was stirred at 150° C. for 5 h. After completion of the reaction, the reaction mixture was brought to room temperature and filtered through a Celite pad. The resulting filtrate was acidified with 2N HCl. The solid formed was filtered and dried under vacuum to give 4-chloro-2-(phenylamino)benzoic acid as a brown solid.

[0291] Process 2 :Synthesis of 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one [ka] A mixture of 4-chloro-2-(phenylamino)benzoic acid (1 equivalent) and urea (5 equivalents) was placed in a round-bottom flask equipped with a stir bar and heated at 200° C. for 2 h. The crude material was poured into water and extracted with EtOAc. The combined organic layers were separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product. The crude material was purified by column chromatography (20-30% EtOAc / hexanes) to provide the title compound as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ = 11.82 (s, 1H), 8.04 (d, J=8.3Hz, 1H), 7.66-7.56 (m, 3H), 7.48-7.44 (m, 2H), 7.31 (dd, J=8.3, 1.9Hz, 1H), 6.31 (d, J=1.8Hz, 1H). m / z [M+H] + 273.18.

[0292] Reference Example 2 Synthesis of 7-chloro-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione [ka] Process 1 Synthesis of 4-chloro-2-(pyridin-3-ylamino)benzamide [ka]

[0293] To a stirred solution of 2,4-dichlorobenzamide (1 eq.) in DMF (0.5 M) was added 3-aminopyridine (1.5 eq.), copper(0) powder (0.5 eq.) and potassium carbonate (2 eq.), and the reaction mixture was stirred at 150° C. for 5 h. After completion of the reaction, the reaction mixture was brought to room temperature and filtered through a Celite pad. The resulting filtrate was acidified with 2N HCl. The solid formed was filtered and dried under vacuum to give the title compound as a brown solid. m / z [M+H] + 249.1.

[0294] Process 2 Synthesis of 7-chloro-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione [ka] A vial was charged with 4-chloro-2-(pyridin-3-ylamino)benzamide (1.0 equiv.) and DMF (0.2 M). To the reaction vessel was added NaH (60% in mineral oil, 3.0 equiv.) at 0° C., and the reaction mixture was stirred at room temperature for 10 minutes. To the vessel was added CDI (1.5 equiv.), and the reaction mixture was stirred at room temperature for 20 minutes. The reaction was quenched by the addition of MeOH (0.5 mL) and AcOH (0.2 mL). The crude reaction mixture was directly purified by reverse-phase column chromatography (20-75% MeCN / water, 0.1% formic acid). 1 H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.69 (d, J=4.9Hz, 1H), 8.61 (s, 1H), 7.99 (d, J=8.4Hz, 1H), 7.91 (d, J=7.9Hz, 1H), 7.68-7.50 (m, 1H), 7.27 (d, J=8.6Hz, 1H), 6.32 (s, 1H). m / z [M+H]+ 274.0.

[0295] Proceeding as described in Reference Example 2, Step 1, 2-((2-chlorophenyl)amino)-6-cyclopropyl-nicotinamide was prepared using 2-chloroaniline and 2-chloro-6-cyclopropylnicotinamide instead of 3-aminopyridine and 2,4-dichlorobenzamide, respectively. [ka]

[0296] Proceeding as described in step 2 above, the following compounds were prepared:

[0297] 7-Chloro-1-(pyridin-4-yl)quinazoline-2,4(1H,3H)-dione was prepared using 4-chloro-2-(pyridin-4-ylamino)benzamide. [ka]

[0298] 1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinamide. [ka]

[0299] 1-(2-Bromophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 2-((2-bromophenyl)amino)-6-(trifluoromethyl)nicotinamide. [ka]

[0300] 1-(2-Fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 2-((2-fluorophenyl)amino)-6-(trifluoromethyl)nicotinamide. [ka]

[0301] 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile was prepared using 4-chloro-2-((3-cyanophenyl)amino)benzamide. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.13-8.00 (m, 3H), 7.85 (dd, J=8.3, 1.7Hz, 2H), 7.34 (dt, J=8.5, 1.7Hz, 1H), 6.43 (d, J=1.7Hz, 1H). [ka]

[0302] Reference Example 3 Synthesis of 7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione [ka] Process 1 Synthesis of 4-chloro-2-fluoro-6-(phenylamino)benzoic acid [ka] To a stirred solution of aniline (2 equivalents) in THF (1M) was added LDA (3 equivalents) at −78° C., and the reaction mixture was stirred for 10 minutes. 4-Chloro-2,6-difluorobenzoic acid (1 equivalent) in THF (1M) was added at −78° C., and the reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction, the crude material was poured into 1N HCl solution and extracted with EtOAc. The combined organic layers were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired 4-chloro-2-fluoro-6-(phenylamino)benzoic acid as a pale yellow solid.

[0303] Process 2 :Synthesis of 4-chloro-2-fluoro-6-(phenylamino)benzamide [ka] To a stirred solution of 4-chloro-2-fluoro-6-(phenylamino)benzoic acid (1 eq.) in DMF (0.4 M), HATU (1.5 eq.) and DIPEA (5 eq.) were added at room temperature and stirred for 30 minutes. Ammonium chloride (5 eq.) was added to the reaction mixture and stirring was continued at room temperature for 16 h. After completion, the crude material was poured into ice-cold water, stirred for 30 minutes, and the solid was filtered and dried under vacuum to give 4-chloro-2-fluoro-6-(phenylamino)benzamide as an off-white solid.

[0304] Process 3 Synthesis of 7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione [ka] To a stirred solution of 4-chloro-2-fluoro-6-(phenylamino)benzamide (1 equiv.) in DMF (0.33 M) was added NaH (2.2 equiv.) at 0° C. and the reaction was stirred for 30 min. CDI (1.1 equiv.) was added to the reaction mixture at 0° C. and stirring was continued for 30 min at 0° C. The crude material was poured into ice-cold water, the mixture was stirred for 30 min, and the solid was filtered and dried under vacuum to afford the title compound (1.1 g, 57%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.77 (br s, 1H), 7.61 (m, 3H), 7.44 (m, 2H), 7.29 (dd, J=10.8, 1.8Hz, 1H), 6.10 (s, 1H). m / z [M+H] + 291.3.

[0305] Proceeding as described in Reference Example 3, Step 2 above, the following compounds were prepared:

[0306] 2-Chloro-4-methoxy-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinic acid. [ka]

[0307] 2,6-Dichloro-4-(trifluoromethyl)benzamide was prepared using 2,6-dichloro-4-(trifluoromethyl)benzoic acid. [ka]

[0308] 5-Bromo-2-fluoro-4-(trifluoromethyl)benzamide was prepared using 5-bromo-2-fluoro-4-(trifluoromethyl)benzoic acid. [ka]

[0309] Reference Example 4 Synthesis of 7-chloro-1-[3-(methoxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione [ka]

[0310] Process 1Synthesis of 4-chloro-2-((3-(methoxymethyl)phenyl)amino)benzamide [ka] A vial was charged under atmospheric pressure with 2-amino-4-chlorobenzamide (1.0 equiv.), copper chloride (0.15 equiv.), 3-(methoxymethyl)phenylboronic acid (1.5 equiv.), and triethylamine (0.5 equiv.). To this reaction vessel, MeOH (0.4 M) was added, and the reaction mixture was stirred at room temperature for 3-12 h. The crude reaction mixture was directly purified by reverse-phase chromatography (20-65% MeCN / water) to yield the title compound. m / z [M+H] + 291.1.

[0311] Process 2 Synthesis of 7-chloro-1-[3-(methoxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione [ka] A vial was charged with 4-chloro-2-((3-(methoxymethyl)phenyl)-amino)benzamide (1.0 equiv.) and DMF (0.2 M) under nitrogen. To this reaction mixture at 0° C. was added NaH (60% in mineral oil, 3.0 equiv.), and the reaction mixture was stirred at room temperature for 10 minutes. CDI (1.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched by the addition of MeOH and AcOH. The crude reaction mixture was directly purified by reverse-phase column chromatography (20-75% MeCN / water, 0.1% formic acid) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.03 (dd, J=8.4, 1.3Hz, 1H), 7.60 (t, J=7.6Hz, 1H), 7.50 (d, J=7.8Hz, 1H), 7.41-7.34 (m, 2H), 7.30 (dt, J=8.4, 1.7Hz, 1H), 6.30 (t, J=1.6Hz, 1H), 4.50 (s, 2H). m / z [M+H] + 317.1.

[0312] Proceeding similarly as above, the following compounds were prepared:

[0313] 7-Chloro-1-(3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting 3-hydroxyphenylboronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0314] 7-Chloro-1-[3-(2-hydroxyethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-(methoxymethyl)phenylboronic acid with (3-(2-hydroxyethyl)phenyl)boronic acid. [ka]

[0315] 7-Chloro-1-(3-fluorophenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting (3-fluorophenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0316] 7-Chloro-1-(3-methylphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting m-tolylboronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0317] 7-Chloro-1-[3-(3-hydroxypropyl)phenyl]-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-(methoxymethyl)phenylboronic acid with 3-(3-hydroxypropyl)phenylboronic acid. [ka]

[0318] 7-Chloro-1-(3-chlorophenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-(methoxymethyl)phenylboronic acid with (3-chlorophenyl)boronic acid. [ka]

[0319] 7-Chloro-1-[3-(hydroxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-(methoxymethyl)phenylboronic acid with (3-(hydroxymethyl)phenyl)boronic acid. [ka]

[0320] 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile was prepared by substituting (3-cyanophenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0321] tert-Butyl (3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzyl)carbamate was prepared by substituting 3-(tert-butoxycarbonylamino)methyl)phenylboronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0322] 7-Chloro-1-(3-methoxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting (3-methoxyphenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0323] 7-Chloro-1-(5-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting 3-fluoro-5-hydroxyphenylboronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0324] 7-Chloro-1-(4-fluorophenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-(methoxymethyl)phenylboronic acid with (4-fluorophenyl)boronic acid. [ka]

[0325] 7-Chloro-1-(2-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting 2-fluoro-3-hydroxyphenylboronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0326] 7-Chloro-1-(4-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting 4-fluoro-3-hydroxyphenylboronic acid for 3-(methoxymethyl)phenylboronic acid. [ka]

[0327] Reference Example 5 : Synthesis of 1-[3-(aminomethyl)phenyl]-7-chloro-1,3-dihydroquinazoline-2,4-dione [ka]

[0328] A vial was charged under nitrogen with tert-butyl (3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzyl)carbamate (1.0 equiv.) and MeCN (0.2 M), 4N HCl / dioxane (10 equiv.) was added, and the reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated, and the crude reaction mixture was directly purified by reverse-phase purification (10-45% MeCN / water, 0.1% formic acid) to give the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.05 (d, J=8.4Hz, 1H), 7.60 (d, J=7.3Hz, 2H), 7.44 (s, 1H), 7.39-7.23 (m, 2H), 6.35 (s, 1H), 3.93 (s, 3H). m / z [M+H] + 302.0.

[0329] Reference Example 6 Synthesis of 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione [ka] Process 1:Synthesis of 2,4-dichloro-N-(o-tolylcarbamoyl)benzamide [ka] A slurry of 2,4-dichlorobenzamide (1 equiv.) in DCE (0.5 M) was treated dropwise with oxalyl chloride (1.35 equiv.) at room temperature. The reaction mixture was then warmed to 55° C. for 1 h and then heated at reflux for an additional 20 h. The reaction mixture was concentrated in vacuo to provide the crude material as a yellow oil. A solution of this crude isocyanate in DCE (1.2 M) at 0° C. was added dropwise to a cooled solution of o-toluidine (0.4 M) in DCE. The ice bath was removed and the reaction mixture was stirred at room temperature for 45 min. The solid was filtered, washed with DCM, and dried to give the title compound as a white solid. m / z [M+H] + 324.0.

[0330] Process 2 Synthesis of 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione [ka] A slurry of 2,4-dichloro-N-(o-tolylcarbamoyl)benzamide in DME:toluene (0.06 M, 1:1 v / v) was cooled to 0 °C and treated portionwise with NaH (60% dispersion in oil, 3.1 equiv.). After the addition, the ice bath was removed and the reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to RT and poured into 20% aqueous HCl. The resulting mixture was stirred vigorously and the off-white solid was filtered, washed with EtO, and dried to give the crude product, which was used in the next step without purification. m / z [M+H] + 287.0.

[0331] Proceeding similarly as described in step 1 above, the following compounds were prepared:

[0332] 4-(1,1-Difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide was prepared by replacing o-toluidine with imidazo[1,2-a]pyridin-5-amine and 2,4-dichlorobenzamide with 4-(1,1-difluoroethyl)-2-fluorobenzamide. [ka]

[0333] 5-Cyano-4-cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide was prepared using 5-cyano-4-cyclopropyl-2-fluorobenzamide as the 2,4-dichlorobenzamide. [ka]

[0334] N-((2-chlorophenyl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide was prepared by substituting 2-chloroaniline for o-toluidine and using 4-(1,1-difluoroethyl)-2-fluorobenzamide for 2,4-dichlorobenzamide (Pharmablock, PBU1050). [ka]

[0335] 4-Chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide was prepared by replacing o-toluidine with imidazo[1,2-a]pyridin-5-amine and 2,4-dichlorobenzamide with 4-chloro-2-fluorobenzamide. [ka]

[0336] 4-Chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide was prepared by replacing o-toluidine with imidazo[1,2-a]pyridin-7-amine and 2,4-dichlorobenzamide with 4-chloro-2-fluorobenzamide. [ka]

[0337] N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was synthesized by using 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-chloroaniline for o-toluidine. [ka]

[0338] 2,4-Dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyrimidin-2-amine for 2,4-dichlorobenzamide. [ka]

[0339] 4-Cyclopropyl-2-fluoro-N-((3-methylpyrazin-2-yl)carbamoyl)benzamide was synthesized using 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 3-methylpyrazin-2-amine for o-toluidine. [ka]

[0340] 4-Cyclopropyl-2-fluoro-N-(pyrazin-2-ylcarbamoyl)benzamide was synthesized using 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and pyrazin-2-amine for o-toluidine. [ka]

[0341] 4-Cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide was synthesized using 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and imidazo[1,2-a]pyridin-5-amine for o-toluidine. [ka]

[0342] N-((3-chloropyridin-2-yl)carbamoyl)-4-ethyl-2-fluorobenzamide was prepared by substituting 3-chloropyridin-2-amine for o-toluidine and 4-ethyl-2-fluorobenzamide for 2,4-dichlorobenzamide. [ka]

[0343] N-((3-chloropyridin-2-yl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide was prepared by replacing o-toluidine with 3-chloropyridin-2-amine and 2,4-dichlorobenzamide with 4-(1,1-difluoroethyl)-2-fluorobenzamide. [ka]

[0344] 4-(1,1-Difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide was prepared by replacing o-toluidine with imidazo[1,2-a]pyridin-7-amine and 2,4-dichlorobenzamide with 4-(1,1-difluoroethyl)-2-fluorobenzamide. [ka]

[0345] 2-Fluoro-N-(pyrazin-2-ylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 2-fluoro-4-(trifluoromethyl)benzamide and o-toluidine with pyrazin-2-amine. [ka]

[0346] 2-Fluoro-N-(pyridazin-3-ylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and pyridazin-3-amine for o-toluidine. [ka]

[0347] 2-Fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared by replacing 2,4-dichlorobenzamide with 2-fluoro-4-(trifluoromethoxy)benzamide and o-toluidine with imidazo[1,2-a]pyridin-5-amine. [ka]

[0348] 2-Chloro-4-cyclopropyl-N-((3-(trifluoromethyl)pyrazin-2-yl)carbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 2-chloro-4-cyclopropylbenzamide and o-toluidine with 3-(trifluoromethyl)pyrazin-2-amine. [ka]

[0349] 5-Bromo-2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared by substituting 5-bromo-2-fluoro-4-(trifluoromethoxy)benzamide for 2,4-dichlorobenzamide. [ka]

[0350] 5-Bromo-2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared by replacing 2,4-dichlorobenzamide with 5-bromo-2-fluoro-4-(trifluoromethoxy)benzamide and o-toluidine with aniline. [ka]

[0351] 4-Bromo-N-((2-chlorophenyl)carbamoyl)-2,5-difluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 4-bromo-2,5-difluorobenzamide and o-toluidine with 2-chloroaniline. [ka]

[0352] 2,6-Difluoro-4-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 2,6-difluoro-4-(trifluoromethyl)benzamide and o-toluidine with 2-(trifluoromethyl)pyridin-3-amine. [ka]

[0353] 4-Cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 4-cyclopropyl-2-fluorobenzamide and o-toluidine with imidazo[1,2-a]pyridin-7-amine. [ka]

[0354] 2-Chloro-N-((2-chloropyridin-3-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared by replacing 2,4-dichlorobenzamide with 2-chloro-6-(trifluoromethyl)nicotinamide and o-toluidine with 2-chloropyridin-3-amine. [ka]

[0355] 2-Chloro-6-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)nicotinamide was prepared by replacing 2,4-dichlorobenzamide with 2-chloro-6-(trifluoromethyl)nicotinamide and o-toluidine with 2-(trifluoromethyl)pyridin-3-amine. [ka]

[0356] 5-Bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)phenyl)carbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 5-bromo-4-cyclopropyl-2-fluorobenzamide and o-toluidine with 2-(trifluoromethyl)aniline. [ka]

[0357] 5-Bromo-4-cyclopropyl-N-((2-cyclopropylphenyl)carbamoyl)-2-fluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 5-bromo-4-cyclopropyl-2-fluorobenzamide and o-toluidine with 2-cyclopropylaniline. [ka]

[0358] 5-Bromo-N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 5-bromo-4-cyclopropyl-2-fluorobenzamide and o-toluidine with 2-bromoaniline. [ka]

[0359] 5-Bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 5-bromo-4-cyclopropyl-2-fluorobenzamide and o-toluidine with 2-(trifluoromethyl)pyridin-3-amine. [ka]

[0360] 5-Bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 5-bromo-2-fluoro-4-(trifluoromethyl)benzamide and o-toluidine with 2-chloroaniline. [ka]

[0361] 5-Bromo-N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 5-bromo-4-cyclopropyl-2-fluorobenzamide and o-toluidine with 2-chloropyridin-3-amine. [ka]

[0362] N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide was prepared by replacing 2,4-dichlorobenzamide with 4-cyclopropyl-2-fluoro-6-methoxybenzamide and o-toluidine with 2-chloropyridin-3-amine. [ka]

[0363] N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 4-cyclopropyl-2-fluorobenzamide and o-toluidine with 2-chloropyridin-3-amine. [ka]

[0364] 2-Fluoro-4-(trifluoromethyl)-N-((1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)carbamoyl)benzamide was prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-amine for o-toluidine. [ka]

[0365] 2-Fluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 2-fluoro-4-(trifluoromethyl)benzamide and o-toluidine with aniline. [ka]

[0366] N-((3-chloropyridin-2-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 4-cyclopropyl-2-fluorobenzamide and o-toluidine with 3-chloropyridin-2-amine. [ka]

[0367] 4-Cyclopropyl-2-fluoro-N-(pyrimidin-5-ylcarbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and pyrimidin-5-amine for o-toluidine. [ka]

[0368] 4-Cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 4-cyclopropyl-2-fluorobenzamide. [ka]

[0369] 2-Fluoro-4-(trifluoromethyl)-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide was prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine for o-toluidine. [ka]

[0370] 4-Cyclopropyl-2-fluoro-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine for o-toluidine. [ka]

[0371] N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 4-cyclopropyl-2-fluorobenzamide and o-toluidine with 2-bromoaniline. [ka]

[0372] 4-Cyclopropyl-2-fluoro-6-methoxy-N-(pyridin-3-ylcarbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 4-cyclopropyl-2-fluoro-6-methoxybenzamide and o-toluidine with pyridin-3-amine. [ka]

[0373] 4-Cyclopropyl-2-fluoro-6-methoxy-N-(o-tolylcarbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluoro-6-methoxybenzamide for 2,4-dichlorobenzamide. [ka]

[0374] 4-Chloro-N-((2-chlorophenyl)carbamoyl)-2,6-difluorobenzamide was prepared by replacing 2,4-dichlorobenzamide with 4-chloro-2,6-difluorobenzamide and o-toluidine with 2-chloroaniline. [ka]

[0375] 4-Chloro-2,6-difluoro-N-(o-tolylcarbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 4-chloro-2,6-difluorobenzamide. [ka]

[0376] N-(benzylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide was prepared by replacing 2,4-dichlorobenzamide with 2-chloro-6-(trifluoromethyl)nicotinamide and o-toluidine with benzylamine. [ka]

[0377] 4-Cyclopropyl-2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide was prepared by replacing 2,4-dichlorobenzamide with 4-cyclopropyl-2-fluorobenzamide and o-toluidine with 2-methylpyridin-3-amine. [ka]

[0378] 2-Chloro-N-((2-chloro-6-fluorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared by replacing 2,4-dichlorobenzamide with 2-chloro-6-(trifluoromethyl)nicotinamide and o-toluidine with 2-chloro-6-fluoroaniline. [ka]

[0379] Proceeding similarly as described in step 2 above, the following compounds were prepared:

[0380] 7-Chloro-1-(2-fluorophenyl)quinazoline-2,4(1H,3H)-dione was prepared by replacing o-toluidine with 2-fluoroaniline. [ka]

[0381] 1-(3-Bromophenyl)-7-chloroquinazoline-2,4(1H,3H)-dione was prepared by replacing o-toluidine with 3-bromoaniline. [ka]

[0382] 7-(1,1-Difluoroethyl)-1-(imidazo[1,2-a]pyridin-8-yl)quinazoline-2,4(1H,3H)-dione was prepared using 4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide. [ka]

[0383] 7-Cyclopropyl-2,4-dioxo-1-(o-tolyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile was prepared using 5-cyano-4-cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide. [ka]

[0384] 7-Chloro-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione was prepared using 4-chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide. [ka]

[0385] 7-Chloro-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione was prepared using 4-chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide. [ka]

[0386] 1-(2-Chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared using N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide. [ka]

[0387] Reference Example 7 Synthesis of bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione [ka] Process 1 Synthesis of 4-cyclopropyl-2-fluorobenzamide [ka] A vial was charged with 4-bromo-2-fluorobenzamide (1 equiv.), cyclopropylboronic acid (3 equiv.), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.1 equiv.). A 1:1 mixture of toluene:t-butanol (0.1 M) was added, followed by aqueous potassium carbonate (2 M, 4 equiv.). The reaction mixture was heated at 100°C for 2 h and then cooled. The crude reaction mixture was diluted with ethyl acetate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-100% ethyl acetate / hexanes) to give the title compound.

[0388] Process 2 Synthesis of 5-bromo-4-cyclopropyl-2-fluorobenzamide [ka] A vial was charged with 4-cyclopropyl-2-fluorobenzamide (1 equivalent) and N-bromo-succinimide (1.2 equivalents). Trifluoroacetic acid (0.5 M) was added, followed by a catalytic amount of sulfuric acid. The reaction mixture was heated at 40° C. for 2 h and then cooled. The crude reaction mixture was poured into water and the title compound was collected by filtration.

[0389] Process 3 Synthesis of 5-bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide [ka] A slurry of 5-bromo-4-cyclopropyl-2-fluorobenzamide (1 equiv.) in DCE (0.5 M) was treated dropwise with oxalyl chloride (1.35 equiv.) at room temperature. The reaction mixture was then warmed to 55° C. for 1 h and then heated at reflux for an additional 20 h. The reaction mixture was concentrated in vacuo to provide the crude material as a yellow oil. A 0° C. solution of this crude isocyanate in DCE (1.2 M) was added dropwise to a cooled solution of 2-chloroaniline (0.4 M) in DCE. The ice bath was removed and the reaction mixture was stirred at room temperature for 45 min. The solid was filtered, washed with DCM, and dried to give the title compound as a white solid.

[0390] Process 4 Synthesis of 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione [ka] A slurry of 5-bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide in DME:toluene (0.06 M, 1:1 v / v) was cooled to 0 °C and treated portionwise with NaH (60% dispersion in oil, 3.1 equiv.). After the addition, the ice bath was removed and the reaction mixture was heated at reflux for 18 h. The reaction mixture was cooled to RT and poured into 20% aqueous HCl. The resulting mixture was stirred vigorously and the off-white solid was filtered, washed with EtO and dried to give the crude product, which was used in the next step without purification. m / z [M+H] + 392.0.

[0391] Reference Example 8 Synthesis of 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide [ka]

[0392] A slurry of 2,4-dichlorobenzamide (1 equiv.) in DCE (0.5 M) was treated dropwise with oxalyl chloride (1.35 equiv.) at room temperature. The reaction mixture was then warmed to 55° C. for 1 h and then heated at reflux for an additional 20 h. The reaction mixture was concentrated in vacuo to provide crude 2,4-dichlorobenzoyl isocyanate as a yellow oil. A 0° C. solution of this crude product in DCE (1.2 M) was added dropwise to a cooled solution of pyrazin-2-amine in DCE (0.4 M). The ice bath was removed and the reaction mixture was stirred at room temperature for 45 min. The solid was then filtered, washed with DCM, and dried to give the title compound as a white solid. m / z [M+H] + 311.0.

[0393] Proceeding similarly as above, the following compounds were prepared:

[0394] 2,4-Dichloro-N-(pyridin-2-ylcarbamoyl)benzamide [ka]

[0395] 2,4-Dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyridin-2-amine. [ka]

[0396] 2,4-Dichloro-N-(pyridazin-3-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyridazin-3-amine. [ka]

[0397] 2,4-Dichloro-N-(pyrimidin-5-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyrimidin-5-amine. [ka]

[0398] N-((1H-pyrazol-4-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using 2,4-dichlorobenzamide and 1H-pyrazol-4-amine. [ka]

[0399] N-((1H-imidazol-2-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using 2,4-dichlorobenzamide and 1H-imidazol-2-amine. [ka]

[0400] 2,4-Dichloro-N-(thiazol-2-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and thiazol-2-amine. [ka]

[0401] 2,4-Dichloro-N-(thiazol-5-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and thiazol-5-amine. [ka]

[0402] N-((1H-pyrazol-5-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using 2,4-dichlorobenzamide and 1H-pyrazol-5-amine. [ka]

[0403] 2-Chloro-N-((2-chlorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and 2-chloroaniline. [ka]

[0404] 2-Chloro-N-((3-methylpyridin-2-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and 3-methylpyridin-2-amine. [ka]

[0405] 2-Chloro-N-((3-chloropyridin-2-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and 3-chloropyridin-2-amine. [ka]

[0406] 2-Chloro-6-isopropyl-N-(phenylcarbamoyl)nicotinamide was prepared using 2-chloro-6-isopropylnicotinamide and aniline. [ka]

[0407] 2,6-Difluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2,6-difluoro-4-(trifluoromethyl)benzamide and aniline. [ka]

[0408] 2-Fluoro-N-((2-methylpyridin-3-yl)carbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2-fluoro-4-(trifluoromethyl)benzamide and 2-methylpyridin-3-amine. [ka]

[0409] N-((2-chlorophenyl)carbamoyl)-2-fluoro-4-(trifluoromethoxy)benzamide was prepared using 2-fluoro-4-(trifluoromethoxy)benzamide and 2-methylpyridin-3-amine. [ka]

[0410] 4-Bromo-5-chloro-N-((2-chlorophenyl)carbamoyl)-2-fluorobenzamide was prepared using 4-bromo-5-chloro-2-fluorobenzamide and 2-chloroaniline. [ka]

[0411] 4-Cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide was prepared using 4-cyclopropyl-2-fluorobenzamide and 2-(trifluoromethyl)pyridin-3-amine. [ka]

[0412] 4-Cyclopropyl-N-((2-(difluoromethoxy)pyridin-3-yl)carbamoyl)-2-fluorobenzamide was prepared using 4-cyclopropyl-2-fluorobenzamide and 2-(trifluoromethoxy)pyridin-3-amine. [ka]

[0413] Reference Example 9 Synthesis of 7-chloro-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione [ka]

[0414] A slurry of 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide in DMF (0.06 M) was treated dropwise with KHMDS (3 equiv.) at rt. The reaction mixture was heated at 95° C. for 18 h. Water was added to the reaction mixture, and upon completion, the product was fully solubilized, which was immediately purified by reverse-phase column chromatography (20-60% MeCN / water, 0.1% formic acid) to give the title compound. m / z [M+H] + 276.0.

[0415] Proceeding similarly as above and substituting 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide, the following compounds were prepared:

[0416] 7-Chloro-1-(pyridin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,4-dichloro-N-(pyridin-2-ylcarbamoyl)benzamide. [ka]

[0417] 7-Chloro-1-(pyrimidin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,4-dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide. [ka]

[0418] 7-Chloro-1-(pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,4-dichloro-N-(pyridazin-3-ylcarbamoyl)benzamide. [ka]

[0419] 7-Chloro-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,4-dichloro-N-(pyrimidin-5-ylcarbamoyl)benzamide. [ka]

[0420] 7-Chloro-1-(1H-pyrazol-4-yl)quinazoline-2,4(1H,3H)-dione was prepared by using N-((1H-pyrazol-4-yl)carbamoyl)-2,4-dichlorobenzamide. [ka]

[0421] 7-Chloro-1-(1H-imidazol-2-yl)quinazoline-2,4(1H,3H)-dione was prepared by using N-((1H-imidazol-2-yl)carbamoyl)-2,4-dichlorobenzamide. [ka]

[0422] 7-Chloro-1-(thiazol-2-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,4-dichloro-N-(thiazol-2-ylcarbamoyl)benzamide. [ka]

[0423] 7-Chloro-1-(thiazol-5-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,4-dichloro-N-(thiazol-5-ylcarbamoyl)benzamide. [ka]

[0424] 7-Chloro-1-(1H-pyrazol-5-yl)quinazoline-2,4(1H,3H)-dione was prepared by using N-((1H-pyrazol-5-yl)carbamoyl)-2,4-dichlorobenzamide. [ka]

[0425] 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using N-((2-chlorophenyl)carbamoyl)-2-fluoro-6-(trifluoromethyl)nicotinamide. [ka]

[0426] 1-(3-chloropyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using N-((2-chlorophenyl)carbamoyl)-2-fluoro-6-(trifluoromethyl)nicotinamide. [ka]

[0427] 1-(3-methylpyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 2-fluoro-N-((3-methylpyridin-2-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide. [ka]

[0428] 7-Isopropyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was used as 2-fluoro-6-isopropyl-N-(phenylcarbamoyl)nicotinamide. [ka]

[0429] 5-Fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,6-difluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide. [ka]

[0430] 1-(2-Methylpyridin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)-4-(trifluoromethyl)benzamide. [ka]

[0431] 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione was prepared by using N-((2-chlorophenyl)carbamoyl)-2-fluoro-4-(trifluoromethoxy)benzamide. [ka]

[0432] 7-Bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-bromo-5-chloro-N-((2-chlorophenyl)carbamoyl)-2-fluorobenzamide. [ka]

[0433] 7-Cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide. [ka]

[0434] 7-Cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-N-((2-(difluoromethoxy)pyridin-3-yl)carbamoyl)-2-fluorobenzamide. [ka]

[0435] 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione was prepared by using N-((2-chlorophenyl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide. [ka]

[0436] 7-Chloro-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2,6-dichloro-N-((2-fluorophenyl)carbamoyl)nicotinamide. [ka]

[0437] 7-Chloro-1-(2-chlorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2,6-dichloro-N-((2-chlorophenyl)carbamoyl)nicotinamide. [ka]

[0438] 7-Chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2,6-dichloro-N-(o-tolylcarbamoyl)nicotinamide. [ka]

[0439] 7-Chloro-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2,6-dichloro-N-(phenylcarbamoyl)nicotinamide. [ka]

[0440] 7-Chloro-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2,6-dichloro-N-(pyridin-3-ylcarbamoyl)nicotinamide. [ka]

[0441] 6-Bromo-1-phenyl-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione was prepared by using 5-bromo-2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethoxy)benzamide. [ka]

[0442] 6-Bromo-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione was prepared by using 5-bromo-2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethoxy)benzamide. [ka]

[0443] 7-Cyclopropyl-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 2-chloro-4-cyclopropyl-N-((3-(trifluoromethyl)pyrazin-2-yl)carbamoyl)benzamide. [ka]

[0444] 1-(Imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione was prepared by using 2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)-4-(trifluoromethoxy)benzamide. [ka]

[0445] 1-(pyridazin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2-fluoro-N-(pyridazin-3-ylcarbamoyl)-4-(trifluoromethyl)benzamide. [ka]

[0446] 1-(pyrazin-2-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2-fluoro-N-(pyrazin-2-ylcarbamoyl)-4-(trifluoromethyl)benzamide. [ka]

[0447] 7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide. [ka]

[0448] 5-Fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,6-difluoro-4-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide. [ka]

[0449] 7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide. [ka]

[0450] 7-Cyclopropyl-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-2-fluoro-N-(pyrazin-2-ylcarbamoyl)benzamide. [ka]

[0451] 7-Cyclopropyl-1-(3-methylpyrazin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-2-fluoro-N-((3-methylpyrazin-2-yl)carbamoyl)benzamide. [ka]

[0452] 1-(3-chloropyridin-2-yl)-7-ethylquinazoline-2,4(1H,3H)-dione was prepared by using N-((3-chloropyridin-2-yl)carbamoyl)-4-ethyl-2-fluorobenzamide. [ka]

[0453] 1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione was prepared by using N-((3-chloropyridin-2-yl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide. [ka]

[0454] 7-(1,1-Difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide. [ka]

[0455] 1-(2-Chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile was prepared using N-((2-chlorophenyl)carbamoyl)-5-cyano-2-fluoro-4-(trifluoromethyl)benzamide. [ka]

[0456] 7-Bromo-1-(2-chlorophenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione was prepared by using 4-bromo-N-((2-chlorophenyl)carbamoyl)-2,5-difluorobenzamide. [ka]

[0457] 1-(2-chloropyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2-chloro-N-((2-chloropyridin-3-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide. [ka]

[0458] 7-(Trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2-chloro-6-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)nicotinamide. [ka]

[0459] 6-Bromo-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)quinazoline-2,4(1H,3H)-dione was prepared by using 5-bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)phenyl)-carbamoyl)benzamide. [ka]

[0460] 6-Bromo-7-cyclopropyl-1-(2-cyclopropylphenyl)quinazoline-2,4(1H,3H)-dione was prepared by using 5-bromo-4-cyclopropyl-N-((2-cyclopropylphenyl)carbamoyl)-2-fluorobenzamide. [ka]

[0461] 6-Bromo-1-(2-bromophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared by using 5-bromo-N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide. [ka]

[0462] 6-Bromo-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 5-bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide. [ka]

[0463] 5-Chloro-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2,6-dichloro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide. [ka]

[0464] 1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione was prepared by using N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide. [ka]

[0465] 1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared by using N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide. [ka]

[0466] 7-(Trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2-fluoro-4-(trifluoromethyl)-N-((1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)carbamoyl)benzamide. [ka]

[0467] 1-Phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide. [ka]

[0468] 1-(3-chloropyridin-2-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared by using N-((3-chloropyridin-2-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide. [ka]

[0469] 7-Cyclopropyl-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione was prepared from 4-cyclopropyl-2-fluoro-N-(pyrimidin-5-ylcarbamoyl)benzamide. [ka]

[0470] 7-(Trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2-fluoro-4-(trifluoromethyl)-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide. [ka]

[0471] 7-Cyclopropyl-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazoline-2,4(1H,3H)-dione was prepared by using 2-chloro-4-cyclopropyl-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide. [ka]

[0472] 1-(2-Bromophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared by using N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide. [ka]

[0473] 7-Cyclopropyl-5-methoxy-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-2-fluoro-6-methoxy-N-(pyridin-3-ylcarbamoyl)benzamide. [ka]

[0474] 7-Cyclopropyl-5-methoxy-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-2-fluoro-6-methoxy-N-(o-tolylcarbamoyl)benzamide. [ka]

[0475] 7-Chloro-5-fluoro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-chloro-2,6-difluoro-N-(o-tolylcarbamoyl)benzamide. [ka]

[0476] 1-Benzyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using N-(benzylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide. [ka]

[0477] 7-Cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared by using 4-cyclopropyl-2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide. [ka]

[0478] 1-(2-chloro-6-fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2-chloro-N-((2-chloro-6-fluorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide. [ka]

[0479] 5-Methoxy-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared by using 2-chloro-4-methoxy-N-(phenylcarbamoyl)-6-(trifluoromethyl)nicotinamide. [ka]

[0480] Reference Example 10 Synthesis of 7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione [ka] Process 1 :Synthesis of 4-chloro-2,5-difluorobenzamide [ka] To a stirred solution of 4-chloro-2,5-difluorobenzoic acid (1 equiv.) in THF (0.9 M) in a sealed flask at 0 °C, DIPEA (5 equiv.), HATU (1.2 equiv.), and NH (0.4 M in THF, 3 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 16 h, and the progress of the reaction was monitored by TLC. The reaction mixture was stirred with crushed ice for 2 h, then filtered and dried under high vacuum to give 4-chloro-2,5-difluorobenzamide as a white solid.

[0481] Process 2 Synthesis of 4-chloro-2,5-difluoro-N-(phenylcarbamoyl)benzamide [ka] To a stirred solution of 4-chloro-2,5-difluorobenzamide (1 equivalent) in toluene (0.5 M) was added phenyl isocyanate (1 equivalent), and the resulting reaction mixture was refluxed for 16 h. The reaction mixture was diluted with EtOAc and then washed with water. The combined organic layers were separated, dried over anhydrous sodium sulfate, and then concentrated. The crude material was purified by column chromatography (10% EtOAc / hexane) to provide the title compound as an off-white solid.

[0482] Process 3 Synthesis of 7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione [ka] To a stirred solution of 4-chloro-2,5-difluoro-N-(phenylcarbamoyl)benzamide (1 equiv.) in THF (0.25 M) was added KHMDS (1 M in THF, 1 equiv.) at 0° C. The resulting reaction mixture was warmed to RT, and 18-crown-6 (0.01 g, catalytic) was added. After heating at 75° C. for 4 h, the reaction mixture was diluted with EtOAc and then washed with water. The organic layer was dried over sodium sulfate and concentrated. The crude solid was washed with diethyl ether and n-pentane, then filtered and dried under high vacuum to give the title compound as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.13-11.95 (m, 1 H), 7.96 (d, J=8.61Hz, 1 H), 7.77-7.55 (m, 3 H), 7.46 (m, 2 H), 6.43 (d, J=5.89Hz, 1 H). m / z [M+H] + 291.13.

[0483] Proceeding similarly as described above in Reference Example 10, Step 2, the following compounds were prepared:

[0484] 2,6-Dichloro-N-((2-fluorophenyl)carbamoyl)nicotinamide was prepared using 1-fluoro-2-isocyanatobenzene and 2,6-dichloronicotinamide. [ka]

[0485] 2,6-Dichloro-n-((2-chlorophenyl)carbamoyl)nicotinamide was prepared using 1-chloro-2-isocyanatobenzene and 2,6-dichloronicotinamide. [ka]

[0486] 2,6-Dichloro-N-(o-tolylcarbamoyl)nicotinamide was prepared using 1-isocyanato-2-methylbenzene and 2,6-dichloronicotinamide. [ka]

[0487] 2,6-Dichloro-N-(phenylcarbamoyl)nicotinamide was prepared using 2,6-dichloronicotinamide. [ka]

[0488] 2,6-Dichloro-N-(pyridin-3-ylcarbamoyl)nicotinamide was prepared using 3-isocyanatopyridine and 2,6-dichloronicotinamide. [ka]

[0489] 2,6-Dichloro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2,6-dichloro-4-(trifluoromethyl)benzamide and 1-isocyanato-2-methylbenzene. [ka]

[0490] 2-Chloro-4-methoxy-N-(phenylcarbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinamide and phenyl isocyanate. [ka]

[0491] The following compounds were prepared in the same manner as in Step 3 of Reference Example 10 above:

[0492] 7-Cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione [ka]

[0493] 6-Bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione [ka]

[0494] 6-Bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione [ka]

[0495] Reference Example 11 Synthesis of 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione [ka] Process 1 :Synthesis of 3,4-dichloro-2-(phenylamino)benzoic acid [ka] A flask was charged with 2-amino-3,4-dichlorobenzoic acid (1 equivalent), triethylamine (4 equivalents), and bromobenzene (1 equivalent). Dioxane (1 M) and copper(II) acetate (1 equivalent) were added, and the reaction mixture was heated at 110° C. for 18 h. The reaction mixture was cooled, and additional bromobenzene (1 equivalent) was added, followed by heating at 110° C. for 24 h. The crude reaction mixture was diluted with saturated ammonium chloride solution and extracted with dichloromethane. The organic layer was washed with 1N HCl and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-50% ethyl acetate / hexanes) to give the title compound.

[0496] Process 2 :Synthesis of 3,4-dichloro-2-(phenylamino)benzamide [ka] To a stirred solution of 3,4-dichloro-2-(phenylamino)benzoic acid (1 equiv.) in THF (0.9 M) in a sealed flask at 0 °C, DIPEA (5 equiv.), HATU (1.2 equiv.), and then NH (0.4 M in THF, 3 equiv.) were added. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was stirred with crushed ice for 2 h, then filtered and dried under high vacuum to provide the title compound as a white solid.

[0497] Process 3 Synthesis of 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione [ka] A vial was charged with 3,4-dichloro-2-(phenylamino)benzamide (1.0 equiv.) and DMF (0.2 M) under nitrogen. NaH (60% in mineral oil, 3.0 equiv.) was added to the reaction vessel at 0° C., and the reaction mixture was stirred at room temperature for 10 minutes. CDI (1.5 equiv.) was added, and the reaction mixture was stirred at room temperature for 20 minutes. The reaction was quenched by the addition of MeOH (0.5 mL) and AcOH (0.2 mL). The crude reaction mixture was directly purified by reverse-phase column chromatography (20-75% MeCN / water, 0.1% formic acid). 1 H NMR (400 MHz, chloroform-d) δ 8.29 (s, 1H), 8.13 (d, J=8.5Hz, 1H), 7.48-7.43 (m, 3H), 7.29 (d, J=7.8Hz, 2H). m / z [M+H] + 307.0.

[0498] Reference Example 12 Synthesis of 7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione [ka] Process 1 Synthesis of 4-chloro-2-fluoro-3-methylbenzamide [ka] A flask was charged with 4-chloro-2-fluoro-3-methylbenzoic acid (1 equivalent), hydroxybenzotriazole (0.2 equivalents), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.5 equivalents). DMF (0.5 M) was added, followed by diisopropylethylamine (2 equivalents). The reaction mixture was stirred for 15 minutes, followed by the addition of ammonium chloride (5 equivalents). The reaction mixture was stirred at room temperature for 2 h. The crude reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with 1N HCl and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound.

[0499] Process 2 Synthesis of 4-chloro-2-fluoro-3-methyl-N-(phenylcarbamoyl)benzamide [ka] A slurry of 4-chloro-2-fluoro-3-methylbenzamide (1 equiv.) in DCE (0.5 M) was treated dropwise with oxalyl chloride (1.35 equiv.) at room temperature. The reaction mixture was then warmed to 55° C. for 1 h and then heated at reflux for an additional 20 h. The reaction mixture was concentrated in vacuo to provide the crude material as a yellow oil. This solution of crude 4-chloro-2-fluoro-3-methylbenzoyl isocyanate (1.2 M) in DCE was added dropwise to a cooled solution of aniline (0.4 M) in DCE at 0° C. The ice bath was removed, and the reaction mixture was stirred at room temperature for 45 min. The solid was then filtered, washed with DCM, and dried to give the title compound as a white solid.

[0500] Process 3 Synthesis of 7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione [ka] A slurry of 4-chloro-2-fluoro-3-methyl-N-(phenylcarbamoyl)benzamide in DMF (0.06 M) was cooled to 0 °C and treated portionwise with NaH (60% dispersion in oil, 3.1 equiv.). After the addition was complete, the ice bath was removed and the reaction mixture was refluxed for 18 h. The reaction mixture was cooled to rt and poured into 20% aqueous HCl. The resulting mixture was stirred vigorously, and the off-white solid was filtered, washed with EtO, and dried to give the title compound, which was used directly in the next step without purification. 1 H NMR (400 MHz, chloroform-d) δ 8.21 (s, 1H), 8.05 (d, J=8.2Hz, 1H), 7.47 (t, J=7.2Hz, 2H), 7.42 (d, J=6.9Hz, 1H), 7.37 (d, J=8.6Hz, 1H), 7.30 (d, J=7.6Hz, 2H), 1.71 (s, 3H). m / z [M+H]+ 287.0.

[0501] Proceeding similarly as above, the following compound was prepared by substituting for 4-chloro-2-fluoro-3-methylbenzamide:

[0502] 2-Fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared by using o-toluidine and 2-fluoro-4-(trifluoromethyl)benzamide. [ka]

[0503] 1-(o-Tolyl)-7-trifluoromethylquinazoline-2,4(1H,3H)-dione was prepared by using 2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide. [ka]

[0504] Reference Example 13 Synthesis of 1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione [ka] Process 1 Synthesis of 2-(phenylamino)-6-(trifluoromethyl)nicotinamide [ka] A round-bottom flask was purged with nitrogen, and a solution of KHMDS (2.5 equiv., 1 M THF) was added to the flask containing a vigorously stirred suspension of 2-chloro-6-(trifluoromethyl)nicotinamide (1 equiv.) and aniline (1.1 equiv.) in toluene or THF (0.4 M) at room temperature. After 2 h, the reaction mixture was evaporated to half its volume to remove the THF. The solid portion was filtered, washed with additional toluene, and dried under vacuum to provide the title compound. m / z [M+H] + 282.1.

[0505] Process 2 Synthesis of 1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione [ka] Proceeding similarly to Reference Example 2 above, but substituting 4-chloro-2-(pyridin-3-ylamino)benzamide for 2-(phenylamino)-6-(trifluoromethyl)nicotinamide, gave the title compound.

[0506] Proceeding in a similar manner to Step 1 of Reference Example 13 above, the following compounds were prepared:

[0507] 2-((2-fluorophenyl)amino)-6-(trifluoromethyl)nicotinamide was prepared by replacing aniline with 2-fluoroaniline. [ka]

[0508] 2-((2-bromophenyl)amino)-6-(trifluoromethyl)nicotinamide was prepared by replacing aniline with 2-bromoaniline. [ka]

[0509] Reference Example 14 Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile [ka] A vial was charged with 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione (1 equivalent) and copper cyanide (2 equivalents). Dimethylformamide was added (0.5 M) and the reaction mixture was heated at 120° C. for 18 h, then cooled. The crude reaction mixture was filtered and purified by reverse phase purification (30-60% MeCN / water, 0.1% formic acid) to give the title compound. m / z [M+H] + 338.0.

[0510] Proceeding similarly to Reference Example 14 above, the following compounds were prepared:

[0511] 1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile was prepared using 6-bromo-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. [ka] m / z [M+H] + 339.0

[0512] 1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile was prepared using 6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione. [ka]

[0513] 7-Cyclopropyl-2,4-dioxo-1-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile was prepared using 6-bromo-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)quinazoline-2,4(1H,3H)-dione. [ka]

[0514] 7-Cyclopropyl-1-(2-cyclopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile was prepared using 6-bromo-7-cyclopropyl-1-(2-cyclopropylphenyl)quinazoline-2,4(1H,3H)-dione. [ka]

[0515] 1-(2-Bromophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile was prepared using 6-bromo-1-(2-bromophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione. [ka]

[0516] 1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared from 6-bromo-1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-hydroxyquinazolin-2(1H)-one. [ka]

[0517] Reference Example 15 Synthesis of 7-chloro-1-(3-vinylphenyl)quinazoline-2,4(1H,3H)-dione [ka] To a stirred solution of 1-(3-bromophenyl)-7-chloro-4-hydroxyquinazolin-2(1H)-one (8 g, 22.8 mmol) in 1,4-dioxane (0.11 M) in a sealed tube, potassium fluoride (3 equiv.) and tributyl(vinyl)stannane (1.5 equiv.) were added at room temperature. The reaction mixture was degassed with argon gas for 20 minutes. Pd(OAc) (10 mol%) was added, and the reaction mixture was again degassed for 5 minutes. The resulting reaction mixture was stirred at 100 °C for 16 h. Upon completion, the reaction mixture was filtered through a bed of Celite. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine solution, and dried over Na SO . The organics were then filtered and concentrated under reduced pressure to afford the crude compound. The crude material was purified by column chromatography (1:6 EtOAc / hexanes) to afford the title compound as a yellow solid. m / z [M−H] + 298.73.

[0518] Reference Example 16 Synthesis of 7-cyclopropyl-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one [ka] Process 1 :Synthesis of 2-bromo-4,6-dichlorobenzoic acid [ka] Butyl nitrite (2 equiv.) was added dropwise to a suspension of CuBr2 (1.2 equiv.) in acetonitrile (0.25 M) at 0 °C. The reaction was stirred for 10 minutes, and 2-amino-4,6-dichlorobenzoic acid (1 equiv.) was added portionwise. The reaction mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C, and the reaction mixture was quenched with 1 N HCl. The solution was then extracted with diethyl ether. The pH of the organic phase was adjusted to pH 12 with 2 N NaOH. The aqueous phase was adjusted to pH 2 with 2 N HCl and then extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 2-bromo-4,6-dichlorobenzoic acid as an off-white solid.

[0519] Process 2 :Synthesis of 2,4-dichloro-6-vinylbenzoic acid [ka] To a stirred solution of 2-bromo-4,6-dichlorobenzoic acid (1 equiv.) in DMSO:HO (3:1, 0.2 M) was added vinylboronic acid pinacol ester (1.2 equiv.), KCO (3 equiv.), and Pd(dppf)Cl (5 mol%) at room temperature. The reaction mixture was purged under argon for 10 minutes, then heated to 120 °C and stirred for 16 h. The reaction mixture was diluted with 1 N HCl and EtOAc, then washed with brine solution. The combined organic layers were separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude material was purified using column chromatography (20% EtOAc / hexanes) and then concentrated under reduced pressure to provide 2,4-dichloro-6-vinylbenzoic acid as a milky white semisolid.

[0520] Process 3 :Synthesis of 2,4-dichloro-6-ethylbenzoic acid [ka] To a stirred solution of 2,4-dichloro-6-vinylbenzoic acid (1 equiv.) in EtOAc (0.3 M) was added 10% Pd / C (10 mol%) at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (1 atm) for 16 h and then filtered through a bed of Celite and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give 2,4-dichloro-6-ethylbenzoic acid as a viscous liquid, which was used further in the next step without purification.

[0521] Process 4 :Synthesis of 2,4-dichloro-6-ethylbenzamide [ka] To a stirred solution of 2,4-dichloro-6-ethylbenzoic acid (1 equiv.) in DMF (0.4 M) was added HATU (1.5 equiv.), DIPEA (5 equiv.), followed by NH4Cl (5 equiv.) at room temperature. The reaction mixture was then stirred at RT for 16 h, then diluted with EtOAc and washed with water. The combined organic layers were separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the crude product. This crude product was purified using column chromatography (30% EtOAc / hexanes) and concentrated under reduced pressure to provide the title compound as an off-white solid.

[0522] Process 5 :Synthesis of 2,4-dichloro-6-ethyl-N-(o-tolylcarbamoyl)benzamide [ka] To a stirred solution of 2,4-dichloro-6-ethylbenzamide (1 equiv.) in DCE (0.3 M) was added oxalyl chloride (1.9 equiv.) at room temperature. The reaction was stirred at 100° C. for 16 h and then concentrated to give crude 2,4-dichloro-6-ethylbenzoyl isocyanate as a gummy liquid. To a stirred solution of o-toluidine (1.2 equiv.) in DCE (1.4 M) at 0° C. was added slowly the crude isocyanate in suspension in DCE (1.5 M) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The solid residue was washed with pentane and dried under vacuum to give the title compound as an off-white solid.

[0523] Process 6 Synthesis of 7-chloro-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one [ka] To a stirred solution of 2,4-dichloro-6-ethyl-N-(o-tolylcarbamoyl)benzamide (1 g, 2.9 mmol) in DMF (0.7 M) was added KHMDS (2 equiv., 1.0 M in THF) dropwise at 0° C. The reaction was stirred at 100° C. for 1 h, then diluted with water and 1 N HCl was added slowly. The precipitated solid was filtered, washed with water, and dried under vacuum to give the title compound as a pale yellow solid.

[0524] Process 7 Synthesis of 7-cyclopropyl-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one [ka] To a stirred solution of 7-chloro-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one (1 eq.) in toluene:HO (8:2, 0.6 M) was added cyclopropylboronic acid (10 eq.) and KPO (3 eq.) at room temperature. The reaction mixture was purged with argon for 5 minutes, and Pd(PPh) (10 mol%) was added. After stirring the reaction mixture at 150 °C for 1 h in a microwave oven, it was diluted with water and extracted with EtOAc. The combined organic layers were separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by column chromatography (10-20% EtOAc / hexanes) and concentrated under reduced pressure to give the title compound as an off-white solid. m / z [M+H] + 321.41.

[0525] Reference Example 17 Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione [ka] Process 1 :Synthesis of 4-bromo-2-fluoro-6-hydroxybenzoic acid [ka] To a stirred solution of 4-bromo-2,6-difluorobenzoic acid (1 equivalent) in N-methyl-2-pyrrolidone (0.85 M) was added sodium hydroxide (4 equivalents) at RT. The reaction mixture was stirred at 120° C. for 45 minutes, then cooled to RT and ice water was added. The mixture was acidified to approximately pH 1 with 2 N HCl (100 mL), and the precipitate was filtered and washed with water to give the title compound as an off-white solid.

[0526] Process 2 Synthesis of methyl 4-bromo-2-fluoro-6-hydroxybenzoate [ka] To a stirred solution of 4-bromo-2-fluoro-6-hydroxybenzoic acid (1 equivalent) in methanol (0.4 M) was added thionyl chloride (0.36 equivalents) at 0° C. The reaction mixture was stirred at 90° C. for 72 h and then concentrated under reduced pressure. The residue was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound as an off-white solid.

[0527] Process 3 Synthesis of methyl 4-bromo-2-(difluoromethoxy)-6-fluorobenzoate [ka] To a stirred solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1 equivalent) in acetonitrile / water (1:1, 0.2 M) was added potassium hydroxide (20 equivalents) at room temperature. The solution was cooled to -78 °C, and diethyl (bromodifluoromethyl)phosphonate (2 equivalents) was added. The reaction mixture was stirred for 20 minutes at RT, then diluted with water and extracted with ether. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the crude product. Purification by column chromatography (5% EtOAC / hexane) yielded the title compound as a colorless liquid.

[0528] Process 4 Synthesis of methyl 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoate [ka] To a stirred solution of methyl 4-bromo-2-(difluoromethoxy)-6-fluorobenzoate (1 equiv.) in toluene / water (1:1, 0.2 M) was added cyclopropylboronic acid (1.5 equiv.) and Na2CO3 (3 equiv.). The resulting reaction mixture was degassed under an argon atmosphere for 20 min, and PdCl2(dppf)·DCM (10 mol%) was added. After stirring at 120 °C for 16 h, the reaction mixture was filtered through Celite, and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide the crude product. Purification by column chromatography using silica (5% EtOAc / hexanes) and concentration under reduced pressure afforded the title compound as a colorless liquid.

[0529] Process 5 Synthesis of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoic acid [ka] To a stirred solution of methyl 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoate (1 equiv.) in MeOH / THF / HO (2:2:1, 0.17 M) was added LiOH·HO (2 equiv.) at room temperature. The reaction mixture was stirred at RT for 16 h. Methanol was removed under reduced pressure, water was added to the remaining residue, and the solution was acidified to approximately pH 1 with 2 N HCl. The precipitate was filtered and dried to give the title compound as an off-white solid.

[0530] Process 6 Synthesis of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide [ka] To a stirred solution of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoic acid (1 equiv.) in DMF (0.4 M) was added NH4Cl (5 equiv.), DIPEA (3 equiv.), and HATU (1.5 equiv.) at RT. The reaction mixture was stirred at RT for 16 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with cold water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a light yellow solid. Process 7 Synthesis of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide [ka] To a stirred solution of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide (1 equiv.) in DCE (0.4 M) was added oxalyl chloride (1.4 equiv.), and the reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was concentrated under reduced pressure to provide crude 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoyl isocyanate. A stirred solution of 2-chloroaniline (1 equiv.) in DCE (0.7 M) was added to a mixture of the crude isocyanate in THF (1 M) at 0° C., and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with water, extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by column chromatography (10% EtOAc / hexanes) and concentrated under reduced pressure to provide the title compound as a light brown solid.

[0531] Process 8 Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione [ka] To a stirred solution of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-(difluoro-methoxy)-6-fluorobenzamide (1 eq.) in DMF (0.5 M) was added KHMDS (2 eq., 1 M in THF) dropwise at 0° C. The reaction mixture was stirred at 100° C. for 2 h, then cooled to RT and acidified to approximately pH 1 with 2N HCl. The white precipitate was filtered, washed with water and dried to afford the title compound as a yellow solid. m / z [M+H] + 379.3.

[0532] Reference Example 18 Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione [ka] Process 1 Synthesis of 4-bromo-2-fluoro-6-methoxybenzamide [ka] To a stirred solution of 4-bromo-2,6-difluorobenamide (1 eq.) in MeOH (200 ml) was added NaOMe (2.5 eq.), and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic layers were separated, washed with brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to provide the crude product. The crude material was purified by column chromatography (40% EtOAc / hexanes) and concentrated under reduced pressure to provide the title compound as a white solid.

[0533] Process 2 Synthesis of 4-cyclopropyl-2-fluoro-6-methoxybenzamide [ka] To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzamide (1 equiv.) in toluene / water (4:1, 0.3 M) was added cyclopropylboronic acid (1.5 equiv.), K2CO3 (3 equiv.), tributylphosphine (20 mol%), and Pd2(dba)3 (10 mol%), and the reaction mixture was stirred at 115 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were separated, washed with brine, and dried over anhydrous sodium sulfate. The solution was then filtered and concentrated under reduced pressure to provide the crude product, which was purified by column chromatography (30% EtOAc / hexanes) and concentrated under reduced pressure to provide the title compound as an off-white solid.

[0534] Process 3 Synthesis of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxy-benzamide [ka] To a stirred solution of 4-cyclopropyl-2-fluoro-6-methoxybenzamide (1 equiv.) in DCE (0.25 M) was added oxalyl chloride (1.3 equiv.) at 0° C., and the reaction mixture was stirred at 55° C. for 1 h and then refluxed for 20 h. Crude 4-cyclopropyl-2-fluoro-6-methoxybenzoyl isocyanate in DCE (1.4 M) was added to a solution of 2-chloroaniline (1 equiv.) in DCE (0.7 M) under a nitrogen atmosphere at 0° C. and stirred at RT for 2 h. The solid was filtered, washed with diethyl ether, and dried under vacuum to provide the title compound as a brown solid.

[0535] Process 4 Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-4-hydroxy-5-methoxyquinazolin-2(1H)-one [ka] To a stirred solution of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide (1 eq.) in DMF (0.05 M) was added KHMDS (1 M in THF, 2.5 eq.) dropwise at 0° C. and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was diluted with water and acidified to approximately pH 1 with 2N HCl. The solid was filtered and dried under vacuum to provide the title compound as an off-white solid. m / z [M+H] + 343.34.

[0536] Reference Example 19 Synthesis of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine [ka] A vial was charged with 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile (1.0 equiv.) and THF (0.5 M) under nitrogen. LAH (2.0 equiv.) was added and the reaction mixture was stirred at 70° C. for 2 h. The reaction mixture was cooled to 0° C. and quenched with wet NaSO. The reaction mixture was filtered over a celite pad and washed with EtOAc. The filtrate was dried over NaSO, filtered, and concentrated to give the title compound; m / z [M+H] + 228.28.

[0537] Reference Example 20 Synthesis of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-amine [ka] Process 1 Synthesis of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one [ka] A vial was charged with 1-(1H-imidazol-4-yl)ethan-1-one (1.0 equiv.) and THF (0.5 M) under nitrogen. Sodium hydride (2.0 equiv.) was added at 0° C., and the reaction mixture was stirred at room temperature for 1 h. (2-(chloromethoxy)ethyl)trimethylsilane (1.6 equiv.) was added at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with ice-cold water and diluted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (20-25% EtOAc / hexanes) provided the title product; m / z [M+H] + 241.4.

[0538] Process 2 Synthesis of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one oxime [ka] A vial was charged with 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one (1 eq.) and methanol (0.5 M) under nitrogen. Hydroxylamine hydrochloride (1.2 eq.) and K2CO3 (3 eq.) were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was passed through a pad of Celite and washed with methanol. The filtrate was dried over Na2SO4, filtered and concentrated to give the title product; m / z [M+H] + 256.39. ...

Claims

1. A compound of formula (IA'), or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the formula: w is CR ３ or N; x is CR ４ or N; y is CR ５ or N; and z is CR ６ or N, with the proviso that no more than two of w, x, y, and z are N; R ３ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C １－６ Alkyl sulfonyl, 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, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or 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 R independently selected from aminoalkyl ａ , R ｂ , and / or R ｃ is substituted by R ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C １－６ Alkyl sulfonyl, 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 Alkoxy-C １－６ Alkoxy, (C １－６ Alkoxy-C １－６ alkyl)amino, C １－６ Aminoalkyl, C １－６ Aminoalkoxy, C １－６ Aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxy-C １－６ Alkoxy or heterocyclyloxy-C １－６ alkylamino, where heterocyclyl or heteroaryl, by itself or as part of another group, is unsubstituted or 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 Hydroxyalkyl, C １－６ Alkoxy-C １－６ Alkyl, and C １－６ R independently selected from aminoalkyl ａ , R ｂ , and / or R ｃ is substituted by R ４ and R ６ are independently hydrogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkyl sulfonyl, 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 where R ７ is C ３－６ Cycloalkyl, bridged cycloalkyl, fused cycloalkyl, C 6－10 Spirocycloalkyl, C 6－10 heterocyclyl selected from aryl, heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, morpholinyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein the aryl, heteroaryl, or heterocyclyl is unsubstituted or ｄ , R ｅ , and / or R ｆ is substituted by R ２ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ Aminoalkyl, aminocarbonyl-C １－６ Alkyl, aminosulfonyl-C １－６ Alkyl, —O—R ８ , -NR ９ R １０ , or -X ｂ -R １１ and R ８ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Hydroxyalkyl, C １－６ Alkoxy-C １－６ Alkyl, C １－６ aminoalkyl, or C ３－６ is cycloalkyl; R ９ is hydrogen, C １－６ Alkyl, C １－６ Deuteroalkyl, or C ３－６ is 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, C ６－１０ Spirocycloalkyl, C 6－10 Aryl-C １－６ Alkyl, heteroaryl, heteroaryl-C １－６ Alkyl, heterocyclyl, or heterocyclyl-C １－６ alkyl, where aryl, heteroaryl, or heterocyclyl, by itself or as part of another group, is unsubstituted or ｊ , R ｋ , and / or R ｌ is substituted by X ｂ is a bond or C １－６ alkylene; R １１ is a monocyclic heteroaryl or heterocyclyl selected from oxetanyl, azetidinyl, 2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, and morpholinyl, wherein the heteroaryl or heterocyclyl is unsubstituted or ｍ , R ｎ , and / or R ｏ is substituted by R ｄ , R ｅ , R ｊ , R ｋ , R ｍ , and R ｎ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy, C １－６ Alkoxy, hydroxy, C １－６ Alkyl sulfonyl, 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 independently selected from dialkylaminocarbonyl; and R ｆ , R ｌ , and R ｏ is C １－６ Alkyl, C ３－６ Cycloalkyl, hydroxy, halo, amino, C １－６ Alkylamino, C 3－６ Cycloalkylsulfonylamino, carboxy-C １－６ Alkyl, and -X ｃ -R １２ (In the formula, X ｃ is a bond or C １－６ alkylene, and R １２ is a substituted or unsubstituted C 6－10 aryl; each heteroaryl has 5 to 10 ring members and 1 to 3 heteroatom ring vertices that are each independently N, O, or S; each heterocyclyl has 4 to 8 ring members, and one or two heteroatom ring vertices are each independently N, O, or S(O)n, where n is 0, 1, or 2; each bridged heteroalkyl has 5 to 7 ring members and two non-adjacent ring atoms are joined by a (CRR')q group, where q is 1 to 3, and R and R' are each independently H or methyl; each bridged heterocyclyl has 5 to 7 ring members, two non-adjacent ring atoms are joined by a (CRR')p group, where p is 1 to 3, and R and R' are each independently H or methyl, and each bridged heterocyclyl has 1 to 2 heteroatom ring vertices that are each independently N, O, or S(O)m, where m is 0, 1, or 2; Each fused cycloalkyl is a saturated C fused to phenyl or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, each independently N, O, or S. 3－６ is cycloalkyl; Each fused heterocyclyl is C 3－６ heterocyclyl fused to a cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, each independently N, O, or S; and Each spiroheterocyclyl is a saturated bicyclic ring having 6 to 10 ring members and having 1 to 3 heteroatom ring vertices, each independently N, O, or S(O)t, where t is 0, 1, or 2; and the bicyclic rings are bonded by only one atom.

2. having a structure of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or (IIIg): 【Chemistry 2】 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. 3. The compound of claim 2 having the structure of formula (IIIa) or a pharmaceutically acceptable salt thereof.

4. 3. The compound of claim 2 having the structure of formula (IIId) or a pharmaceutically acceptable salt thereof.

5. The R ２ But, -NR ９ R １０ 5. The compound according to any one of claims 1 to 4, wherein:

6. The R ２ But, -OR ８ or R １１ 5. The compound according to any one of claims 1 to 4, wherein:

7. The R ９ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

8. The R ９ But C １－６ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

9. The R ９ The compound according to any one of claims 1 to 5 and 8, or a pharmaceutically acceptable salt thereof, wherein is methyl or ethyl.

10. The R １０ But 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, C １－６ Alkylaminocarbonyl, C １－６ Dialkylaminocarbonyl, C １－６ Alkylaminocarbonyl-C １－６ Alkyl, or C １－６ Dialkylaminocarbonyl-C １－６ The compound according to any one of claims 1 to 5 and 7 to 9, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

11. The R １０ The compound according to any one of claims 1 to 5 and 7 to 10, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

12. The R ８ or R １０ But C １－６ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

13. The R １０ But C ３－６ Cycloalkyl or C ３－６ Cycloalkyl-C １－６ alkyl, and each ring is independently unsubstituted or C １－６ The compound according to any one of claims 1 to 5 and 7 to 9, or a pharmaceutically acceptable salt thereof, optionally substituted by 1 or 2 substituents independently selected from alkyl, halo, and cyano.

14. The R １０ is heteroaryl or heteroaryl-C １－６ alkyl, where heteroaryl is by itself or heteroaryl-C １－６ As part of the alkyl, it may be unsubstituted or R ｊ , R ｋ , and / or R ｌ The compound according to any one of claims 1 to 5 and 7 to 9, or a pharmaceutically acceptable salt thereof, which is substituted by:

15. The R ５ But C １－６ Alkyl, C １－６ Alkoxy, Halo, C １－６ Haloalkyl, C １－６ Haloalkoxy, C 3－６ cycloalkyl, cyano, aminocarbonyl, heteroaryl, or heterocyclyl, where the heterocyclyl or heteroaryl is unsubstituted or 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 Hydroxyalkyl, C １－６ Alkoxy-C １－６ Alkyl, and C １－６ R independently selected from aminoalkyl ａ , R ｂ , and / or R ｃ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, substituted by:

16. The R ５ is methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclopentyl, cyano, pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, oxetan-3-yl, pyrrolidin-1-yl, tetrahydrofuranyl, 2-oxoazetidin-1-yl, or 2-oxopyrrolidin-1-yl, wherein each of pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, oxetan-3-yl, pyrrolidin-1-yl, tetrahydrofuranyl, 2-oxoazetidin-1-yl, and 2-oxopyrrolidin-1-yl is unsubstituted or 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 Hydroxyalkyl, C １－６ Alkoxy-C １－６ Alkyl, and C １－６ R independently selected from aminoalkyl ａ , R ｂ , and / or R ｃ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, substituted by:

17. The R ５ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is chloro, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl, or cyclopropyl.

18. The R ５ The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein is chloro, trifluoromethyl, or ethyl.

19. The R ４ and R ６ is independently selected from hydrogen, methyl, chloro, fluoro, bromo, methoxy, methylthio, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, and dimethylaminocarbonyl, or a pharmaceutically acceptable salt thereof.

20. The R ４ is hydrogen, fluoro, bromo, methyl, methoxy, or cyano; and R ６ The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

21. The R ４ and R ６ The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

22. The R ３ But hydrogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkyl sulfonyl, 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 22. The compound according to any one of claims 1 to 21, which is dialkylaminocarbonyl, or a pharmaceutically acceptable salt thereof.

23. The R ３ The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

24. The R ３ is methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano, methylsulfonyl, aminocarbonyl, methylamino, or dimethylamino, or a pharmaceutically acceptable salt thereof.

25. The R １ But, R ７ where R ７ is unsubstituted or R ｆ and R is phenyl substituted by 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 on the phenyl ring attached to the quinazolone nitrogen, or a pharmaceutically acceptable salt thereof.

26. The R １ is unsubstituted or R ｆ pyridinyl substituted by 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 on the pyridinyl ring that is attached to the quinazolone nitrogen, or a pharmaceutically acceptable salt thereof.

27. A compound of formula (IIIa), or a pharmaceutically acceptable salt thereof: 【Chemistry 3】 (In the formula: R ３ is hydrogen; R ５ is C １－６ Haloalkyl, halo, or C ３－６ is cycloalkyl; R ４ is hydrogen or cyano; R ６ is hydrogen; R １ is R ７ where R ７ is phenyl or 5-6 membered heteroaryl, where the phenyl or heteroaryl is unsubstituted or R ｄ , R ｅ , and / or R ｆ is substituted by R ２ is -NR ９ R １０ and R ９ is hydrogen; R １０ is hydrogen, C １－６ Hydroxyalkyl, C １－６ Alkyl, or C ３－６ cycloalkyl, where C ３－６ cycloalkyl is unsubstituted or substituted with halo; R ｄ and R ｅ are independently １－６ Alkyl, halo, C １－６ Haloalkoxy, C １－６ haloalkyl, and hydroxy; and R ｆ is C １－６ Alkyl, halo, C １－６ Haloalkoxy, C １－６ haloalkyl, and hydroxy.

28. A compound of formula (IIId), or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 (In the formula: R ３ is hydrogen; R ５ is C １－６ haloalkyl; R ４ is hydrogen; R １ is R ７ where R ７ is phenyl or 5-6 membered heteroaryl, where the phenyl or heteroaryl is unsubstituted or R ｄ , R ｅ , and / or R ｆ is substituted by R ２ is -NR ９ R １０ and R ９ is hydrogen; R １０ is hydrogen, C １－６ Alkyl, or C ３－６ cycloalkyl, where C ３－６ cycloalkyl is unsubstituted or substituted with halo; R ｄ and R ｅ are independently １－６ Alkyl, halo, C １－６ alkoxy, and cyano; and R ｆ is C １－６ Alkyl, halo, C １－６ alkoxy, and cyano).

29. 【Chemical 5】 or a pharmaceutically acceptable salt thereof.

30. [Chemical 6] or a pharmaceutically acceptable salt thereof.

31. [Chemical 7] or a pharmaceutically acceptable salt thereof.

32. [Chemical 8] A compound which is

33. 【Chemical 9】 or a pharmaceutically acceptable salt thereof.

34. [Catalog 10] A compound which is

35. 【Chemical 11-1】 【Chemistry 11-2】 【Chemistry 11-3】 【Chemistry 11-4】 【Chemistry 11-5】 【Chemistry 11-6】 【Chemistry 11-7】 【Chemistry 11-8】 【Chemistry 11-9】 【Chemistry 11-10】 【Chemistry 11-11】 【Chemistry 11-12】 【Chemistry 11-13】 【Chemistry 11-14】 【Chemistry 11-15】 【Chemistry 11-16】 【Chemistry 11-17】 【Chemistry 11-18】 【Chemistry 11-19】 【Chemistry 11-20】 【Chemistry 11-21】 【Chemistry 11-22】 【Chemistry 11-23】 【Chemistry 11-24】 【Chemistry 11-25】 【Chemistry 11-26】 【Chemistry 11-27】 【Chemistry 11-28】 【Chemistry 11-29】 【Chemistry 11-30】 【Chemistry 11-31】 【Chemistry 11-32】 【Chemistry 11-33】 【Chemistry 11-34】 【Chemistry 11-35】 【Chemistry 11-36】 【Chemistry 11-37】 【Chemistry 11-38】 【Chemistry 11-39】 【Chemistry 11-40】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

36. 36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

37. 1. A pharmaceutical composition for treating a disease treatable by inhibition of MAT2A in a patient, comprising: A pharmaceutical composition comprising the compound of any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

38. 38. The pharmaceutical composition of claim 37 for treating cancer in a patient.

39. 39. The pharmaceutical composition of claim 37 or 38 for treating an MTAP-null cancer in a patient.

40. 39. The pharmaceutical composition of claim 38 for treating a cancer characterized by reduced or defective MTAP gene expression, a defect in the MTAP gene, or reduced function of the MTAP protein in a patient.

41. The pharmaceutical composition according to any one of claims 38 to 40, wherein the cancer is leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, esophageal cancer, gastric cancer, or mesothelioma.

42. 37. Use of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, or a composition according to claim 36, for the manufacture of a pharmaceutical composition for use in combination with one additional therapeutic agent.

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