RU2830169C2 - 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to a compound of formula (IA') or a pharmaceutically acceptable salt thereof, which have inhibitory action on methionine adenosyltransferase 2A (MAT2A). In formula (IA') w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; z is CR⁶ or N, provided that not more than two of w, x, y and z are N, R³ is a hydrogen atom, C_1-6 alkyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, C_3-6 cycloalkyl-C_1-6 alkyloxy, cyano, C_1-6 hydroxyalkoxy, C_1-6 aminoalkoxy, heteroaryl, heterocyclyl or heterocyclyloxy, where heterocyclyl or heteroaryl separately or as part of another group is unsubstituted or is substituted with R^a, R^b and/or R^c independently selected from C_1-6 alkyl, halogen and C_1-6 alkoxycarbonyl; R⁵ is C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_1-6 alkoxy, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_3-6 cycloalkyl, cyano, C_1-6 dialkylamino, C_1-6 alkoxycarbonyl, C_1-6 hydroxyalkyl, heteroaryl or heterocyclyl; R⁴ and R⁶ independently represent a hydrogen atom, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkylthio, halogen, C_1-6 haloalkyl, C_1-6 haloalkoxy or cyano; R¹ is R⁷, where R⁷ is C_3-6 cycloalkyl, C_6-10 aryl or heteroaryl, where C_6-10 aryl or heteroaryl is unsubstituted or substituted with R^d, R^e and/or R^f; R² is C_1-6 alkyl, -O-R⁸, -NR⁹R¹⁰ or -X^b-R¹¹, where R⁸ is C_1-6 alkyl or C_3-6 cycloalkyl; R⁹ is a hydrogen atom, C_1-6 alkyl, C_1-6 deuteroalkyl or C_3-6 cycloalkyl; R¹⁰ is a hydrogen atom, 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, C_1-6 aminosulphonyl, C_1-6 thioureidoalkyl, C_1-6 alkylsulphonyl, 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, heterocyclyl-C_1-6 alkyl or spiroheterocyclyl, where aryl, heteroaryl or heterocyclyl separately or as part of another group is unsubstituted or substituted R^j, R^k and/or R^l; X^b is a bond or C_1-6 alkylene; R¹¹ is monocyclic heteroaryl or heterocyclyl selected from oxetanyl, azetidinyl, 2-oxo-azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperidinyl and morpholinyl, where heteroaryl or heterocyclyl is unsubstituted or substituted R^m, Rⁿ and/or R^o; R^d, R^e, R^j, R^k, R^m and Rⁿ are independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 haloalkoxy, C_1-6 alkoxy, hydroxy, C_1-6 alkylsulphonyl, halogen, cyano, carboxy, C_1-6 alkoxycarbonyl, C_1-6 hydroxyalkyl, C_1-6 alkoxy-C_1-6 alkyl, and so forth; R^f, R^l and R^o are independently selected from C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_3-6 cycloalkyl, hydroxy, halogen, cyano, amino, C_1-6 alkylamino, C_3-6 cycloalkylsulfonylamino, carboxy-C_1-6 alkyl and -X^c-R¹², where X^c is a bond or C_1-6 alkylene, R¹² is unsubstituted C_6-10 aryl. Each heteroaryl has from 5 to 10 ring members and from 1 to 3 heteroatoms in ring vertices, each independently selected from N, O or S; each heterocyclyl has 4 to 8 ring members and 1 to 2 heteroatoms at ring vertices, each independently selected from N, O or S(O)_n, where n is 0, 1 or 2; each bridged cycloalkyl has from 5 to 7 members in a cycle in which two non-neighboring ring atoms are linked by a group (CRR’)_q, where q is 1–3 and each R and R' independently represents H or methyl; and each spiroheterocyclyl is a saturated bicyclic ring having from 6 to 10 ring members and from 1 to 3 heteroatomic ring vertices, each independently selected from N, O or S(O)_n, where n is 0, 1 or 2; and the bicyclic ring is bonded only through one atom. Invention also relates to a specific compound and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing said compounds, and methods of treating cancer.

EFFECT: there are disclosed 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors.

26 cl, 4 tbl, 16 ex

Description

Prior art

Cancer is one of the leading causes of death worldwide. A limitation of the prevailing treatment approaches, such as chemotherapy and immunotherapy, is that their cytotoxic effects are not limited to cancer cells and may cause unwanted side effects in normal tissues. Therefore, new strategies are needed to better target cancer cells.

Synthetic lethality occurs when a combination of deficiencies in the expression of two or more genes results in cell death, whereas a deficiency in only one of these genes does not. The concept of synthetic lethality arose from studies of model systems in Drosophila, in which a combination of mutations in two or more individual genes results in cell death (in contrast to viable variants where only one of the genes is mutated or deleted). More recently, several studies have identified maladaptive genetic alterations in cancer cells that render them susceptible to synthetic lethality approaches. Such tumor-specific genetic defects have led to the use of targeted agents that induce cell death in cancer cells while sparing normal cells.

Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to produce s-adenosylmethionine (SAM). SAM is the primary methyl donor in cells, used to methylate several substrates including DNA, RNA, and proteins. One methylase that utilizes SAM as a methyl donor is arginine N-methyltransferase 5 (PRMT5). SAM is required for PRMT5 function, and PRMT5 is competitively inhibited by 5'methylthioadenosine (MTA). Because MTA is involved in the methionine salvage pathway, cellular MTA levels remain low during the process initiated by methylthioadenosine phosphorylase (MTAP).

MTAP is located at a locus on chromosome 9 that is frequently deleted in cells from patients with cancers originating from several tissues, including the central nervous system, pancreas, esophagus, bladder, and lung (cBioPortal database). Loss of MTAP results in accumulation of MTA, making MTAP-deleted cells more dependent on SAM production and hence MAT2A activity than MTAP-expressing cells. In an shRNA cell line screen of approximately 400 cancer cell lines, MAT2A knockdown resulted in loss of viability in a higher percentage of MTAP-deleted cells compared to MTAP wild-type cells (see McDonald et. al. 2017 Cell 170, 577–592). Furthermore, induced knockdown of MAT2A protein reduced tumor growth in vivo (see Marjon et al., 2016 Cell Reports 15(3), 574-587). These results suggest that MAT2A inhibitors may be a new type of cancer therapy, including MTAP-deleted tumors.

Brief description of the invention

The present invention describes certain 2-oxoquinazoline derivatives that are methionine adenosyltransferase 2A (MAT2A) inhibitors. Also described are pharmaceutical compositions containing these compounds and methods for treating diseases treatable by inhibiting MAT2A, such as cancer, including cancers characterized by decreased or absent methylthioadenosine phosphorylase (MTAP) activity.

The first aspect describes a compound having the formula (IA'):

(IA'),

Where:

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 represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁵ represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl or -X ^a -R ⁷ , where X ^a is a bond or alkylene, and R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, where aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

R ² represents a hydrogen atom, alkyl, halogen, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl, deuteroalkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , R ^h , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene and R ¹² is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl, with the proviso that when R ¹ is heterocyclyl and one of R ^d and R ^e is hydroxy then R ^f is not hydroxy; or

its pharmaceutically acceptable salt; provided that:

(1) when represents , where: (a) when R ² is chlorine, piperazin-1-yl, 2-methylpiperazin-1-yl or 1H-benzo[d][1.2.3]triazol-1-yl, R ³ and R ⁶ represent a hydrogen atom, R ⁴ is chlorine, and R ⁵ is bromo or 5-methylindazol-4-yl, then R ¹ is not 2-isopropylphenyl; (b) when R ² is furan-2-yl, thien-2-yl, methyl or butyl, R ³ , R ⁴ and R ⁶ represent a hydrogen atom and R ⁵ is methyl, then R ¹ is not isopropyl; (c) when R ² is a hydrogen atom, R ³ , R ⁵ and R ⁶ represent a hydrogen atom and R ⁴ is chlorine, then R ¹ is not benzyl; (d) when R ² is a hydrogen atom, R ³ , R ⁵ and R ⁶ are a hydrogen atom, and R ⁴ is bromo, then R ¹ is not 2-morpholin-4-ylethyl; (e) when R ² is cyclopropyl, methyl, difluoromethyl or pentafluoroethyl, R ³ , R ⁵ and R ⁶ are a hydrogen atom, and R ⁴ is chlorine or fluorine, then R ¹ is not 4-methoxybenzyl; (f) when R ² is cyclohexyl, pyridin-2-yl or furan-2-yl, R ³ , R ⁵ and R ⁶ are a hydrogen atom, and R ⁴ is chlorine, then R ¹ is not cyclopropylmethyl; (g) when R ² is a hydrogen atom or thien-2-yl, R ³ , R ⁵ and R ⁶ are a hydrogen atom, and R ⁴ is methoxy; or R ² is thien-2-yl, R ³ , R ⁴ and R ⁶ represent a hydrogen atom, and R ⁵ is methyl, then R ¹ is not cyclopropylmethyl or 2,2,2-trifluoroethyl; (h) when R ² and R ⁶ are methyl, and R ³ , R ⁴ and R ⁵ represent a hydrogen atom; or R ² and R ³ are methyl, and R ⁴ , R ⁵ and R ⁶ represent a hydrogen atom, then 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) when R ² is trifluoromethyl, R ³ is methoxy or methyl, and R ⁴ , R ⁵ and R ⁶ represent a hydrogen atom; or R ² is trifluoromethyl, R ³ is fluorine or a hydrogen atom, R ⁴ is halogen, methyl, methoxy, isopropyl or trifluoromethyl, and R ⁵ and R ⁶ are a hydrogen atom, then R ¹ is not 4-methoxybenzyl or naphth-1-ylmethyl; (j) when R ² and R ³ are chlorine, and R ⁴ , R ⁵ and R ⁶ are a hydrogen atom; or R ² is trifluoromethyl, R ³ is chlorine, and R ⁴ , R ⁵ and R ⁶ are a hydrogen atom; or ^R4 is amino, ^R3 , ^R5 and ^R6 are a hydrogen atom, and ^R2 is 1-methyl-1-pyrimidin-2-ylethylamino, 1-cyclopropylethylamino, 1-pyrimidin-2-ylethylamino, 2-hydroxy-1-methylethylamino or 3-hydroxy-1-methylpropylamino; or ^R3 is methoxy, ^R4 , ^R5 and ^R6 are a hydrogen atom, and ^R2 is 2-methyl-2-phenylpropylamino; or R ⁴ is chlorine, R ³ , R ⁵ and R ⁶ are H, and R ² is 1-naphth-2-ylmethylpiperidin-4-ylamino, 1-ethoxycarbonylpiperidin-4-ylamino or 1-quinoline-6-ylmethylpiperidin-4-ylamino, then R ¹ is not methyl; (k) when R ² is methyl, R ³ and R ⁶ are a hydrogen atom, and R ⁴ and R ⁵ are methoxy, then R ¹ is not methyl, 2-pyridin-2-ylethyl or 3-phenylpropyl; (l) when R ² is trifluoromethyl, R ³ , R ⁵ and R ⁶ represent a hydrogen atom, and R ⁴ is chlorine, methoxy or fluorine, then R ¹ is not benzyl, 4-methylbenzyl or 3,5-dimethylbenzyl; (m) when R ² is methyl, R ³ , R ⁵ and R ⁶ represent a hydrogen atom, and R ⁴ is bromine, then R ¹ is not ethyl; (n) when R ² is 4-methoxycyclohexylamino, R ³ , R ⁵ and R ⁶ represent a hydrogen atom, and R ⁴ is iodine; or R ² is methyl, R ³ and R ⁴ represent methoxy, and R ⁵ and R ⁶ represent a hydrogen atom; then R ¹ is not methyl; (o) when R ² is amino or acetylamino, R ⁴ is dimethylamino, and R ³ , R ⁵ and R ⁶ represent a hydrogen atom, then R ¹ is not 4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (p) when R ⁴ is chlorine, R ³ , R ⁵ and R ⁶ represent a hydrogen atom, and R ¹ is 2,2,2-trifluoroethyl, then R ² is not 1-ethoxycarbonylpiperidin-4-ylamino or 8-azabicyclo[3.2.1]oct-3-ylamino; (q) when R ⁵ is fluorine, R ³ , R ⁴ and R ⁶ are a hydrogen atom, and R ² is -4-aminocarbonylmethyl-2-methylphenylamino, then 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) when R ⁶ is fluorine, R ³ , R ⁴ and R ⁵ are a hydrogen atom, and R ² is 4-aminocarbonylmethyl-2-methylphenylamino, then R ¹ is not 4-fluoro-2-methoxyphenyl; (s) when R ¹ is 4-chloro-2-ethoxyphenyl, R ⁵ is fluoro, and R ³ , R ⁴ and R ⁶ are a hydrogen atom, then R ² is not 3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino; and (t) when R ⁴ is chlorine, R ³ , R ⁵ and R ⁶ are a hydrogen atom, and R ¹ is pentyl, then R ² is not 1-naphth-1-ylmethylpiperidin-4-ylamino, 1-naphth-2-ylmethylpiperidin-4-ylamino or 1-ethoxycarbonylpiperidin-4-ylamino.

(2) when represents , then (a) when R ² is a hydrogen atom, R ³ and R ⁵ are methyl, and R ⁴ is a hydrogen atom, then R ¹ is not 2-dimethylaminoethyl or 2-diisopropylaminoethyl; (b) when R ² is chlorine, R ³ is 3-pentyloxy, R ⁴ is a hydrogen atom, and R ⁵ is methyl, then R ¹ is not 2,4,6-trimethylphenyl; (c) when R ² is cyclohexyl, 3-hydroxy- or 4-hydroxycyclohexyl or 3-methylcyclohexyl, R ³ and R ⁴ are a hydrogen atom, and R ⁵ is methyl, hydroxymethyl or ethyl, then R ¹ is not ethyl; (d) when R ² and R ³ represent a hydrogen atom, R ⁴ is cyano, and R ⁵ is amino, then R ¹ is not allyl, benzyl, methyl or ethyl;

(3) when represents , then (a) when R ² is a hydrogen atom, R ³ is chlorine, and R ⁵ is 1,3-dihydroxyprop-2-ylamino, 3-diethylaminopropylamino, or 4-(4-methylpiperidin-1-yl)piperidin-1-yl, then R ¹ is not 2,4-difluorophenyl, 2,6-difluorophenyl, or 4-trifluoromethylphenyl; (b) when R ² and R ³ are both hydrogen atom and R ⁵ is pyridin-4-ylamino, then R ¹ is not cyclopentyl; (c) when R ¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, R ⁵ is amino, and R ³ is methoxy; or when R ¹ is 4-methoxybenzyl, R ³ is methoxy, and R ⁵ is amino; then R ² is not amino;

(4) when represents , then (a) when R ² and R ⁵ are methoxy and R ⁴ is a hydrogen atom; or when R ² is a hydrogen atom, amino or dimethylamino, and one of R ⁴ and R ⁵ is a hydrogen atom and the second of R ⁴ and R ⁵ is methyl, or R ⁴ and R ⁵ are methyl; then R ¹ is not methyl; (b) when R ¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, one of R ⁴ and R ⁵ is a hydrogen atom and the second of R ⁴ and R ⁵ is methyl, or R ⁴ and R ⁵ are both methyl, then R ² is not amino;

(5) when represents , then (a) when R ² is 4-hydroxycyclohexylamino, dimethylaminocarbonylmethylamino or 4-(2-hydroxyethyl)piperazin-1-yl, R ⁵ is chloro or 6-methoxypyridin-3-yl, and R ⁶ is a hydrogen atom, then R ¹ is not 2-ethoxyethyl, and (b) when R ² is 4-hydroxycyclohexylamino, 4-(2-hydroxyethyl)piperazin-1-yl, 4-hydroxypiperidin-1-yl, 2-hydroxyethylamino, piperidin-4-ylamino, dimethylaminocarbonylmethylamino or 2-morpholin-4-ylethylamino, R ⁵ is chloro or 6-methoxypyridin-3-yl, and R ⁶ is a hydrogen atom, then R ¹ is not 2-propyloxyethyl;

(6) when represents , then when R ² is 4-(2-hydroxyethyl)piperazin-1-yl or 4-hydroxycyclohexylamino, R ⁴ and R ⁶ are a hydrogen atom, and R ⁵ is chloro or 6-methoxypyridin-3-yl, then R ¹ is not 2-propoxyethyl; and

(7) when represents , then when R ² is 2-isopropyloxyethylamino, 4-hydroxycyclohexylamino, 4-(2-hydroxyethyl)piperazin-1-yl, 2-(morpholin-4-yl)ethylamino, R ³ and R ⁶ are a hydrogen atom, and R ⁵ is 6-methoxypyridin-3-yl, then R ¹ is not 2-propoxyethyl.

In one embodiment of the first aspect, a compound having formula (IA) is described:

(IA),

Where:

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 represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁵ represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl or -X ^a -R ⁷ , where X ^a is a bond or alkylene, and R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, where aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

R ² represents a hydrogen atom, alkyl, halogen, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl, deuteroalkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , ^Rh , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, amino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene and R ¹² is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl, with the proviso that when R ¹ is heterocyclyl and one of R ^d and R ^e is hydroxy then R ^f is not hydroxy; or

its pharmaceutically acceptable salt.

In another embodiment of the first aspect, a compound having formula (I) is described:

(I),

Where:

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:

^R3 and ^R5 independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by ^Ra , ^Rb and/or ^Rc , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl or -X ^a -R ⁷ , where X ^a is a bond or alkylene, and R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, where aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

R ² represents a hydrogen atom, alkyl, halogen, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , ^Rh , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl; or

its pharmaceutically acceptable salt.

In the second aspect, a pharmaceutical composition is described comprising:

(a) a compound having the formula (IIA'):

(IIA'),

Where:

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 represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁵ represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl or -X ^a -R ⁷ , where X ^a is a bond or alkylene, and R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, where aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

R ² represents a hydrogen atom, alkyl, halogen, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl, deuteroalkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , ^Rh , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, amino, alkylamino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene and R ¹² is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl, with the proviso that when R ¹ is heterocyclyl and one of R ^d and R ^e is hydroxy then R ^f is not hydroxy; or

(b) a compound having the formula (IIA):

(IIA),

Where:

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 represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁵ represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl or -X ^a -R ⁷ , where X ^a is a bond or alkylene, and R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, where aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

R ² represents a hydrogen atom, alkyl, halogen, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl, deuteroalkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , ^Rh , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, amino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl;

(c) a compound having the formula (II):

(II),

Where:

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:

^R3 and ^R5 independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by ^Ra , ^Rb and/or ^Rc , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl or -X ^a -R ⁷ , where X ^a is a bond or alkylene, and R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, where aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

R ² represents a hydrogen atom, alkyl, halogen, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , ^Rh , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl;

(d) a compound having the formula (IVA):

(IVA),

Where:

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 independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom, and (iii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ represents a hydrogen atom;

R ¹ is a 5- to 8-membered cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl and spiroheterocyclyl are unsubstituted or substituted with R ^d , R ^e and/or R ^f , wherein R ^d and R ^e are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, 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, halogen, cyano or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; or a tautomeric form thereof; or

(e) a compound having the formula (IA'), (IA), (I) or (IV);

(or any of its variants described herein), or a pharmaceutically acceptable salt thereof;

and at least one pharmaceutically acceptable excipient.

In a third aspect, a method of treating a disease mediated by MAT2A in a patient is described, comprising administering to the patient a therapeutically effective amount of a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of the third aspect, the patient has an established need for such treatment. In a second embodiment of the third aspect and the first embodiment, the compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof described herein), or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition. In a third embodiment of the third aspect and the first and second embodiments, the disease is mediated by overexpression of MAT2A. In a fourth embodiment of the third aspect and the first, second and third embodiments, the disease is cancer.

In a fourth aspect, a method of treating MTAP-null cancer in a patient is described, comprising administering to the patient a therapeutically effective amount of a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or embodiments thereof described herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of the fourth aspect, the patient has an established need for such treatment. In a second embodiment of the fourth aspect and the first embodiment, the compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof described herein), or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.

In a fifth aspect, a method is described for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by the enzyme MAT2A in cells, comprising contacting the cell with an effective amount of a compound having formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or embodiments thereof described in the present invention), or a pharmaceutically acceptable salt thereof.

In a sixth aspect, a method of treating cancer in a patient is described, wherein the cancer is characterized by a decrease or absence of methylthioadenosine phosphorylase (MTAP) gene expression, an absence of the MTAP gene, or a decreased function of the MTAP protein, comprising administering to the subject a therapeutically effective amount of a compound having formula (IA'), (IA), (I), (IIA), (II), (IVA), or (IV) (or embodiments thereof described in the present invention), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

In a seventh aspect, a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or embodiments thereof described in the present invention) or a pharmaceutically acceptable salt thereof is described for inhibiting the synthesis of S-adenosyl methionine (SAM) from methionine and ATP by the enzyme MAT2A in a cell.

In an eighth aspect, a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof described in the present invention) or a pharmaceutically acceptable salt thereof is described for use in the treatment of a disease in a patient, wherein said disease is mediated by overexpression of MAT2A.

In a ninth aspect, a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof described in the present invention) or a pharmaceutically acceptable salt thereof is described for use in the treatment of cancer in a patient, wherein the cancer is characterized by a decrease or absence of methylthioadenosine phosphorylase (MTAP) gene expression, an absence of the MTAP gene or a decreased function of the MTAP protein.

The tenth aspect describes compounds having formula (IV):

(IV),

Where:

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 independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom, and (iii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ represents a hydrogen atom;

R ¹ is a 5- to 8-membered cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl and spiroheterocyclyl are unsubstituted or substituted with R ^d , R ^e and/or R ^f , wherein R ^d and R ^e are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, 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, halogen, cyano or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; or a tautomeric form thereof; or

its pharmaceutically acceptable salt; provided that in the compound having formula (IV):

(1) R ¹ is not (a) 5-hydroxymethyltetrahydrofuran-2-yl or 5-hydroxymethyltetrahydrofuran-2-yl substituted with hydroxy or fluoro; (b) 3-hydroxy-4-hydroxymethylcyclopentyl; and (c) 5-aminomethyltetrahydrofuran-2-yl substituted with fluoro or hydroxy;

(2) when represents , where: (a) when R ³ and R ⁵ are fluorine and R ⁴ and R ⁶ are a hydrogen atom; or R ⁴ and R ⁵ are fluorine and R ³ and R ⁶ are a hydrogen atom; or R ⁵ is fluorine and R ³ , R ⁴ and R ⁶ are a hydrogen atom, then R ¹ is not cyclopentyl or tetrahydrofuran-3-yl; (b) when R ⁵ is chlorine and R ³ , R ⁴ and R ⁶ are a hydrogen atom, then 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) when R ³ is fluorine and R ⁴ , R ⁵ and R ⁶ represent a hydrogen atom, then R ¹ is not 4-chlorophenyl; (d) when R ⁴ is bromine and R ³ , R ⁵ and R ⁶ represent a hydrogen atom, then R ¹ is not 2,4-dibromophenyl or 2-bromo-4-methylphenyl; (e) when R ⁴ is chlorine, R ⁵ is bromine and R ³ and R ⁶ represent a hydrogen atom, then R ¹ is not 3-cyanophenyl, 2-isopropylphenyl, 1-methylpropylphenyl or 3-cyclopropylpyridin-4-yl; (f) when R ⁴ is trifluoromethyl and R ³ , R ⁵ and R ⁶ represent a hydrogen atom, then R ¹ is not 5-chloro-2-hydroxyphenyl or 5-chloro-2-methoxyphenyl; (g) when R ⁴ is 2,2-difluoroethoxy and R ³ , R ⁵ and R ⁶ represent a hydrogen atom, then R ¹ is not piperidin-4-yl; and (h) when R ⁵ is methoxy and R ³ , R ⁴ and R ⁶ represent a hydrogen atom; or R ⁴ and R ⁵ are fluoro, R ³ represents a hydrogen atom and R ⁶ is methyl, then R ¹ is not phenyl;

(3) when represents , then (a) when R ³ and R ⁵ are methyl and R ⁴ is a hydrogen atom, then R ¹ is not 4-ethoxyphenyl; (b) when R ³ is 3-pentyloxy, R ⁵ is methyl and R ⁴ is a hydrogen atom, then R ¹ is not 2,4,6-trimethylphenyl; (c) when R ⁴ and R ⁵ are chlorine and R ³ is a hydrogen atom, then R ¹ is not 2-isopropyl-6-methylphenyl; (d) when R ⁵ is trifluoromethyl and R ³ and R ⁴ are a hydrogen atom, then R ¹ is not phenyl, 4,6-dimethoxypyrimidin-2-yl or 4-hydroxy-6-methoxypyrimidin-2-yl; (e) when R ⁴ is amino and R ³ and R ⁵ are a hydrogen atom, then 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) when R ⁴ is bromine and R ³ and R ⁵ are a hydrogen atom; or R ⁴ is a hydrogen atom and one of R ³ and R ⁵ is methyl and the second of R ³ and R ⁵ is a hydrogen atom; or R ⁴ is a hydrogen atom and R ³ and R ⁵ are methyl; or R ⁵ is amino, R ³ and R ⁴ are a hydrogen atom; R ⁵ is amino, R ³ is a hydrogen atom, and R ⁴ is cyano; or R ⁴ is 2-hydroxyethyl, R ³ is a hydrogen atom, and R ⁵ is methyl, then R ¹ is not phenyl; and (g) R ³ is furan-2-yl, R ⁴ and R ⁵ are a hydrogen atom, then R ¹ is not cyclohexyl;

(4) when represents , then (a) when R ⁴ and R ⁵ are methyl, then R ¹ is not phenyl, 2-chlorophenyl, 3-chlorophenyl, 2-methoxyphenyl, 4-methylphenyl or 4-methoxyphenyl; and

(5) when represents , then when R ³ and R ⁵ are ethylamino or chlorine, then R ¹ is not phenyl.

In one embodiment of the tenth aspect, w, x, y, z, R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ in formula (IV) have the meanings specified in Embodiments 5, 21, 22, 23, 27-34 described below and the sub-embodiments contained therein.

Compounds having formula (IV) can be used as intermediates for the synthesis of compounds having formula (IA), (I), (IIA) and (II), and also inhibit MAT2A.

Detailed description of the invention

Before describing the present invention in detail, it should be understood that the present invention is not limited to the particular embodiments described herein, and it should also be understood that the terminology used is for the purpose of describing particular embodiments only and is not limiting.

The singular used in the description and the Claims also include the plural forms, unless the context clearly states otherwise. It should also be noted that any optional element may be excluded from the Claims. Thus, the terminology of excluding certain features by means of the words "only", "exclusively", etc. in relation to the claimed elements, or the use of "negative" features, is used.

When a range of values is specified, it is to be understood that each value included in the specified range between the upper and lower limits, as well as any separately specified value from this range, unless otherwise clearly follows from the context, are included within the scope of the present invention. The upper and lower limits of narrower ranges can be independently included in narrower ranges that are also encompassed by the present invention, except for the expressly excluded limits in the specified ranges. When the specified ranges include one or both limits, the present invention also includes ranges excluding one or both of these included limits. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by one of ordinary skill in the art to which this invention pertains.

If necessary, any definition given in this text may be used in combination with any other definition to describe a composite structural group. For convenience, the element listed last in such a definition is assumed to be attached to the remainder of the molecule. For example, the composite group alkoxyalkyl means that the alkoxy group is attached to the remainder of the molecule through the alkyl group.

The publications cited in this application are provided solely to describe the prior art as of the filing date of this application. The publication dates cited may differ from the actual publication dates and may require independent confirmation.

Definitions

Unless otherwise specified, the terms used in the description and claims listed below have the meanings indicated below:

“Alkyl” means a linear saturated monovalent hydrocarbon radical containing from one to six carbon atoms, or a branched saturated monovalent hydrocarbon radical containing from three to six carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. One skilled in the art will appreciate that the term “alkyl” may include “alkylene” groups.

“Alkylene” means a linear saturated divalent hydrocarbon radical containing from one to six carbon atoms, or a branched saturated divalent hydrocarbon radical containing from three to six carbon atoms, unless otherwise specified, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc.

“Alkenyl” means a linear monovalent hydrocarbon radical containing from two to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms containing a double bond, such as propenyl, butenyl, etc.

“Alkynyl” means a linear monovalent hydrocarbon radical containing from two to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms containing a triple bond, such as ethynyl, propynyl, butynyl, etc.

“Alkoxy” means an -OR radical where R is an alkyl group as defined above, such as methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, etc.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical containing from one to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms, substituted by one alkoxy group, the definition of which is given above, for example, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl, 2-ethoxyethyl, etc.

“Alkoxyalkoxy” means the -OR radical where R is an alkoxyalkyl as defined above, e.g., methoxyethyloxy, ethyloxypropyloxy, etc.

“Alkoxyalkylamino” means the -NRR' radical where R is a hydrogen atom or alkyl and R' is an alkoxyalkyl as defined above, such as methoxyethylamino, methoxypropylamino, etc.

“Alkylcarbonyl” means a -C(O)R radical where R is alkyl as defined herein, such as methylcarbonyl, ethylcarbonyl, etc.

“Alkoxycarbonyl” means a -C(O)OR radical where R is alkyl as defined above, such as methoxycarbonyl, ethoxycarbonyl, etc.

“Alkoxycarboxyalkyl” means an alkyl radical as defined above that is substituted by an alkoxycarboxy group, such as methylcarboxymethyl, ethylcarboxyethyl, etc.

“Alkylthio” means the -SR radical where R is alkyl as defined above, such as methylthio, ethylthio, etc.

“Alkylsulfonyl” means the _-SO2R radical, where R is alkyl as defined above, such as methylsulfonyl, ethylsulfonyl, etc.

“Alkylsulfonylalkyl” means a -(alkylene) _-SO2R radical where R is alkyl as defined above, such as methylsulfonylethyl, ethylsulfonylmethyl, etc.

“Amino” means -NH ₂ .

“Alkylamino” means a -NHR radical where R is alkyl as defined above, such as methylamino, ethylamino, propylamino or 2-propylamino, etc.

“Aminoalkyl” means a linear monovalent hydrocarbon radical containing from one to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms, substituted with a group -NR'R", where R' and R" independently represent a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or alkylcarbonyl, as defined herein, for example, aminomethyl, aminoethyl, methylaminomethyl, etc.

“Aminoalkoxy” means an -OR radical where R is aminoalkyl as defined above, such as aminoethyloxy, methylaminopropyloxy, dimethylaminoethyloxy, diethylaminopropyloxy, etc.

“Aminoalkylamino” means a -NRR' radical where R is a hydrogen atom or alkyl, and R' is aminoalkyl as defined above, such as aminoethylamino, methylaminopropylamino, dimethylaminoethylamino, diethylaminopropylamino, etc.

“Aminocarbonyl” means the -CONH ₂ radical.

“Alkylaminocarbonyl” means a -CONHR radical where R is alkyl as defined above, such as methylaminocarbonyl, ethylaminocarbonyl, etc.

“Aminosulfonyl” means -SO ₂ NH ₂ radical.

“Aminosulfonylalkyl” means a -(alkylene) _SO2NRR ' radical where R is a hydrogen atom or alkyl, and R' is a hydrogen atom, alkyl or cycloalkyl, or R and R' together with the nitrogen atom to which they are attached form a heterocyclyl as defined above, such as methylaminosulfonylethyl, dimethylsulfonylethyl, etc.

“Alkylaminosulfonyl” means a -SO ₂ NHR radical where R is alkyl as defined above, such as methylaminosulfonyl, ethylaminosulfonyl, etc.

“Aminocarbonylalkyl” means a -(alkylene)-CONRR' radical where R' and R'' are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl as defined herein, such as aminocarbonylethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, etc.

“Aminosulfonylalkyl” means a -(alkylene) _-SO2NRR ' radical where R' and R'' are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl as defined herein, such as aminosulfonylethyl, methylaminosulfonylethyl, dimethylaminosulfonylethyl, etc.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical containing 6 to 10 ring atoms, such as phenyl or naphthyl.

“Aralkyl” means a -(alkylene)-R radical where R is aryl as defined above, such as benzyl, phenethyl, etc.

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

“Bridged cycloalkylalkyl” means a -(alkylene)-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.

"Bridged heterocyclyl" means a saturated monocyclic ring containing 5 to 7 ring carbon atoms in which two non-adjacent atoms are linked by a (CRR')n group, wherein n is from 1 to 3, and each R is independently H or methyl (may also be referred to herein as a "bridged" group), and further wherein one or two ring carbon atoms, including the atom in the bridging group, are replaced by a heteroatom selected from 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, halogen, 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.

“Bridged heterocyclylalkyl” means a -(alkylene)-R radical where R is a bridged heterocyclyl (including certain bridged heterocyclyl rings) as defined above.

“Cycloalkyl” means a monocyclic monovalent hydrocarbon radical containing from three to six carbon atoms, which may be saturated or may contain one double bond. Cycloalkyl may be unsubstituted or have one or two substituents independently selected from alkyl, halogen, 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 cycloalkyl contains a double bond, it may be referred to herein as cycloalkenyl.

“Cycloalkylalkyl” means a -(alkylene)-R radical, wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, and the like.

“Cycloalkylalkyloxy” means an -O-R radical wherein R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyloxy, cyclobutylmethyloxy, and the like.

“Cycloalkyloxyalkyl” means a -(alkylene)-OR radical wherein R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxyethyl, and the like.

“Cycloalkylsulfonylamino” means a -NRSO ₂ -R' radical, where R is hydrogen or alkyl, and R' is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylsulfonylamino, N-cyclopropylsulfonylN(CH ₃ ), and the like.

“Cyanoalkyl” means an alkyl radical as defined above that is substituted by a cyano group, such as cyanomethyl, cyanoethyl, etc.

“Carboxy” means -COOH radical.

“Carboxyalkyl” means an alkyl radical as defined above that is substituted by a carboxy group, such as carboxymethyl, carboxyethyl, etc.

“Deuteroalkyl” means an alkyl radical as defined above wherein 1-6 hydrogen atoms in the alkyl chain are replaced by deuterium atoms. Examples include, but are not limited to, _-CD3 , _-CH2CHD2 , _etc.

“Dialkylamino” means the -NRR' radical where R and R' are alkyl as defined above, such as dimethylamino, methylethylamino, etc.

“Dialkylaminocarbonyl” means a -CONRR' radical where R and R' are alkyl as defined above, such as dimethylaminocarbonyl, diethylaminocarbonyl, etc.

“Dialkylaminosulfonyl” means a -SO ₂ NRR' radical where R and R' are alkyl as defined above, such as dimethylaminosulfonyl, diethylaminosulfonyl, etc.

"Conjugated cycloalkyl" means a saturated monovalent hydrocarbon radical containing from three to six carbon atoms which is conjugated to a phenyl or 5-6 membered heteroaryl ring as defined herein and optionally substituted with one, two or three substituents independently selected from alkyl, halogen, 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.

“Conjugated heterocyclyl” means a heterocyclyl, as defined herein, that is fused to a phenyl or 5-6 membered heteroaryl ring, as defined herein. The conjugated heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halogen, 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.

“Conjugated heterocyclylalkyl” means a -(alkylene)-R radical where R is a conjugated heterocyclyloxy (including certain conjugated heterocyclyl rings) as defined above.

“Halogen” means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

“Haloalkyl” means an alkyl radical as defined above substituted by 1 to 5 halogen atoms such as fluorine or chlorine, including substitution by different halogens, for example, -CH ₂ Cl, -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CF(CH ₃ ) ₂ , etc. When alkyl is substituted only by fluorine, it may be referred to in this text as fluoroalkyl.

“Haloalkoxy” means an -OR radical where R is a haloalkyl as defined above, such as -OCF ₃ , -OCHF ₂ , etc. When R is a haloalkyl in which the alkyl is substituted only by fluorine, it may be referred to in this text as fluoroalkoxy.

“Haloalkoxyalkyl” means an alkyl radical which is substituted by a haloalkoxy group as defined above, such as trifluoromethoxyethyl, etc.

“Heteroalkylene” means a linear saturated divalent hydrocarbon radical containing from two to six carbon atoms, or a branched saturated divalent hydrocarbon radical containing from three to six carbon atoms, wherein one or more carbon atoms are replaced by -O-, -NR-, -NR'CO-, -CONR'-, _SO2NR'- , or _-NR'SO2- , wherein R and R' are independently H or alkyl as defined herein unless otherwise indicated, such as _-CH2O- , _-OCH2- , -( _CH2 ) _2O- , -O( _CH2 ) _2- , -( _CH2 ) _2NH- , -NH( _CH2 ) _2- , etc.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical containing from one to six carbon atoms, or a branched monovalent hydrocarbon radical containing from three to six carbon atoms, substituted by one or two hydroxy groups, provided that if two hydroxy groups are present, they cannot both be located 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.

“Hydroxyalkoxy” means an -OR radical where R is hydroxyalkyl as defined above, such as hydroxyethyloxy, hydroxypropyloxy, etc.

“Hydroxyalkylamino” means a -NRR' radical where R is a hydrogen atom or alkyl, and R' is hydroxyalkyl as defined above, such as hydroxyethylamino, hydroxypropylamino, etc.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical containing 5-10 ring atoms, unless otherwise indicated, wherein one or more (in one embodiment, one, two or three) ring atoms are a heteroatom selected from N, O or S, and the remaining ring atoms are carbon atoms. Non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolyl, phthalazinyl, benzotriazinyl, purinyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazalyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, etc., and the terms “heteroaryl” and “aryl” are mutually exclusive. When a heteroaryl ring contains 5 or 6 ring atoms, it is also referred to in this text as a 5- or 6-membered heteroaryl.

“Heteroaralkyl” means an -(alkylene)-R radical where R is heteroaryl (including particular ring variants) as defined above.

“Heteroaryloxy” means -OR, where R is heteroaryl (including particular ring variations) as defined above.

“Heteroaralkyloxy” means an -O-(alkylene)-R radical where R is heteroaryl (including particular ring variants) as defined above.

“Heteroarylcarbonyl” means -COR, where R is heteroaryl (including particular ring variations) as defined above.

“Heteroarylamino” means -NRR', where R is hydrogen or alkyl, and R' is heteroaryl (including particular ring variations) as defined above.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclic group containing 4 to 8 ring atoms, in which one or two ring atoms are a heteroatom selected from N, O, or S(O) _n , where n is an integer from 0 to 2, and the remaining atoms are C. Furthermore, one or two carbon atoms in the heterocyclyl ring may optionally be 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 a heterocyclyl ring is unsaturated, it may contain one or two double bonds in the ring, provided that the ring is not aromatic. When a heterocyclyl contains at least one nitrogen atom, it may be referred to in this text as heterocycloamino.

“Heterocyclylalkyl” means a -(alkylene)- R radical, where R is a heterocyclyl (including particular variants of the heterocyclyl ring) as defined above. For example, oxetanylethyl, piperidinylethyl, etc.

“Heterocyclyloxy” means the -OR radical where R is heterocyclyl (including particular variations of the heterocyclyl ring) as defined above.

“Heterocyclylalkyloxy” means an -O-(alkylene)-R radical, where R is a heterocyclyl (including particular variants of the heterocyclyl ring) as defined above. For example, oxetanylethyloxy, piperidinylethyloxy, etc.

“Heterocyclylcarbonyl” means -COR, where R is heterocyclyl (including particular ring variations) as defined above.

“Heterocyclylamino” means the -NRR' radical, where R is hydrogen or alkyl and R' is heterocyclyl (including particular variations of the heterocyclyl ring) as defined above.

“Heterocyclyloxyalkyl” means a -(alkylene)-OR radical where R is heterocyclyl (including particular variants of the heterocyclyl ring) as defined above. For example, oxetanyloxyethyl, piperidinyloxyethyl, etc.

“Heterocyclyloxyalkoxy” means an -O-(alkylene)-R radical, where R is heterocyclyloxy (including particular variants of the heterocyclyl ring) as defined above. For example, oxetanyloxyethyloxy, piperidinyloxyethyloxy, etc.

“Heterocyclyloxyalkylamino” means -NR-(alkylene)-R' radical, where R is hydrogen or alkyl, and R' is heterocyclyloxy (including particular embodiments of the heterocyclyl ring) as defined above. For example, oxetanyloxyethylamino, piperidinyloxyethylamino, etc.

The term “oxo” when used in this text alone or in combination means =(O).

The term "pharmaceutically acceptable salts" includes salts of the active substances prepared with relatively non-toxic acids or bases, depending on the particular substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be prepared by reacting the neutral form of such compounds with a sufficient amount of the desired base, without a solvent or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron (II), iron (III), lithium, magnesium, manganese, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines, etc., 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, purines, theobromine, thiethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be prepared by reacting the neutral form of such compounds with a sufficient amount of the desired acid, without a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts with inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrophosphoric, dihydrophosphoric, sulfuric, monohydrosulfuric, hydroiodic or phosphorous acid and the like, as well as salts with relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic and the like. Also included are salts with amino acids such as arginates and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge, S. M., et al, “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain particular compounds of the present invention contain both basic and acidic functional groups, allowing such compounds to form both base addition and acid addition salts.

Neutral forms of the compounds can be regenerated by reacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound differs from the various salt forms in certain physical characteristics, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent compounds for the purposes of the present invention.

The present invention also includes protected derivatives of the compounds of the present invention. For example, when the compounds of the present invention contain groups such as a hydroxy group, a carboxy group, a thiol group, or any group containing nitrogen atom(s), these groups can be protected with suitable protecting groups. A complete list of suitable protecting groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, ^5th Ed., John Wiley & Sons, Inc. (2014), the entire contents of which are incorporated herein by reference. Protected derivatives of the compounds of the present invention can be prepared by methods well known in the art.

The present invention also includes prodrugs of a compound of formula (I) (IA), (II), (IIA) and (IVA) and (IV), or a pharmaceutically acceptable salt thereof. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield the compounds of the present invention. A non-limiting example of a prodrug is a compound that is administered as an ester (a "prodrug"), which is then metabolically hydrolyzed to a carboxylic acid that is the active ingredient. In addition, prodrugs can be converted into the compounds of the present invention by chemical or biochemical methods in an ex vivo setting. For example, prodrugs can be slowly converted into the compounds of the present invention by placing them in a reservoir of a transdermal patch with a suitable enzymatic or chemical reagent.

Certain compounds of formula (I) (IA), (II), (IIA) and (IVA) and (IV) may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms, and all are encompassed by the present invention. Certain compounds of formula (I) (IA), (II), (IIA) and (IVA) and (IV) may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses covered by the present invention and are within the scope of the present invention.

Some compounds having formula (I) (IA), (II), (IIA) and (IVA) and (IV) have asymmetric carbon atoms (optical centers) or double bonds; all racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are within the scope of the present invention. When a stereochemical structure is indicated, it means a compound in which one of the isomers is present and which contains substantially no other isomer. "Substantially free" of another isomer means a ratio of the two isomers of at least 80/20, more preferably 90/10, or 95/5 or more. In some embodiments, one of the isomers is present in an amount of at least 99%.

Compounds having formulae (I) (IA), (II), (IIA) and (IVA) and (IV) may also contain unnatural amounts of isotopes of one or more of the atoms comprising such compounds. An unnatural amount of an isotope may be defined as a range from the naturally occurring amount to 100% of the atom in question. Examples of isotopes that can be included in the compounds of the present invention, such as compounds of formula (I) (IA), (II), (IIA) and (IVA) and (IV), (and any variants thereof described herein, including particular variants of the compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 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 I, respectively. Isotopically labeled compounds (e.g., compounds labeled with ³ H and ¹⁴ C isotopes) can be ^used in tissue distribution studies of the compound. Tritium (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) labeled compounds can be used to facilitate their preparation and detection. In addition, substitution with heavy isotopes such as deuterium (i.e., ² H) can provide some therapeutic advantages due to higher metabolic stability (e.g., increased half-life in vivo or reduced dosage requirements). In some embodiments, the compounds described herein, including the compounds in Table 1 below, have one or more hydrogen atoms replaced with ² H or ³ H, or one or more carbon atoms replaced with ¹³ C- or ¹⁴ C-rich carbon. Positron-emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁵ F can be used in positron emission tomography (PET) used to determine the degree of receptor occupancy by a substrate. Isotopically labeled compounds can generally be prepared by methods similar to those described in the schemes or examples in this application, by replacing the non-isotopically labeled compound with an isotopically labeled reagent.

“Optionally substituted aryl” means aryl that is optionally substituted with one, two, or three substituents independently selected from alkyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, haloalkyl, haloalkoxy, and cyano.

“Optionally substituted heteroaryl” means a heteroaryl, as defined above, that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

“Optionally substituted heterocyclyl” means a heterocyclyl, as defined above, that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halogen, haloalkyl, haloalkoxy, and cyano, unless otherwise specified.

"Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and not in any way objectionable, or an excipient that is acceptable for veterinary use as well as for human pharmaceutical use. The term "pharmaceutically acceptable carrier/excipient" as used in this specification and in the claims includes both one and more than one such excipient.

“Spirocycloalkyl” means a saturated bicyclic ring containing 6-10 carbon atoms in the ring, wherein the rings are connected through only one atom, and the connecting atom is also called a spiro atom, most often a quaternary carbon atom (“spiro carbon atom”). The spirocycloalkyl ring is optionally substituted with one or two substituents independently selected from alkyl, halogen, 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.

“Spirocycloalkylalkyl” means a radical -(alkylene)-R, where R is spirocycloalkyl (including certain spirocycloalkyls), as defined above.

“Spiroheterocyclyl” means a saturated bicyclic ring containing 6-10 ring atoms, wherein one, two or three of the ring atoms are a heteroatom 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, and the connecting atom is also called a spiro atom, most often a quaternary carbon atom (“spiro carbon atom”). Spirogeterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halogen, 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, etc.

“Spiroheterocyclylalkyl” means the radical -(alkylene)-R, where R is spiroheterocyclyl (including certain spiroheterocyclyls), as defined above.

“Sulfonylamino” means a radical _-NRSO2R ', where R is hydrogen or alkyl, and R' is alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, as defined herein.

“Substituted cycloalkyl” means a saturated monocyclic monovalent hydrocarbon radical containing from three to six carbon atoms that is substituted with one, two, or three substituents, wherein two of the three substituents are independently selected from alkyl, halogen, alkoxy, hydroxy, haloalkyl, or haloalkoxy, and the third substituent is alkyl, halogen, hydroxyalkyl, haloalkyl, haloalkoxy, or cyano. Examples include, but are not limited to, 3-hydroxy-3-trifluorocyclobutyl, 2,2-dimethyl-3-hydroxycyclobutyl, and the like.

“Substituted cycloalkylalkyl” means -(alkylene)-substituted cycloalkyl, wherein each term has the meaning specified herein. Examples include, but are not limited to, 1-hydroxymethylcycloprop-1-ylmethyl, and the like.

The term “about” or “approximately” in this text means a numerical value which it modifies by indicating that such value represents a variable within the error limits. When no specific error value is given, such as a standard deviation from the mean value indicated in a graph or table, the term “about” or “approximately” should be understood as indicating a range covering ±10%, preferably ±5%, of the stated value.

The term “disease” in this text is understood to be generally synonymous with and used interchangeably with the terms “disorder,” “disorder,” “syndrome,” and “condition” (as in describing a medical or pathological condition), all of which terms reflect an abnormal condition of the human or animal body or one of its parts that interferes with normal functioning, usually manifests itself in the form of specific signs and symptoms, and causes a decrease in the life expectancy of a human or animal or a reduction in the quality of life.

The term “patient” is generally synonymous with the term “subject” and, when used herein, includes all mammals, including humans. Examples of patients include humans, farm animals such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

The term "in need of treatment" as used herein means the judgment of the treating physician or other person providing care to the subject that the subject needs treatment or that treatment would benefit the subject. Such judgment is based on a number of factors that are within the professional judgment of the treating physician or other person providing care to the subject.

The terms "administration", "administer", etc., when used with respect to, for example, a patient, a cell, tissue, organ or biological fluid, mean contact of, for example, a compound having formula (I), a pharmaceutical composition containing it or a diagnostic agent, with the subject, cell, tissue, organ or biological fluid. In the case of a cell, administration includes contact (for example, in vitro or ex vivo) of a reagent with the cell, as well as contact of the reagent with a liquid, where the liquid is in contact with the cell.

"A therapeutically effective amount" as used herein means an amount of a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof described herein and/or a pharmaceutically acceptable salt thereof, which when administered to a patient for the treatment of a disease, alone or as part of a pharmaceutical composition, in a single dose or as part of a dose series, is sufficient to provide the desired treatment for the disease. "A therapeutically effective amount" varies depending on the compound, the disease and its severity, as well as the age, body weight, etc. of the mammal being treated. A therapeutically effective amount can be determined by measuring relevant physiological effects and can be selected in conjunction with the administration regimen and diagnostic analysis of the subject's condition, etc. For example, measuring the blood level of a compound of formula (I) (or, for example, a metabolite thereof) at a certain time after administration may be indicative of whether a therapeutically effective amount has been administered.

“Treatment” of the disease includes:

(1) preventing a disease, i.e. preventing the development of clinical symptoms of a disease in a mammal that may be susceptible or predisposed to the disease but does not yet experience or exhibit symptoms of the disease;

(2) suppression of the disease, i.e. stopping or reducing the progression of the disease or its clinical symptoms; or

(3) alleviation of the disease, i.e. causing regression of the disease or its clinical symptoms.

"Inhibition," "attenuation," "reduction," or any variation of these terms with respect to MAT2A includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in MAT2A activity by about, at most, 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, or any range therebetween, compared to normal activity.

“Ureido” means a radical -NHCONRR', where R and R' independently represent a hydrogen atom or an alkyl atom as defined above, for example, -NHCONHmethyl, -NHCON(CH ₃ ) ₂ , etc. “Thioureidoalkyl” means a radical -(alkylene)-NHSO ₂ NRR', where R and R' independently represent a hydrogen atom or an alkyl atom as defined above, for example, -ethylene-NHSO ₂ NHmethyl, -propylene-NHSO ₂ NH ₂ , etc.

Representative compounds having formula (I) are listed below in Table 1.

Table 1 Conn. Structure Name Mass spectrum 1 4,7-dichloro-1-phenylquinazolin-2(1H)-one 2 7-chloro-4-(methylamino)-1-phenyl-quinazolin-2(1H)-one 3 7-bromo-4-(methylamino)-1-phenyl-quinazolin-2(1H)-one 4 7-fluoro-1-phenylquinazolin-2(1H)-one 5 7-chloro-1-(5-fluoro-3-hydroxy-phenyl)-4-(methylamino)-hydroquinazolin-2-one 6 7-chloro-6-fluoro-4-(methylamino)-1-phenyl-quinazolin-2(1H)-one 7 7-chloro-5-fluoro-4-(methylamino)-1-phenyl-quinazolin-2(1H)-one 8 7-chloro-4-(methylamino)-1-(pyridin-4-yl)-quinazolin-2(1H)-one 9 7-chloro-4-(methylamino)-1-(pyridin-3-yl)-quinazolin-2(1H)-one 10 7-chloro-4-(methylamino)-1-(pyridin-2-yl)-quinazolin-2(1H)-one 11 7-chloro-4-(methylamino)-1-pyrimidin-2-yl-quinazolin-2(1H)-one 12 7-chloro-4-(methylamino)-1-(pyrazin-2-yl)-quinazolin-2(1H)-one 13 7-chloro-4-(methylamino)-1-(pyridazin-3-yl)-quinazolin-2(1H)-one 14 7-chloro-4-(methylamino)-1-(pyrimidin-5-yl)-quinazolin-2(1H)-one 15 7-chloro-4-(methylamino)-1-(1H-pyrazol-4-yl)-quinazolin-2(1H)-one 16 7-chloro-1-(1H-imidazol-2-yl)-4-(methylamino)-quinazolin-2(1H)-one 17 7-chloro-4-(methylamino)-1-(thiazol-2-yl)-quinazolin-2(1H)-one 18 7-chloro-4-(methylamino)-1-(thiazol-5-yl)-quinazolin-2(1H)-one 19 7-chloro-4-(methylamino)-1-(1H-pyrazol-5-yl)-quinazolin-2(1H)-one 20 7-chloro-4-(cyclopropylamino)-1-phenylquinazolin-2(1H)-one 21 7-chloro-4-(oxetan-3-ylamino)-1-phenylquinazolin-2(1H)-one 22 (S)-7-chloro-1-phenyl-4-((tetrahydro-furan-3-yl)amino)-quinazolin-2(1H)-one 23 4-(benzylamino)-7-chloro-1-phenyl-quinazolin-2(1H)-one 24 7-chloro-4-(dimethylamino)-1-phenyl-quinazolin-2(1H)-one 25 4-(azetidin-1-yl)-7-chloro-1-phenyl-quinazolin-2(1H)-one 26 (S)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one 27 7-chloro-4-(4-methylpiperazin-1-yl)-1-phenyl-quinazolin-2(1H)-one 28 7-chloro-4-morpholino-1-phenyl-quinazolin-2(1H)-one 29 7-chloro-1-phenyl-4-(1H-pyrazol-1-yl)quinazolin-2(1H)-one 30 7-chloro-4-(ethylamino)-1-phenyl-quinazolin-2(1H)-one 31 7-chloro-4-((2,2-difluoroethyl)amino)-1-phenyl-quinazolin-2(1H)-one 32 7-chloro-1-phenyl-4-(pyridin-2-yl-amino)quinazolin-2(1H)-one 33 7-chloro-1-phenyl-4-(pyridin-4-yl-amino)quinazolin-2(1H)-one 34 7-bromo-4-(dimethylamino)-1-phenyl-quinazolin-2(1H)-one 35 4-(dimethylamino)-7-fluoro-1-phenyl-quinazolin-2(1H)-one 36 4-(dimethylamino)-7-chloro-1-(4-fluorophenyl)-hydroquinazolin-2-one 37 4-(dimethylamino)-7-chloro-1-(5-fluoro-3-hydroxyphenyl)hydro-quinazolin-2-one 38 4-azetidinyl-7-chloro-1-(5-fluoro-3-hydroxyphenyl)hydroquinazolin-2-one 39 7-chloro-4-(cyclopropylmethylamino)-1-(3-fluorophenyl)hydroquinazolin-2-one 40 4-amino-7-chloro-1-(5-fluoro-3-hydroxyphenyl)-hydroquinazolin-2-one 41 4-amino-7-chloro-1-(4-fluorophenyl)-hydro-quinazolin-2-one 42 7,8-dichloro-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one 43 7-chloro-4-(dimethylamino)-8-methyl-1-phenyl-quinazolin-2(1H)-one 44 7-methyl-4-(methylamino)-1-phenyl-quinazolin-2(1H)-one 45 7-cyclopropyl-4-(methylamino)-1-phenylquinazolin-2(1H)-one 46 7-chloro-1-(3-hydroxyphenyl)-4-(methylamino)-hydroquinazolin-2-one 47 7-chloro-1-[3-(2-hydroxyethyl)phenyl]-4-(methylamino)-hydroquinazolin-2-one 48 7-chloro-1-[3-(3-hydroxypropyl)-phenyl]-4-(methylamino)hydro-quinazolin-2-one 49 7-methoxy-4-(methylamino)-1-phenyl-quinazolin-2(1H)-one 50 4-(methylamino)-2-oxo-1-phenyl-1,2-dihydro-quinazoline-7-carbonitrile 51 4-(methylamino)-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one 52 N-(3-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)-methanesulfonamide 54 4-(dimethylamino)-7-chloro-1-(3-hydroxyphenyl)hydroquinazolin-2-one 55 7-chloro-4-(methylamino)-1-(3-methylphenyl)hydroquinazolin-2-one 56 7-chloro-1-(3-chlorophenyl)-4-(methylamino)hydroquinazolin-2-one 57 7-chloro-1-(2-fluorophenyl)-4-(methylamino)quinazolin-2(1H)-one 58 7-chloro-4-(methylamino)-1-(2-methylphenyl)hydroquinazolin-2-one 59 4-amino-7-chloro-1-phenylquinazolin-2(1H)-one 60 1-(3-bromophenyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one 61 7-chloro-1-(3-fluorophenyl)-4-(methylamino)quinazolin-2(1H)-one 62 7-chloro-4-methoxy-1-phenyl-quinazolin-2(1H)-one 63 7-chloro-4-((2-(dimethylamino)ethyl)-(methyl)-amino)-1-phenylquinazolin-2(1H)-one 64 7-chloro-4-((2-(dimethylamino)ethyl)-amino)-1-phenylquinazolin-2(1H)-one 65 4-amino-7-chloro-1-cyclohexyl-quinazolin-2(1H)-one 66 7-chloro-1-phenyl-4-(piperidin-1-yl)-quinazolin-2(1H)-one 67 7-chloro-1-phenyl-4-(pyrrolidin-1-yl)-quinazolin-2(1H)-one 68 7-methyl-4-(methylamino)-1-phenyl-pyrido[2,3-d]pyrimidin-2(1H)-one 69 7-methyl-4-(methylamino)-1-phenyl-pyrido[4,3-d]pyrimidin-2(1H)-one 70 7-chloro-5-methoxy-4-(methylamino)-1-phenylquinazolin-2(1H)-one 71 7-chloro-1-(3-methoxyphenyl)-4-(methylamino)quinazolin-2(1H)-one 73 7-chloro-6-methoxy-4-(methylamino)-1-phenylquinazolin-2(1H)-one 74 7-chloro-4-(3-hydroxyazetidin-1-yl)-1-phenylquinazolin-2(1H)-one 75 7-chloro-4-(dimethylamino)-1-(3-(2-phenoxyethyl)phenyl)quinazolin-2(1H)-one 76 4-(dimethylamino)-7-chloro-1-(3-methoxyphenyl)hydroquinazolin-2-one 77 4-(dimethylamino)-7-chloro-1-[3-(hydroxymethyl)phenyl]hydroquinazolin-2-one 78 4-(dimethylamino)-7-(oxetan-3-yl)-1-phenylquinazolin-2(1H)-one 79 4-(dimethylamino)-1-phenyl-7-(tetrahydrofuran-3-yl)quinazolin-2(1H)-one 80 (R)-7-chloro-4-(3-fluoropyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one 81 3-[4-(dimethylamino)-7-chloro-2-oxohydroquinazolinyl]benzenecarbonitrile 82 1-(7-chloro-1-(3-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)azetidin-3-carbonitrile 83 7-chloro-1-(3-fluorophenyl)-4-((3-hydroxypropyl)(methyl)amino)quinazolin-2(1H)-one 85 5-azetidin-3-yloxy-7-chloro-4-(methylamino)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 357.1 86 7-chloro-4-(methylamino)-1-[3-(trifluoromethyl)phenyl]hydroquinazolin-2-one m/z [M+H]+ 354.04 87 4-((3R)-3-hydroxypyrrolidin-1-yl)-1-(2-bromophenyl)-7-chlorohydroquinazolin-2-one m/z [M+H]+ 420.04 88 1-(2-chlorophenyl)-4-((1-methylcyclo-propyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 395.05 89 1-(2-chlorophenyl)-4-[(2,2-difluoroethyl)amino]- 7-(trifluoromethyl)-pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 405.1 90 1-(2-methoxypyridin-4-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 352.0 91 1-(6-methoxypyridin-2-yl)-4-(methylamino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 352.0 92 1-(4-methoxypyridin-3-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 352.0 93 1-(4-methoxypyridin-2-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 352.0 94 4,7-di(azetidin-1-yl)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 333.2 94 4,7-bis(dimethylamino)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 309.2 96 4-(methylamino)-1-phenyl-7-vinylhydroquinazolin-2-one m/z [M+H]+ 278.15 97 4-(methylamino)-1-phenyl-7-propylhydroquinazolin-2-one m/z [M+H]+ 294.2 99 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 340.0 100 1-(2-chlorophenyl)-4-[(2,2-difluoroethyl)amino]-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 404.0 101 1-(2-chlorophenyl)-4-[(2,2,2-trifluoroethyl)amino]-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 422.0 102 1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 354.1 103 1-(2-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 341.0 104 7-chloro-4-(methylethyl)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 299.19 105 7-chloro-4-ethyl-1-phenylhydroquinazolin-2-one m/z [M+H]+ 285.21 106 7-chloro-1-(4-methoxypyrimidin-2-yl)-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 318.12 107 3-(7-chloro-2,4-dioxo-3,4-dihydro-quinazolin-1(2H)-yl)-2-methyl-benzonitrile m/z [M+H]+ 310.13 108 3-(7-chloro-2,4-dioxo-3,4-dihydro-quinazolin-1(2H)-yl)-4-methyl-benzonitrile m/z [M+H]+ 310.06 109 7-chloro-1-(3-hydroxy-6-methylphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 316.18 110 7-chloro-1-(3-hydroxy-2-methylphenyl)-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 303.13 112 4-amino-7-chloro-1-phenyl-5-(1,2,3-triazol-2-yl)hydroquinazolin-2-one m/z [M+H]+ 339.11 113 7-chloro-4-(methylamino)-1-[4-(trifluoromethyl)(1,3-thiazol-2-yl)]hydroquinazolin-2-one m/z [M+H]+ 361.0 114 7-chloro-4-(methylamino)-1-(3-pyridyl)-hydroquinazolin-2-one m/z [M+H]+ 287.1 115 7-ethyl-4-(methylamino)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 280.1 116 7-chloro-1-(5-methyl(1,3-thiazol-2-yl))-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 307.0 117 7-chloro-1-(4-methyl(1,3-thiazol-2-yl))-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 307.0 118 1-phenyl-4-[(2,2,2-trifluoroethyl)amino]-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 388.0 119 4-[(2,2-difluoroethyl)amino]-1-phenyl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 370.0 120 4-methoxy-1-pyrimidin-2-yl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 323.0 121 1-pyrimidin-2-yl-4-[(2,2,2-trifluoroethyl)amino]-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 390.0 122 4-[(2,2-difluoroethyl)amino]-1-pyrimidin-2-yl-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 372.0 123 4-(methylamino)-1-pyrimidin-2-yl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 322.0 124 4-amino-1-pyrimidin-2-yl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 308.0 125 4-amino-1-(2-methylphenyl)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 320.0 126 1-(2-methylphenyl)-4-[(2,2,2-trifluoroethyl)amino]-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 402.0 127 4-[(2,2-difluoroethyl)amino]-1-(2-methylphenyl)-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 384.0 128 4-((3R)-3-hydroxypyrrolidin-1-yl)-1-(2-methylphenyl)-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 390.0 129 4-(methylamino)-1-(2-methylphenyl)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 334.0 130 7-cyclopropyl-1-phenyl-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 279.21 132 tert-butyl 3-[7-chloro-4-(methylamino)-2-oxo-1-phenylhydroquinazolin-5-yl-oxy]azetidine carboxylate m/z [M+H]+ 457.13 133 3-[7-chloro-4-(methylamino)-2-oxo-hydroquinazolin-1-yl]benzoic acid m/z [M+H]+ 330.11 134 3-[7-chloro-4-(methylamino)-2-oxo-hydroquinazolin-1-yl]benzamide m/z [M+H]+ 329.11 135 4-((3R)-3-hydroxypyrrolidin-1-yl)-7-chloro-1-(2-chlorophenyl)hydro-quinazolin-2-one m/z [M+H]+ 376.10 136 1-phenyl-4-((2,2,2-trifluoroethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 389.0 137 4-((2,2-difluoroethyl)amino)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 371.0 138 4-amino-1-phenyl-7-(trifluoromethyl)-hydropyridino[2,3-d]pyrimidin-2-one m/z [M+H]+ 307.0 139 3-[4-(3-hydroxyazetidinyl)-2-oxo-7-(trifluoromethyl)hydroquinazolinyl]benzenecarbonitrile m/z [M+H]+ 387.0 140 3-[4-amino-2-oxo-7-(trifluoromethyl)-hydroquinazolinyl]benzenecarbonitrile m/z [M+H]+ 331.0 141 3-[4-((3R)-3-hydroxypyrrolidinyl)-2-oxo-7-(trifluoromethyl)hydroquinazolinyl]benzenecarbonitrile m/z [M+H]+ 401.1 142 3-[4-(methylamino)-2-oxo-7-(trifluoromethyl)hydroquinazolinyl]benzenecarbonitrile m/z [M+H]+ 345.1 143 7-(difluoromethyl)-4-(methylamino)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 302.0 144 4-methoxy-1-phenyl-7-(trifluoromethyl)-hydroquinazolin-2-one m/z [M+H]+ 321.0 145 4-((3R)-3-hydroxypyrrolidinyl)-1-phenyl-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 376.0 146 4-amino-1-phenyl-7-(trifluoromethyl)-hydroquinazolin-2-one m/z [M+H]+ 306.0 147 1-(2-methylphenyl)-7-(trifluoromethyl)-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 321.0 148 4-amino-7-chloro-1-(2-chlorophenyl)-hydroquinazolin-2-one m/z [M+H]+ 307.06 149 4-amino-1-(2-bromophenyl)-7-chlorohydroquinazolin-2-one m/z [M+H]+ 349.98 150 4-amino-7-methyl-1-phenylhydropyridino[2,3-d]pyrimidin-2-one m/z [M+H]+ 353.24 151 4-((3R)-3-hydroxypyrrolidin-1-yl)-7-chloro-1-(2-methoxyphenyl)hydro-quinazolin-2-one m/z [M+H]+ 372.10 153 4-((3R)-3-hydroxypyrrolidin-1-yl)-7-chloro-1-(2-chlorophenyl)hydro-quinazolin-2-one m/z [M+H]+ 376.04 154 4-amino-7-chloro-1-(2-methylphenyl)-hydroquinazolin-2-one m/z [M+H]+ 386.0 155 3-[7-chloro-4-(methylamino)-2-oxo-hydroquinazolinyl]benzenecarbonitrile m/z [M+H]+ 311.12 156 3-(7-chloro-4-hydroxy-2-oxohydro-quinazolinyl)benzoic acid m/z [M+H]+ 317.06 157 7-chloro-1-(3-hydroxy-2-methylphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 316.12 159 [1-(7-chloro-2-oxo-1-phenylhydroquinazolin-4-yl)azetidin-3-yl]-N,N-dimethylcarboxamide m/z [M+H]+ 383.1 160 7-(chloromethyl)-4-(methylamino)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 300.0 161 1-(2-chlorophenyl)-4-(3-hydroxy-azetidinyl)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 397.1 162 3-(4-(3-hydroxyazetidin-1-yl)-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile m/z [M+H]+ 388.1 163 4-amino-7-bromo-1-phenylhydro-quinazolin-2-one m/z [M+H]+ 316.0 164 4-(3-hydroxyazetidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 362.0 165 4-(3-hydroxyazetidinyl)-1-(2-methyl-phenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 377.24 166 7-(difluoromethyl)-1-phenyl-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 289.0 167 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 341.10 168 3-(4-amino-2-oxo-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-1(2H)-yl)-benzonitrile m/z [M+H]+ 332.10 169 4-amino-1-(2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 321.1 170 (R)-4-(3-hydroxypyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 377.15 171 4-(3-hydroxyazetidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 363.0 172 (S)-7-chloro-4-(2-(hydroxymethyl)-azetidin-1-yl)-1-phenylquinazolin-2(1H)-one m/z [M+H]+ 342.1 173 3-[7-chloro-4-(methylamino)-2-oxo-hydroquinazolinyl]-2-methylbenzenecarbonitrile m/z [M+H]+ 325.11 174 3-(7-chloro-4-(methylamino)-2-oxo-quinazolin-1(2H)-yl)-2-methyl-benzonitrile m/z [M+H]+ 325.11 175 3-(7-chloro-4-(methylamino)-2-oxo-quinazolin-1(2H)-yl)benzamide m/z [M+H]+ 343.1 176 1-(2-chlorophenyl)-4-(pyrrolidin-1-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 395.10 177 3-(2-oxo-4-(pyrrolidin-1-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile m/z [M+H]+ 385.15 178 1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 355.10 179 3-[4-(methylamino)-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile m/z [M+H]+ 346.1 180 4-(methylamino)-1-(2-methylphenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 335.10 181 (S)-1-(2-chlorophenyl)-4-(3-hydroxy-pyrrolidin-1-yl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 411.10 182 (S)-3-(4-(3-hydroxypyrrolidin-1-yl)-2-oxo-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile m/z [M+H]+ 402.1 183 (R)-4-(3-hydroxypyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 391.2 184 4-(methylamino)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 321.1 185 7-chloro-5-(2-hydroxyethoxy)-4-(methylamino)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 346.17 186 7-chloro-4-[2-(hydroxymethyl)azetidin-1-yl]-1-phenylhydroquinazolin-2-one m/z [M+H]+ 342.17 187 (R)-7-chloro-4-(2-(hydroxymethyl)-azetidin-1-yl)-1-phenylquinazolin-2(1H)-one m/z [M+H]+ 342.17 188 7-chloro-4-(methylamino)-1-(1-methyl-imidazol-2-yl)hydroquinazolin-2-one m/z [M+H]+ 290.0 189 (R)-7-chloro-4-(3-methoxypyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one m/z [M+H]+ 356.24 190 7-chloro-4-(methylamino)-2-oxo-1-phenylhydroquinazoline-6-carbonitrile m/z [M+H]+ 311.18 191 7-chloro-1-phenylhydroquinazolin-2-one m/z [M+H]+ 257.26 192 7-methyl-4-(methylamino)-1-phenyl-pyrido[3,2-d]pyrimidin-2(1H)-one m/z [M+H]+ 267.29 193 7-methyl-1-phenylpyrido[3,2-d]-pyrimidine-2,4(1H,3H)-dione m/z [M+H]+ 254.24 194 7-methyl-1-phenylpyrimido[4,5-d]-pyrimidine-2,4(1H,3H)-dione m/z [M+H]+ 254.26 195 (2S)-1-(7-chloro-2-oxo-1-phenylhydro-quinazolin-4-yl)pyrrolidine-2-carboxylic acid m/z [M+H]+ 370.12 196 (S)-7-chloro-4-(3-methoxypyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one m/z [M+H]+ 356.24 197 7-chloro-4-[methylbenzylamino]-1-phenylhydroquinazolin-2-one m/z [M+H]+ 376.24 188 2-((7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)(methyl)amino)-N-methylacetamide m/z [M+H]+ 343.10 199 Methyl 1-(7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)azetidine-3-carboxylate m/z [M+H]+ 370.10 200 N-(7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)methanesulfonamide m/z [M+H]+ 350.04 201 4-(3-aminopyrrolidin-1-yl)-7-chloro-1-phenylquinazolin-2(1H)-one m/z [M+H]+ 341.11 202 7-chloro-4-(methylamino)-5-oxetan-3-yloxy-1-phenylhydroquinazolin-2-one m/z [M+H]+ 358.10 203 N-(7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)acetamide m/z [M+H]+ 314.12 204 1-(7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)-N-methyl-azetidine-3-carboxamide m/z [M+H]+ 369.22 205 4-[(2,2-difluoroethyl)methylamino]-7-chloro-1-phenylhydroquinazolin-2-one m/z [M+H]+ 350.10 206 7-chloro-4-(2-oxoazetidin-1-yl)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 326.17 207 4-(3,3-difluoropyrrolidin-1-yl)-7-chloro-1-phenylhydroquinazolin-2-one m/z [M+H]+ 328.17 208 7-chloro-4-(methylamino)-1-phenyl-5-(1H-pyrazol-1-yl)quinazolin-2(1H)-one m/z [M+H]+ 352.18 209 7-chloro-4-(methylamino)-1-phenyl-5-(1,2,3-triazol-2-yl)quinazolin-2(1H)-one m/z [M+H]+ 353.1 210 7-chloro-1-(4-hydroxypyrimidin-2-yl)-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 291.0 211 4-(dimethylamino)-7-chloro-1-(3-{[(methylcyclopropyl)sulfonyl]amino}phenyl)-hydroquinazolin-2-one m/z [M+H]+ 433.1 212 7-(hydroxymethyl)-1-phenyl-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 269.0 213 ethyl 2,4-dioxo-1-phenyl-1,3-dihydro-quinazoline-7-carboxylate m/z [M+H]+ 311.0 214 7-chloro-4-(methylamino)-1-pyrazol-5-ylhydroquinazolin-2-one m/z [M+H]+ 276.1 215 7-chloro-1-(1-methylimidazol-2-yl)-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 277.1 216 4-((3S)-3-hydroxy-3-methylpyrrolidin-1-yl)-7-chloro-1-phenylhydroquinazolin-2-one m/z [M+H]+ 256.12 217 4-((3R)-3-hydroxy-3-methylpyrrolidin-1-yl)-7-chloro-1-phenylhydroquinazolin-2-one m/z [M+H]+ 256.12 218 7-chloro-1-(2-chlorophenyl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H]+ 320.0 219 2-(7-chloro-4-(methylamino)-2-oxo-quinazolin-1(2H)-yl)benzonitrile m/z [M+H]+ 311.0 220 2-((7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)(methyl)amino)-N,N-dimethylacetamide m/z [M+H]+ 371.18 221 2-((7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)(methyl)amino)-,N-methylacetamide m/z [M+H]+ 357.12 222 4-(3-azabicyclo[3.1.0]hex-3-yl)-7-chloro-1-phenylhydroquinazolin-2-one m/z [M+H]+ 338.13 223 7-chloro-4-(2-methylazetidin-1-yl)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 326.13 224 (2R)-1-(7-chloro-2-oxo-1-phenylhydro-quinazolin-4-yl)pyrrolidine-2-carboxylic acid m/z [M+H]+ 370.12 225 1-(2-bromophenyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one m/z [M+H]+ 364.0 226 7-chloro-1-(2-methoxyphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 316.0 227 4-(dimethylamino)-7-chloro-1-[3-(3-phenylpropyl)phenyl]hydroquinazolin-2-one m/z [M+H]+ 418.2 228 4-(dimethylamino)-1-phenyl-7-(1,3-thiazol-4-yl)hydroquinazolin-2-one m/z [M+H]+ 349.0 229 7-chloro-1-(4-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 289.1 230 7-chloro-4-(3-methoxypyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one m/z [M+H]+ 356.12 231 2-[(7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)amino]-N,N-dimethylacetamide m/z [M+H]+ 357.12 232 7-chloro-4-[(oxetan-3-ylmethyl)amino]-1-phenylhydroquinazolin-2-one m/z [M+H]+ 342.23 233 7-chloro-4-{[(1-methylpyrazol-3-yl)-methyl]amino}-1-phenylhydro-quinazolin-2-one m/z [M+H]+ 366.24 234 7-chloro-4-[methyl(pyridin-4-ylmethyl)-amino]-1-phenylhydroquinazolin-2-one m/z [M+H]+ 377.1 235 7-chloro-4-[methyl(pyridin-3-ylmethyl)-amino]-1-phenylhydroquinazolin-2-one m/z [M+H]+ 377.24 236 7-chloro-4-[methyl(pyridin-2-ylmethyl)-amino]-1-phenylhydroquinazolin-2-one m/z [M+H]+ 377.12 237 7-chloro-4-[methyl(2,2,2-trifluoroethyl)-amino]-1-phenylhydroquinazolin-2-one m/z [M+H]+ 368.18 238 4-(3,3-dimethylpyrrolidin-1-yl)-7-chloro-1-phenylhydroquinazolin-2-one m/z [M+H]+ 354.12 239 4-((3R)-3-hydroxypyrrolidinyl)-7-chloro-1-phenylhydroquinazolin-2-one m/z [M+H]+ 342.19 240 (2S)-1-(7-chloro-2-oxo-1-phenylhydro-quinazolin-4-yl)pyrrolidin-2-carboxamide m/z [M+H]+ 369.18 241 (2R)-1-(7-chloro-2-oxo-1-phenylhydro-quinazolin-4-yl)pyrrolidin-2-carboxamide m/z [M+H]+ 369.19 242 7-chloro-4-methyl-1-phenylhydroquinazolin-2-one m/z [M+H]+ 271.1 243 3-chloro-8-(methylamino)-5-phenyl-5-hydropyrimidino[5,4-c]pyridazin-6-one m/z [M+H]+ 288.16 244 1-(2-chlorophenyl)-4-(dimethylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 369.05 245 1-(2-chlorophenyl)-4-(spiro[3.3]heptan-2-ylamino)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 435.10 246 1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 395.05 247 1-(2-chlorophenyl)-4-[(3-hydroxypropyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 399.05 248 1-(2-chlorophenyl)-4-[(3-methoxy-propyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 413.10 249 4-[(2,2-difluoroethyl)amino]-7-chloro-1-(4-hydroimidazo[1,2-a]pyridin-6-yl)-hydroquinazolin-2-one m/z [M+H]+ 376.0 250 4-((3R)-3-hydroxypyrrolidin-1-yl)-7-chloro-1-(4-hydroimidazo[1,2-a]pyridin-6-yl)-hydroquinazolin-2-one m/z [M+H]+ 382.00 251 7-chloro-1-(4-hydroimidazo[1,2-a]-pyridin-6-yl)-4-(methylamino)hydro-quinazolin-2-one m/z [M+H]+ 326.00 252 4-amino-7-chloro-1-(4-hydroimidazo-[1,2-a]pyridin-6-yl)hydroquinazolin-2-one m/z [M+H]+ 312.00 253 1-benzothiazol-2-yl-7-chloro-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 330.0 254 1-(1H-indazol-4-yl)-7-chloro-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 313.0 255 1-(2-chlorophenyl)-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-7-(trifluoromethyl)hydropyridino-[2,3-d]pyrimidin-2-one m/z [M+H]+ 425.37 256 1-(2-chlorophenyl)-4-(2-pyridylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 418.35 257 1-(2-chlorophenyl)-4-{[(1-methyl-pyrazol-3-yl)methyl]amino}-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 435.35 258 1-(2-chlorophenyl)-4-[(methylethyl)-amino]-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 383.34 259 4-[(tert-butyl)amino]-1-(2-chloro-phenyl)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 397.39 260 1-(3-methyl(2-pyridyl))-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 336.37 261 1-(3-chloro(2-pyridyl))-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 356.36 262 7-chloro-1-(imidazol-4-ylmethyl)-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 290.36 263 4-amino-1-(2-methyl(3-pyridyl))-7-(trifluoromethyl pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 322.10 264 1-(2-chlorophenyl)-4-{[2-(methylsulfonyl)ethyl]amino}-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 447.00 265 1-(2-chlorophenyl)-4-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 425.00 266 4-{[3-(dimethylamino)propyl]amino}-1-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 426.00 267 4-{[2-(dimethylamino)ethyl]amino}-1-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 412.00 268 1-(2-chlorophenyl)-4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 425.00 269 1-(2-chlorophenyl)-4-(((1s,3s)-3-hydroxy-1-methylcyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 425.00 270 1-(2-chlorophenyl)-4-(((1s,3s)-3-methoxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 425.00 271 1-(2-chlorophenyl)-4-[(oxetan-2-ylmethyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 411.00 272 4-((methyl-d3)amino)-1-(2-methyl-phenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 338.20 273 4-[((1S)-2-hydroxy-isopropyl)amino]-(1Ra)-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 399.00 274 1-(2-chlorophenyl)-4-(oxetan-3-yl-amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 397.0 275 4-{[(cis)-3-hydroxy-3-(trifluoromethyl)-cyclobutyl]amino}-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 479.00 276 4-[((cis)-3-hydroxy-2,2-dimethylcyclo-butyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]-pyrimidine-2( 1H)-on m/z [M+H]+ 439.00 277 1-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile m/z [M+H]+ 420.00 278 3-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido-[2,3-d]pyrimidin-4-yl)amino)-propanenitrile m/z [M+H]+ 394.00 279 (R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)-1-(1H-indazol-5-yl)quinazolin-2(1H)-one m/z [M+H]+ 382.0 280 7-chloro-4-(dimethylamino)-1-(1H-indazol-5-yl)quinazolin-2(1H)-one m/z [M+H]+ 340.0 281 (R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)-1-(1H-benzimidazol-5-yl)quinazolin-2(1H)-one m/z [M+H]+ 382.0 282 4-((2,2-difluoroethyl)amino)-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H]+ 385.0 283 4-((3R)-3-hydroxypyrrolidinyl)-1-(2-methylpyridin-3-yl))-7-(trifluoromethyl)-hydroquinazolin-2-one m/z [M+H]+ 391.0 284 1-(2-methylpyridin-3-yl))-4-(methylamino)-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 335.0 285 4-amino-1-(2-methylpyridin-3-yl))-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 321.0 286 1-(2-chlorophenyl)-4-morpholin-4-yl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 411.40 287 2-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)acetamide m/z [M+H]+ 398.36 288 1-(2-chlorophenyl)-4-hydroxy-7-(trifluoromethyl)hydropyridino[2,3-d]-pyrimidin-2-one m/z [M+H]+ 342.31 289 7-chloro-5-(2,5-dihydro-1H-pyrrol-3-yl)-4-hydroxy-1-phenylquinazolin-2(1H)-one m/z [M+H]+ 340.37 290 tert-butyl 3-(7-chloro-4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinazolin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate m/z [M+H]+ 440.12 291 7-chloro-4-hydroxy-1-phenyl-5-(pyridin-4-yl)quinazolin-2(1H)-one m/z [M+H]+ 350.09 292 4-[((1S)-2-hydroxy-isopropyl)amino]-(1Sa)-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 399.10 293 4-[((2S)-2-hydroxypropyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 399.10 294 4-[((2R)-2-hydroxypropyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 399.10 295 1-(2-chlorophenyl)-4-{[(hydroxycyclopropyl)methyl]amino}-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 411.10 296 1-(2-chlorophenyl)-4-[(2-hydroxyethyl)amino]-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 385.10 297 1-(2-chlorophenyl)-4-[(3-hydroxy-bicyclo[1.1.1]pentyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 423.10 298 4-[((trans)-3-hydroxy-1-methylcyclo-butyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidine-2(1H)- He m/z [M+H]+ 425.10 299 4-{[(trans)-3-hydroxy-3-(trifluoromethyl)cyclobutyl]amino}-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 479.10 300 4-[((trans)-3-hydroxy-3-methylcyclo-butyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 425.10 301 4-[(trans)-3-methoxycyclobutyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 425.10 302 6-bromo-1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H]+ 432.0 303 6-bromo-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H]+ 398.0 304 1-(2-chlorophenyl)-6-fluoro-4-(methylamino)-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 372.0 305 1-benzimidazol-7-yl-7-chloro-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 313.0 306 1-benzimidazol-5-yl-4-(dimethylamino)-7-chlorohydroquinazolin-2-one m/z [M+H]+ 340.0 307 1-benzimidazol-5-yl-7-chloro-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 326.0 308 1-(2-chlorophenyl)-4-(cyclopropylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 381.28 309 7-cyclopropyl-4-(methylamino)-1-pyrimidin-2-ylhydroquinazolin-2-one m/z [M+H]+ 294.30 310 7-chloro-1-(4-fluoro-3-hydroxyphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 320.34 311 7-chloro-1-(2-fluoro-5-methoxyphenyl)-quinazoline-2,4(1H,3H)-dione m/z [M+H]+ 321.31 312 1-(3-chloro-pyridin-4-yl))-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 356.00 313 4-(methylamino)-1-(pyridin-4-yl))-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 322.00 314 1-(6-methyl-pyridin-3-yl))-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 336.0 315 1-(2-chlorophenyl)-4-(3-fluoroazetidin-1-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 399.10 316 1-(2-chlorophenyl)-4-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 485.10 317 1-(2-chlorophenyl)-4-[(2-methoxyethyl)-amino]-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 399.10 318 (1s,3s)-3-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile m/z [M+H]+ 420.10 319 1-(2-chlorophenyl)-4-[(methylcyclobutyl)amino]-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 409.20 320 1-(2-chlorophenyl)-4-(cyclobutylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 395.10 321 (1s,3s)-3-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)cyclobutane-1-carbonitrile m/z [M+H]+ 411.10 322 1-(2-chlorophenyl)-4-{[(hydroxymethyl)cyclopropyl]amino}-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 411.10 323 (R)-(1S _a )-(2-chlorophenyl)-4-((1-hydroxypropan-2-yl)amino)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 399.10 324 (R)-(1R _a )-(2-chlorophenyl)-4-((1-hydroxypropan-2-yl)amino)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 399.10 325 4-[(2,2-difluoroethyl)amino]-1-(pyridin-3-yl)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 371.0 326 4-((3R)-3-hydroxypyrrolidinyl)-1-(pyridin-3-yl)-7-(trifluoromethyl)-hydroquinazolin-2-one m/z [M+H]+ 372.0 327 4-amino-1-(pyridin-3-yl)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 307.0 328 1-(1H-indazol-5-yl)-7-chloro-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 326.0 329 7-chloro-5-methoxy-4-(methylamino)-1-(2-methylphenyl)hydroquinazolin-2-one m/z [M+H]+ 330.1 330 7-chloro-1-(4-fluoro-3-methoxyphenyl)-4-hydroxyhydroquinazolin-2-one m/z [M+H]+ 319.05 331 7-chloro-1-(6-fluoro-3-hydroxyphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 319.06 332 7-chloro-1-(2-fluoro-3-methoxyphenyl)-4-hydroxyhydroquinazolin-2-one m/z [M+H]+ 320.06 333 7-chloro-1-(2-fluoro-3-hydroxyphenyl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H]+ 320.27 334 1-(2-chlorophenyl)-4-(((1r,3r)-3-hydroxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 411.00 335 4-[((2S,1R)-2-hydroxycyclobutyl)amino]-(1S _a )-(2-chlorophenyl)-7-(trifluoromethyl)hydropyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 411.00 336 4-[((2S,1R)-2-hydroxycyclobutyl)amino]-(1R _a )-(2-chlorophenyl)-7-(trifluoromethyl)hydropyridino[2,3-d]-pyrimidin-2-one m/z [M+H]+ 411.00 337 4-[((1S,2S)-2-hydroxycyclobutyl)amino]-(1Sa)-(2-chlorophenyl)-7-(trifluoromethyl)hydropyridino[2,3-d]-pyrimidin-2-one m/z [M+H]+ 411.00 338 4-[((1S,2S)-2-hydroxycyclobutyl)amino]-(1Ra)-(2-chlorophenyl)-7-(trifluoromethyl)hydropyridino[2,3-d]-pyrimidin-2-one m/z [M+H]+ 411.00 339 4-(bis(methyl-d3)amino)-1-(2-chloro-phenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 375.00 340 1-(1H-benzo[d]imidazol-5-yl)-7-chloroquinazoline-2,4(1H,3H)-dione m/z [M+H]+ 313.0 341 4-(methylamino)-1-(pyridin-3-yl)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 321.0 342 8-chloro-1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)-hydroquinazolin-2-one m/z [M+H]+ 388.0 343 8-chloro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 354.04 344 4-((2R)-2-methylpyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 375.1 345 4-((2S)-2-methylpyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 375.1 346 1-phenyl-4-(1,3-thiazolidin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 379.1 347 7-chloro-1-(2-chlorophenyl)-4-((methyl-d3)amino)quinazolin-2(1H)-one m/z [M+H]+ 324.1 348 7-chloro-5-(cyclopropylmethoxy)-4-(methylamino)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 356.32 349 7-chloro-4-(methylamino)-5-(methylethoxy)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 344.33 350 7-chloro-4-(methylamino)-1-phenyl-5-(2,2,2-trifluoroethoxy)hydroquinazolin-2-one m/z [M+H]+ 384.31 351 1-(2-bromophenyl)-7-cyclopropyl-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 370.26 352 7-cyclopropyl-4-(methylamino)-1-(2-methylphenyl)hydroquinazolin-2-one m/z [M+H]+ 306.33 353 7-chloro-1-(3-cyclopropylphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 326.32 354 7-chloro-1-(3-difluoromethylphenyl)-quinazoline-2,4(1H,3H)-dione m/z [M+H]+ 323.26 355 7-chloro-1-(3-(difluoromethyl)phenyl)-4-(methylamino)-3,4-dihydroquinazolin-2(1H)-one m/z [M+H]+ 336.30 356 7-chloro-1-(3-trifluoromethylphenyl)-quinazoline-2,4(1H,3H)-dione m/z [M+H]+ 339.29 357 1-(1H-indazol-5-yl)-7-chloro-4-hydroxy-hydroquinazolin-2-one m/z [M+H]+ 313.0 358 1-(4-chloropyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione m/z [M+H]+ 343.0 359 1-(pyridin-3-yl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione m/z [M+H]+ 309.00 360 8-chloro-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione-1 m/z [M-H]- 373.0 361 8-chloro-1-phenyl-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione m/z [M-H]- 339.0 362 1-(pyridin-3-yl)-7-(trifluoromethyl)-1,3-dihydroquinazoline-2,4-dione m/z [M+H]+ 308.0 363 1-benzothiazol-7-yl-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione m/z [M+H]+ 365.0 364 1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione m/z [M+H]+ 323.1 365 1-(4-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2,4(1H,3H)-dione m/z [M+H]+ 323.1 366 4-((methyl-d3)amino)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 324.1 367 4-((methyl-d3)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H]+ 337.2 368 1-(2-bromophenyl)-7-chloro-4-((methyl-d3)amino)quinazolin-2(1H)-one m/z [M+H]+ 367.0 369 4-((methyl-d3)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H]+ 323.2 370 7-chloro-1-(3-chloro(2-pyridyl))-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 321.26 371 7-chloro-1-(3-methylpyridin-2-yl))-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 301.3 372 7-cyclopropyl-4-(3-hydroxyazetidin-1-yl)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 334.36 373 7-cyclopropyl-4-((2-fluoropropyl)-amino)-1-phenylquinazolin-2(1H)-one m/z [M+H]+ 342.35 374 4-((3R)-3-hydroxypyrrolidinyl)-7-cyclopropyl-1-phenylhydroquinazolin-2-one m/z [M+H]+ 348.37 375 7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione m/z [M+H]+ 293.25 376 4-(methylamino)-1-(4-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 336.1 377 1-(4-chloropyridin-3-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 356.00 378 4-(methylamino)-1-(pyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 322.10 379 1-(2-chlorophenyl)-4-((methyl-d3)-amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 358.00 380 4-(methylamino)-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 336.1 381 1-benzothiazol-7-yl-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 378.0 382 4-(methylamino)-7-(methylpropyl)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 308.2 383 4-amino-5,7-dichloro-1-phenyl-hydroquinazolin-2-one m/z [M+H]+ 306.23 384 4-(3-hydroxyazetidin-1-yl)-7-methyl-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 309.32 385 7-cyclopropyl-1-phenyl-4-[(2,2,2-trifluoroethyl)amino]hydroquinazolin-2-one m/z [M+H]+ 360.36 386 7-cyclopropyl-1-phenyl-4-pyrrolidin-1-ylhydroquinazolin-2-one m/z [M+H]+ 332.38 387 4-amino-7-chloro-1-phenyl-5-pyrazol-1-ylhydroquinazolin-2-one m/z [M+H]+ 338.31 388 1-(2-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydropyridino[2,3-d]pyrimidine-2,4-dione m/z [M+H]+ 342.0 389 1-(2-chlorophenyl)-4-[(2,2,2-trifluoroethyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 423.10 390 1-(5-hydroxypyridin-3-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 338.10 391 1-(2-hydroxypyridin-4-yl)-4-(methylamino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 338.10 392 1-(4-hydroxypyridin-3-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 338.10 393 1-(5-hydroxypyridin-2-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 338.10 394 7-ethynyl-4-(methylamino)-1-phenyl-hydroquinazolin-2-one m/z [M+H]+ 276.0 395 4-((3R)-3-hydroxypyrrolidin-1-yl)-1-(2-chlorophenyl)-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M+H]+ 410.0 396 4-methoxy-7-methyl-1-phenylpyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 268.12 397 7-methyl-1-phenyl-4-[(2,2,2-trifluoroethyl)amino]pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 335.16 398 4-[(2,2-difluoroethyl)amino]-7-methyl-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 317.17 399 7-cyclopropyl-4-methoxy-1-phenyl-hydroquinazolin-2-one m/z [M+H]+ 293.1 400 4-amino-7-cyclopropyl-1-phenylhydro-quinazolin-2-one m/z [M+H]+ 278.21 401 1-(3-bromophenyl)-7-chloro-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 363.97 402 5-(2-aminoethoxy)-7-chloro-4-(methylamino)-1-phenylhydroquinazolin-2-one m/z [M+H]+ 345.1 403 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-(methylsulfonyl)ethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H]+ 443.1 404 4-[((1R,2R)-2-fluorocyclopropyl)-amino]-1-(2-chlorophenyl)-7-(trifluoromethoxy)hydroquinazolin-2-one m/z [M+H]+ 414.0. 405 4-methoxy-7-methyl-1-(2-methyl-pyridin-3-yl)quinazolin-2(1H)-one m/z [M+H]+ 336.40 406 5-(difluoromethoxy)-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 392.3. 407 1-(2-chlorophenyl)-7-cyclopropyl-4-{[(fluorocyclopropyl)methyl]amino}-5-methoxyhydroquinazolin-2-one m/z [M+H]+ 414.39 408 1-(2-chlorophenyl)-7-cyclopropyl-4-((oxetan-2-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H]+ 407.0 409 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H]+ 391.0 410 7-cyclopropyl-5-ethyl-4-(methylamino)-1-(2-methylphenyl)hydroquinazolin-2-one m/z [M+H]+ 334.37. 411 6-chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-[(cyclopropylmethyl)amino]-hydroquinazolin-2-one m/z [M+H]+ 400.1. 412 7-bromo-6-chloro-1-(2-chlorophenyl)-4-(isoxazol-4-ylamino)hydroquinazolin-2-one m/z [M+H]+ 452.9 (major) 413 4-[((2S,1R)-2-fluorocyclopropyl)amino]-1-(2-chlorophenyl)-7-cyclopropyl-hydroquinazolin-2-one m/z [M+H]+ 370.0 414 4-(methylamino)-7-(methylethyl)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 295.1 415 7-cyclopropyl-4-[(cyclopropylmethyl)-amino]-1-[2-(trifluoromethyl)(3-pyridyl)]hydroquinazolin-2-one m/z [M+H]+ 399.1 416 1-[2-(difluoromethoxy)(3-pyridyl)]-7-cyclopropyl-4-[(cyclopropylmethyl)-amino]hydroquinazolin-2-one m/z [M+H]+ 401.1. 417 6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)hydroquinazolin-2-one m/z [M+H]+ 404.0 418 1-(2-chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one m/z [M+H]+ 414.0. 419 2-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)acetic acid m/z [M+H]+ 344.30. 420 5-fluoro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M+H]+ 338.1. 421 1-(2-chlorophenyl)-4-(pyridin-4-yl-amino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H]+ 418.00. 422 1-(2-chlorophenyl)-4-cyclopropoxy-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H]+ 382.33 423 1-(2-chlorophenyl)-7-cyclopropyl-4-methoxyhydroquinazolin-2-one m/z [M+H]+ 327.16. 424 4-(((1S,2R)-2-fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H]+ 364.1 425 1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)-quinazolin-2(1H)-one m/z [M+H]+ 390.1 426 1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M+H]+ 326.0 427 (S)-4-(pyrrolidin-3-ylamino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 389.15 428 (R)-4-(2-(hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 391.1 429 N-methyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethane-1-sulfonamide m/z [M+H] ⁺ 442.1 430 N-methyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)propane-1-sulfonamide m/z [M+H] ⁺ 456.1 431 N-cyclopropyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethane-1-sulfonamide m/z [M+H] ⁺ 468.1 432 4-(((1S,2R)-2-fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 379.1 433 4-(((1R,2S)-2-fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 379.1 434 N,N-dimethyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propan-1-sulfonamide m/z [M+H] ⁺ 469.1 435 N,N-dimethyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamide m/z [M+H] ⁺ 455.1 436 tert-butyl (R)-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)pyrrolidine-1-carboxylate m/z [M+H] ⁺ 489.2 437 4-((2-(morpholinosulfonyl)ethyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 497.1 438 (S)-4-(3-(methylamino)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 403.1 439 N-cyclopropyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamide m/z [M+H] ⁺ 467.1 440 (R)-4-(2-(hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 390.1 441 4-(3-(hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 390.1 442 (R)-4-(2-(methoxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 404 443 4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 406.1 444 4-(((1R,2S)-2-fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 378.1 445 4-(((1S,2R)-2-fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 378.1 446 3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-amino)propane-1-sulfonamide m/z [M+H] ⁺ 441.1 447 N-methyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propan-1-sulfonamide m/z [M+H] ⁺ 455.1 448 2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)-amino)ethane-1-sulfonamide m/z [M+H] ⁺ 427.05 449 N-methyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamide m/z [M+H] ⁺ 441.1 450 (S)-4-(2-(hydroxymethyl)morpholino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 420.1 451 4-(3-methoxyazetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 390.1 452 (4-(4-methyl-3-oxopiperazin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 417.1 453 4-(3-hydroxyazetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 376.1 454 1-(2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)azetidine-3-carbonitrile m/z [M+H] ⁺ 385.1 455 amino(3-{[1-(2-methylphenyl)-2-oxo-7-(trifluoromethyl)hydroquinazolin-4-yl]-amino}propyl)sulfonamide m/z [M+H] ⁺ 456.1 456 amino(2-{[1-(2-methylphenyl)-2-oxo-7-(trifluoromethyl)hydroquinazolin-4-yl]-amino}ethyl)sulfonamide m/z [M+H] ⁺ 442.1 457 (3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)-amino)propane-1-sulfonamide m/z [M+H] ⁺ 433.1 458 3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylpropane-1-sulfonamide m/z [M+H] ⁺ 447.0 459 2-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)-amino)ethane-1-sulfonamide m/z [M+H] ⁺ 419.0 460 2-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylethane-1-sulfonamide m/z [M+H] ⁺ 433.1 461 1-(2-chlorophenyl)-7-cyclopropyl-4-(4-(hydroxymethyl)piperidin-1-yl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 410.1 462 1-(2-chlorophenyl)-7-cyclopropyl-4-(3-hydroxypiperidin-1-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 396.1 463 1-(2-chlorophenyl)-7-cyclopropyl-4-(3-hydroxyazetidin-1-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 368.1 464 (3-{[1-(2-chlorophenyl)-7-cyclopropyl-2-oxohydroquinazolin-4-yl]amino}-propyl) sulfonamide m/z [M+H] ⁺ 448.1 465 (2-{[1-(2-chlorophenyl)-7-cyclopropyl-2-oxohydroquinazolin-4-yl]amino}ethyl)sulfonamide m/z [M+H] ⁺ 434.0 466 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-(difluoromethyl)pyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 439.1 467 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-cyclopropylpyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 429.1 468 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-(difluoromethoxy)pyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 455.1 469 1-(2-chlorophenyl)-7-cyclopropyl-4-((3-methyl-1,2,4-oxadiazol-5-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 394.1 470 1-(2-chlorophenyl)-7-cyclopropyl-4-((oxazol-5-ylmethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 393.1 471 1-(2-chlorophenyl)-7-cyclopropyl-4-((isoxazol-3-ylmethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 393.1 472 1-(2-chlorophenyl)-7-cyclopropyl-4-((5-methylisoxazol-3-yl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 393.1 473 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 406.1 474 1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-3-ylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 379.05 475 1-(2-chlorophenyl)-7-cyclopropyl-4-((5-methoxypyridin-3-yl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 419.1 476 1-(2-chlorophenyl)-7-cyclopropyl-4-((6-methylpyridin-3-yl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 403.1 477 1-(2-chlorophenyl)-7-cyclopropyl-4-((6-methoxypyridin-3-yl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 419.1 478 1-(2-chlorophenyl)-7-cyclopropyl-4-((pyridin-4-ylmethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 403.1 479 1-(2-chlorophenyl)-7-cyclopropyl-4-((pyridin-3-ylmethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 403.1 480 1-(2-chlorophenyl)-7-cyclopropyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 403.1 481 1-(2-chlorophenyl)-7-isopropyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 329.1 482 1-(2-chlorophenyl)-7-(difluoromethyl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 336.0 483 1-(2-chlorophenyl)-7-isopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 328.1 484 1-(2-chlorophenyl)-7-cyclopropyl-4-(pyrimidin-5-ylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 390.05 485 1-(2-chlorophenyl)-7-cyclopropyl-4-(pyridin-3-ylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 389.05 486 1-(2-chlorophenyl)-7-cyclopropyl-4-(pyridin-4-ylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 389.05 487 4-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)picolinonitrile m/z [M+H] ⁺ 414.1 488 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-methoxypyridin-4-yl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 419.1 489 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-morpholinopyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 474.1 490 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-fluoropyridin-4-yl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 407.0 491 1-(2-chlorophenyl)-4-((2-chloropyridin-4-yl)amino)-7-cyclopropylquinazolin-2(1H)-one m/z [M+H] ⁺ 423.0 492 1-(2-chlorophenyl)-5-methoxy-4-(methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 384.1 493 1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 394.1 494 5-methoxy-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 350.1 495 (R)-1-(2-chlorophenyl)-7-(trifluoromethyl)-4-((1,1,1-trifluoropropan-2-yl)-amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 436.0 496 (1,3-trans)-3-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-quinazolin-4-yl)amino)-cyclobutane-1-carbonitrile m/z [M+H] ⁺ 419.05 497 4-(isopropylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 348.1 498 1-(2-chlorophenyl)-4-(isopropylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 382.0 499 1-(2-chlorophenyl)-4-(cyclopropylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 380.0 500 1-(2-chlorophenyl)-4-(isoxazol-4-yl-amino)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 406.75 501 1-(2-chlorophenyl)-4-((1,3-difluoro-propan-2-yl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 418.1 502 1-(2-chlorophenyl)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 398.05 503 1-(2-chlorophenyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 398.1 504 4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 360.1 505 7-isopropyl-4-(methylamino)-1-phenyl-quinazolin-2(1H)-one m/z [M+H] ⁺ 294.2 506 4-((2,2-difluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 382.05 507 4-((1,3-difluoropropan-2-yl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 384.1 508 (R)-4-((1-cyclopropylethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 374.1 509 4-(((1-fluorocyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 378.1 510 4-((((trans)-2-(hydroxymethyl)cyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 390.1 511 1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 360.1 512 1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 327.1 513 7-cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 333.1 514 7-methoxy-4-(methylamino)-1-phenyl-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 283.1 515 1-(3-chloropyridin-2-yl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 355.0 516 4-(methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 389.1 517 4-(methylamino)-1-(pyrimidin-5-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 322.1 518 (S)-1-phenyl-7-(trifluoromethyl)-4-((1,1,1-trifluoropropan-2-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 402.1 519 4-((oxetan-2-ylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 376.1 520 4-(((1R,2S)-2-fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 364.1 521 4-(((1,2-trans)-2-fluorocyclopropyl)-amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 364.1 522 4-(((2,2-difluorocyclopropyl)methyl)-amino)-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 396.1 523 (R)-4-((1-hydroxypropan-2-yl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 364.1 524 4-(oxetan-3-ylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 362.1 525 4-(((1,3-trans)-3-methoxycyclobutyl)-amino)-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 390.1 526 4-((3-methoxypropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺
378.1 527 4-((2-methoxyethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 364.1 528 4-((3-methoxypropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺
378.1 530 4-((2-(difluoromethoxy)ethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 400.1 531 7-cyclopropyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 293.1 532 (R)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 405.00 533 (R)-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 405.00 534 4-(pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 375.2 535 4-(3-(2-hydroxyethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 418.1 536 (R)-4-(2-(methoxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 418.1 537 (R)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 404.1 538 (S)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 404.1 539 (R)-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 404.1 540 4-(((3-methoxyisoxazol-5-yl)methyl)-amino)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 431.1 541 4-((isoxazol-3-ylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 417.1 542 5-methoxy-4-(((3-methoxyisoxazol-5-yl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 447.1 543 5-methoxy-4-((oxazol-4-ylmethyl)-amino)-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 417.1 544 4-((isoxazol-4-ylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 417.1 545 5-methoxy-4-((oxazol-2-ylmethyl)-amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 417.1 546 4-(isobutylamino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 392.15 547 1-(2-chlorophenyl)-7-cyclopropyl-4-((3,5-dimethylisoxazol-4-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 407.1 548 1-(2-chlorophenyl)-7-cyclopropyl-4-((3-methylisoxazol-4-yl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 393.1 549 1-(2-chlorophenyl)-7-cyclopropyl-4-((5-methylisoxazol-4-yl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 393.1 550 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)(methyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 380.15 551 4-((cyclopropylmethyl)amino)-2-oxo-1-(o-tolyl)-7-(trifluoromethoxy)-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 415.1 552 4-((cyclopropylmethyl)amino)-6-methyl-1-(o-tolyl)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 404.1 553 6-methyl-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one m/z [M+H] ⁺ 364.1 554 4-((cyclopropylmethyl)amino)-6-methyl-1-phenyl-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 390.1 555 6-bromo-4-((cyclopropylmethyl)amino)-1-(o-tolyl)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 468.0, 470.0 556 6-bromo-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one m/z [M+H] ⁺ 430.0, 428.0 557 6-bromo-4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 456.1, 454.1 558 4-(((1R,2S)-2-fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 394.05 559 4-(((1S,2R)-2-fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 394.05 560 4-amino-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 336.0 561 4-(((trans)-2-fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 394.05 562 7-cyclopropyl-4-(cyclopropylmethylamino)-1-(3-(trifluoromethyl)pyrazin-2-yl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 402.1 563 7-cyclopropyl-4-(methylamino)-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 362.1 564 4-(((trans)-2-hydroxycyclobutyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 406.1 565 (S)-4-((2-hydroxypropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 394.1 566 5-methoxy-4-((2-methoxyethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 394.1 567 4-((2-hydroxyethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 380.1 568 4-((cyclopropylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 390.1 569 5-fluoro-4-((trans-2-fluorocyclopropyl)-amino)-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 382.1 570 (R)-6-chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxypropyl)-amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 405.05 571 (S)-6-chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxypropyl)-amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 405.1 572 1-(2-chlorophenyl)-7-cyclopropyl-4-((3-methoxypropyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 384.1 573 1-(2-chlorophenyl)-7-cyclopropyl-4-((3-hydroxypropyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 370.1 574 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-methoxyethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 370.1 575 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxyethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 356.1 576 1-(2-chlorophenyl)-7-cyclopropyl-4-(((S)-1-hydroxypropan-2-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 370.1 577 1-(2-chlorophenyl)-7-cyclopropyl-4-(((R)-1-hydroxypropan-2-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 370.1 578 1-(2-chlorophenyl)-7-cyclopropyl-4-((1-methylcyclobutyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 380.15 579 4-amino-6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazolin-2(1H)-one m/z [M+H] ⁺ 347.0 580 4-amino-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 347.0 581 4-amino-1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one m/z [M+H] ⁺ 356.0 582 1-(2-chlorophenyl)-7-cyclopropyl-4-(((trans)-2-hydroxycyclobutyl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 382.1 583 6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-4-ylamino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 458.0 584 1-(2-chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 426.1 585 6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)-amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 445.0 586 6-chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 360.0 587 6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 428.0 588 6-chloro-1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 388.0 589 7-bromo-6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 439.9 590 7-bromo-6-chloro-1-(2-chlorophenyl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 399.9 591 7-cyclopropyl-4-(methylamino)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 361.1 592 7-cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 359.1 593 4-((cyclopropylmethyl)amino)-1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 416.1 594 1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 376.1 595 1-(2-chlorophenyl)-4-(isoxazol-4-ylamino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 423.0 596 7-cyclopropyl-4-(isothiazol-4-ylamino)-1-(o-tolyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 375.1 597 7-cyclopropyl-4-(isoxazol-4-ylamino)-1-(o-tolyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 359.1 598 1-(2-chlorophenyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 414.05 599 1-(2-chlorophenyl)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 414.05 600 1-(2-chlorophenyl)-4-(isothiazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 424.0 601 4-(methylamino)-1-(pyridazin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 322.1 602 4-((cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 396.2 603 7-cyclopropyl-4-((cyclopropylmethyl)-amino)-1-(imidazo[1,2-a]pyridin-5-yl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 372.15 604 4-(methylamino)-1-(pyrazin-2-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 322.1 605 4-(cyclopropylamino)-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 382.2 606 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-methoxyethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 370.1 607 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxyethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 356.1 608 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 366.1 609 1-(2-chlorophenyl)-7-cyclopropyl-4-(cyclopropylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 352.1 610 7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 356.1 611 1-(2-chlorophenyl)-4-((2-hydroxyethyl)-amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one m/z [M+H] ⁺ 400.1 612 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-3-hydroxycyclobutyl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 406.1 613 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-((2-methoxyethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 394.05 614 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-((2-hydroxyethyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 380.05 615 1-(2-chlorophenyl)-4-(cyclopropylamino)-7-(1,1-difluoroethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 376.1 616 1-(2-chlorophenyl)-4-(((trans)-3-hydroxycyclobutyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 426.1 617 1-(2-chlorophenyl)-4-((2-methoxyethyl)-amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one m/z [M+H] ⁺ 414.0 618 1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M+H] ⁺ 410.0 619 1-(2-chlorophenyl)-4-(cyclopropylamino)-7-(trifluoromethoxy)quinazolin-2(1H)-one m/z [M+H] ⁺ 396.0 620 1-(2-chlorophenyl)-7-(trifluoromethyl)-4-((2-(trifluoromethyl)pyridin-4-yl)-amino)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 486.05 621 7-ethyl-4-(methylamino)-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 282.15 622 1-(2-chlorophenyl)-4-((2-methoxy-pyridin-4-yl)amino)-7-(trifluoromethyl)-pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 448.1 623 1-(2-chlorophenyl)-4-((2-methylpyridin-4-yl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one 624 7-ethyl-1-(2-fluorophenyl)-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 299.1 625 1-(2-chlorophenyl)-7-ethyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 315.1 626 7-ethyl-4-(methylamino)-1-(o-tolyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 295.15 627 7-ethyl-4-(methylamino)-1-phenyl-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 281.2 628 1-(2-chlorophenyl)-4-((5-methyl-isoxazol-3-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 422.05 629 1-(2-chlorophenyl)-4-(isoxazol-4-yl-amino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 408.0 630 1-(2-chlorophenyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 421.0 631 1-(2-chlorophenyl)-4-((1-methyl-1H-pyrazol-3-yl)amino)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 421.0 632 1-(2-chlorophenyl)-4-((1-methyl-1H-imidazol-4-yl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 421.0 633 1-(2-chlorophenyl)-4-((1-methyl-1H-pyrazol-5-yl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 421.0 634 1-(2-chlorophenyl)-4-(pyridin-3-yl-amino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 418.0 635 1-(2-fluorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 339.1 636 1-(2-bromophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 401.0, 399.0 637 (R)-4-(3-hydroxypyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 377.1 638 4-amino-1-(2-chlorophenyl)-7-cyclopropylquinazolin-2(1H)-one m/z [M+H] ⁺ 312.00 639 1-(2-chlorophenyl)-7-cyclopropyl-4-(isopropylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 354.20 640 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 370.00 641 1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-4-ylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 379.00 642 1-(2-chlorophenyl)-7-cyclopropyl-4-(isothiazol-4-ylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 395.00 643 1-(2-chlorophenyl)-7-cyclopropyl-4-((2-(trifluoromethyl)pyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 457.00 644 7-cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 332.00 645 7-cyclopropyl-4-((cyclopropylmethyl)-amino)-1-(pyrazin-2-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 334.20 646 7-cyclopropyl-4-(methylamino)-1-(3-methylpyrazin-2-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 308.20 647 7-cyclopropyl-4-((cyclopropylmethyl)-amino)-1-(3-methylpyrazin-2-yl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 348.20 648 7-cyclopropyl-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 332.00 649 5-methoxy-4-(methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)-pyridin-3-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 419.00 650 4-((cyclopropylmethyl)amino)-5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)-pyridin-3-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 447.00 651 4-amino-7-chloro-1-(imidazo[1,2-a]-pyridin-7-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 312.0 652 7-chloro-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 326.0 653 7-chloro-4-((2,2-difluoroethyl)amino)-1-(imidazo[1,2-a]pyridin-7-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 376.0 654 7-chloro-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 326.0 655 1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethoxy)quinazolin-2(1H)-one m/z [M+H] ⁺ 370.1 656 4-amino-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 336.1 657 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(isoxazol-4-ylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 403.0 658 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 350.1 659 1-(3-chloropyridin-2-yl)-7-ethyl-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 315.0 660 4-amino-1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 337.0. 661 1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 351.0 662 4-amino-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 342.1 663 7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 356.0 664 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-methoxyquinazolin-2(1H)-one m/z [M+H] ⁺ 396.2 665 6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 448.0/450.0 666 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 395.0 667 1-(2-chlorophenyl)-7-cyclopropyl-4-(((trans)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 395.0 668 4-amino-1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 337.0 669 1-(2-chlorophenyl)-7-cyclopropyl-4-((1-(hydroxymethyl)cyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 421.0 670 1-(2-chlorophenyl)-4-(methylamino)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 379.0 671 1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 419.0 672 1-(2-chlorophenyl)-7-cyclopropyl-6-fluoro-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 344.0 673 7-bromo-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 381.9/384.0. 674 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-fluoroquinazolin-2(1H)-one m/z [M+H] ⁺ 384.0 675 1-(2-chlorophenyl)-7-cyclopropyl-4-((2,2-difluoroethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 410.1 676 6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 428.0/430.0 677 6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one m/z [M+H] ⁺ 472.0/474.0 678 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrile m/z [M+H] ⁺ 375.0 679 1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 415.0 680 7-cyclopropyl-4-(methylamino)-2-oxo-1-(o-tolyl)-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 331.2 681 7-cyclopropyl-4-((cyclopropylmethyl)-amino)-2-oxo-1-(o-tolyl)-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 371.2 682 1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)-6-(methylthio)-quinazolin-2(1H)-one m/z [M+H] ⁺ 372.0 683 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-(methylthio)quinazolin-2(1H)-one m/z [M+H] ⁺ 412.0 684 6-bromo-4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 438.0/440.0 685 6-bromo-4-((cyclopropylmethyl)-(methyl)amino)-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 452.0/454.0 686 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile m/z [M+H] ⁺ 392.1 687 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydropyrido[2,3-d]-pyrimidine-6- carbonitrile m/z [M+H] ⁺ 396.0 688 7-chloro-4-((2,2-difluoroethyl)amino)-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 380.35 689 7-chloro-5-fluoro-4-(((1r,3r)-3-methoxy-cyclobutyl)amino)-1-(o-tolyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 400.33 690 7-chloro-1-(2-chlorophenyl)-5-methoxy-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 350.2 691 5-methoxy-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 364.19 692 5-methoxy-4-(methylamino)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 351.3 693 1-(2-chloro-6-fluorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 373.2 694 7-cyclopropyl-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 307.22 695 1-(2-chlorophenyl)-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one, single enantiomer (configuration unknown) m/z [M+H] ⁺ 425.1 696 1-benzyl-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 335.3 697 1-(2-chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 411.3 698 1-(2-chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 411.3 699 4-amino-1-(2-bromophenyl)-7-cyclopropylquinazolin-2(1H)-one m/z [M+H] ⁺ 356.1 700 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxy-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 356.35 701 4-amino-1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazolin-2(1H)-one m/z [M+H] ⁺ 342.31 702 7-cyclopropyl-5-methoxy-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 366.44 703 4-amino-7-cyclopropyl-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 322.36 704 7-cyclopropyl-5-methoxy-4-(methylamino)-1-(pyridin-3-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 323.36 705 4-amino-7-cyclopropyl-5-methoxy-1-(pyridin-3-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 309.36 706 7-cyclopropyl-4-(pyridin-4-ylamino)-1-(o-tolyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 369.39 707 1-(2-chlorophenyl)-4-(thiazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 424.2 708 1-(2-chlorophenyl)-4-((isoxazol-4-yl-methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 422.3 709 1-(2-chlorophenyl)-4-((isoxazol-3-yl-methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 422.3 710 1-(2-chlorophenyl)-4-((isoxazol-5-yl-methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M+H] ⁺ 422.2 711 1-(2-chlorophenyl)-4-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)- He m/z [M+H] ⁺ : 435.27 712 2-chlorophenyl)-4-(((1-methyl-1H-imidazol-4-yl)methyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 435.27 713 cyclopropyl-4-(methylamino)-1-(pyrazin-2-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 294.4 714 7-cyclopropyl-4-(methylamino)-1-(pyrimidin-5-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 294.33 715 4-amino-1-(3-chloropyridin-2-yl)-7-cyclopropylquinazolin-2(1H)-one m/z [M+H] ⁺ 313.3 716 4-amino-7-cyclopropyl-1-(pyrazin-2-yl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 280.4 717 4-amino-7-cyclopropyl-1-(pyrimidin-5-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 280.26 718 4-((trans-2-hydroxycyclobutyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M+H] ⁺ 376.36 719 1-(2-bromophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one, the only atropisomer m/z [M+H] 370.3 720 1-(2-chlorophenyl)-7-cyclopropyl-4-(isopropylamino)-5-methoxy quinazolin-2(1H)-one m/z [M+H] ⁺ 384.4 721 1-(2-chlorophenyl)-7-cyclopropyl-4-(cyclopropylamino)-5-methoxy-quinazolin-2(1H)-one m/z [M+H] ⁺ 382.35 722 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-5-methoxyquinazolin-2(1H)-one m/z [M+H] ⁺ 400.33 723 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-5-methoxy-quinazolin-2(1H)-one m/z [M+H] ⁺ 396.4 724 1-(2-chlorophenyl)-7-cyclopropyl-4-(((2,2-difluorocyclopropyl)methyl)-amino)-5-methoxyquinazolin-2(1H)-one m/z [M+H] ⁺ 432.4 725 1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 327.3 726 1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-methoxyquinazolin-2(1H)-one m/z [M+H] ⁺ 328.3 727 1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxy-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 357.37 728 1-(2-chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 398.3 729 1-(2-chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 398.3 730 1-(2-chlorophenyl)-4-(((1R,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 398.3 731 1-(2-chlorophenyl)-4-(((1R,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 398.3 732 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)-quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 370.34 733 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)-quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 370.34 734 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)-quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 370.34 735 1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 367.4 736 1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 371.3 737 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((1R,2R)-2-hydroxycyclobutyl)-amino)quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 406.37 738 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((1R,2R)-2-hydroxycyclobutyl)-amino)quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 406.37 739 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((1S,2S)-2-hydroxycyclobutyl)-amino)quinazolin-2(1H)-one, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 406.37 740 1-(2-chlorophenyl)-4-(((1R,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one, single enantiomer (configuration unknown) m/z [M+H] ⁺ 414.3 741 1-(2-chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one, single enantiomer (configuration unknown) m/z [M+H] ⁺ 414.3 742 1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydroquinazolin-6-carbonitrile m/z [M+H] ⁺ 352.4 743 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-hydroxycyclobutyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile, single enantiomer (configuration unknown)/atropisomer m/z [M+H] ⁺ 407.47 744 1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-4-((2-(trifluoromethyl)pyridin-4-yl)-amino)-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 482.5 745 1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-4-(thiazol-5-ylamino)-1,2-dihydro-quinazoline-6-carbonitrile m/z [M+H] ⁺ 420.1 746 1-(2-chlorophenyl)-7-cyclopropyl-4-((1-methyl-1H-pyrazol-5-yl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 417.36 747 1-(2-chlorophenyl)-7-cyclopropyl-4-((isoxazol-5-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 418.35 748 1-(2-chlorophenyl)-7-cyclopropyl-4-((isoxazol-3-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 418.3 749 1-(2-chlorophenyl)-7-cyclopropyl-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 431.38 750 1-(2-chlorophenyl)-7-cyclopropyl-6-methyl-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 340.34 751 1-(2-chlorophenyl)-6-methyl-4-(methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 368.4 752 1-(2-chlorophenyl)-7-cyclopropyl-6-(difluoromethyl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 376.4 753 1-(2-chlorophenyl)-6-(difluoromethyl)-4-(methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 404.4 754 6-bromo-1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 405.2 755 6-bromo-7-cyclopropyl-4-(methylamino)-1-(2-(trifluoromethyl)pyridin-3-yl)-quinazolin-2(1H)-one m/z [M+H] ⁺ 439.4 756 1-(2-bromophenyl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrile, single atropisomer (configuration unknown) m/z [M+H] ⁺ 395.41 757 1-(2-bromophenyl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrile, single atropisomer (configuration unknown) m/z [M+H] ⁺ 395.41 758 7-cyclopropyl-1-(2-cyclopropylphenyl)-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 357.40 759 7-cyclopropyl-4-(methylamino)-2-oxo-1-(2-(trifluoromethyl)phenyl)-1,2-dihydroquinazoline-6-carbonitrile m/z [M+H] ⁺ 385.44 760 4-(((1R,2R)-2-fluorocyclopropyl)-amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one, single enantiomer (configuration unknown) m/z [M+H] ⁺ 394.4 761 4-(((1S,2S)-2-fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one, single enantiomer (configuration unknown) m/z [M+H] ⁺ 394.4 762 2-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]-pyrimidin-4-yl)amino)-N,N-dimethylethanesulfonamide m/z [M+H] ⁺ 454.19 763 3-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]-pyrimidin-4-yl)amino)-N-methylpropanamide m/z [M+H] ⁺ 426.4. 764 7-cyclopropyl-4-((2-(dimethylamino)-ethyl)amino)-1-(2-methylpyridin-3-yl)-quinazolin-2(1H)-one m/z [MH] ⁺ 362.52 765 2-((7-cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)-amino)-N,N-dimethylethane-1-sulfonamide m/z [M+H] ⁺ 428.49 766 3-((7-cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)-amino)-N-methylpropanamide m/z [M+H] ⁺ 378.47 767 7-cyclopropyl-1-(2-methylpyridin-3-yl)-4-((3-morpholinopropyl)amino)-quinazolin-2(1H)-one m/z [M+H] ⁺ 420.31 768 4-(methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 390.4 769 1-(2-chloropyridin-3-yl)-4-(methylamino)-7-(trifluoromethyl)-pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M+H] ⁺ 356.3 770 1-(2-chlorophenyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one, single enantiomer (configuration unknown) m/z [M+H] ⁺ 399.4. 771 1-(2-chlorophenyl)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one, single enantiomer (configuration unknown) m/z [M+H] ⁺ 399.4 772 (R)-1-(2-bromophenyl)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)quinazolin-2(1H)-one m/z [M+H] ⁺ 420.0, 422.0 773 1-((1H-imidazol-4-yl)methyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M+H] ⁺ 294.4 774 (S)-1-(1-(1H-imidazol-4-yl)ethyl)-4-(methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, Single enantiomer (configuration unknown) m/z [M+H] 338.3. 775 (R)-1-(1-(1H-imidazol-4-yl)ethyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one, single enantiomer (configuration unknown) m/z [M+H] 338.3 776 1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)-6-(methylthio)-quinazolin-2(1H)-one m/z [M+H] ⁺ 324.35

Additional compounds having formula (I) within the scope of the present invention are listed below in Table 2.

Table 2 Structure Name 7-chloro-4-(2-oxopyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one 7-chloro-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one 7-chloro-1-phenyl-4-((pyridin-2-ylmethyl)amino)-quinazolin-2(1H)-one 7-chloro-1-phenyl-4-((pyridin-3-ylmethyl)amino-)quinazolin-2(1H)-one 7-chloro-1-phenyl-4-((pyridin-4-ylmethyl)amino)-quinazolin-2(1H)-one 7-chloro-4-(methyl(pyridin-2-ylmethyl)amino)-1-phenylquinazolin-2(1H)-one 7-chloro-4-(methyl(pyridin-3-ylmethyl)amino)-1-phenylquinazolin-2(1H)-one 7-chloro-4-((methylamino)methyl)-1-phenylquinazolin-2(1H)-one 7-chloro-4-cyclopropyl-1-phenylquinazolin-2(1H)-one 7-chloro-4-((dimethylamino)methyl)-1-phenylquinazolin-2(1H)-one 2-(7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)acetamide 7-chloro-4-(3-hydroxypropyl)-1-phenylquinazolin-2(1H)-one 7-chloro-4-(2-(dimethylamino)ethyl)-1-phenylquinazolin-2(1H)-one 7-chloro-4-(2-(methylamino)ethyl)-1-phenylquinazolin-2(1H)-one 7-chloro-4-(1H-imidazol-2-yl)-1-phenylquinazolin-2(1H)-one 7-chloro-4-(1H-imidazol-5-yl)-1-phenylquinazolin-2(1H)-one 7-chloro-1-phenyl-4-(thiazol-5-yl)quinazolin-2(1H)-one 7-chloro-1-phenyl-4-(thiazol-4-yl)quinazolin-2(1H)-one 7-chloro-4-(isothiazol-4-yl)-1-phenylquinazolin-2(1H)-one 7-chloro-1-phenyl-4-(thiazol-2-yl)quinazolin-2(1H)-one 7-chloro-4-(methyl(pyridin-4-ylmethyl)amino)-1-phenylquinazolin-2(1H)-one 4-amino-7-chloro-1-phenyl-5-(1H-pyrazol-3-yl)quinazolin-2(1H)-one 7-chloro-1-phenyl-5-(pyridin-4-yl)quinazolin-2(1H)-one 4-amino-7-chloro-5-(5-oxopyrrolidin-3-yl)-1-phenylquinazolin-2(1H)-one 4-amino-7-chloro-1-phenyl-5-(4H-1,2,4-triazol-4-yl)quinazolin-2(1H)-one 4-amino-7-chloro-1-phenyl-5-(pyridin-4-yl)quinazolin-2(1H)-one 4-amino-7-chloro-5-(2-oxopyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one 4-amino-7-chloro-5-morpholino-1-phenylquinazolin-2(1H)-one 4-amino-7-chloro-5-cyclopropyl-1-phenylquinazolin-2(1H)-one 4-amino-7-chloro-1-phenyl-5-(1H-pyrazol-1-yl)quinazolin-2(1H)-one 5-(4-amino-7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-5-yl)oxazolidin-2-one 7-chloro-4-(methylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-5-carbonitrile 7-chloro-4-(methylamino)-5-(2-(methylamino)ethoxy)-1-phenylquinazolin-2(1H)-one 7-chloro-4-(methylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-6-carboxamide 7-chloro-4-(methylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-5-carboxamide 4-amino-7-chloro-5-(2-morpholinoethoxy)-1-phenylquinazolin-2(1H)-one 3-methyl-8-(methylamino)-5-phenylpyrimido[5,4-c]pyridazin-6(5H)-one 7-methyl-4-(methylamino)-1-phenylpteridin-2(1H)-one 7-methyl-4-(methylamino)-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one 4-(dimethylamino)-7-(1-methyl-1H-imidazol-4-yl)-1-phenyl-quinazolin-2(1H)-one (S)-4-(dimethylamino)-7-(3-hydroxypyrrolidin-1-yl)-1-phenyl-quinazolin-2(1H)-one 4-(dimethylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-7-carboxamide 7-(difluoromethyl)-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one 4-(dimethylamino)-1-phenyl-7-(tetrahydrofuran-2-yl)quinazolin-2(1H)-one 7-cyclopentyl-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one 4-(dimethylamino)-1-phenyl-7-(trifluoromethoxy)quinazolin-2(1H)-one 4-(dimethylamino)-7-(2-hydroxypropan-2-yl)-1-phenylquinazolin-2(1H)-one 4-(dimethylamino)-7-(2-oxoazetidin-1-yl)-1-phenylquinazolin-2(1H)-one 4-(dimethylamino)-7-(2-oxopyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one 4-(dimethylamino)-8-fluoro-7-methyl-1-phenylquinazolin-2(1H)-one 7-(tert-butyl)-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one 4-(dimethylamino)-7-isopropyl-1-phenylquinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(4-oxo-1,4-dihydropyridin-3-yl)quinazolin-2(1H)-one 6-chloro-1-(methylamino)-4-(2-oxo-1,2-dihydropyridin-3-yl)isoquinolin-3(4H)-one 7-chloro-4-(methylamino)-1-(6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2(1H)-one 7-chloro-1-(4-hydroxypyrimidin-2-yl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(5-hydroxypyridin-3-yl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(2-hydroxypyridin-4-yl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(6-hydroxypyridin-2-yl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(3-(methoxymethyl)phenyl)-4-(methylamino)quinazolin-2(1H)-one 1-(3-(aminomethyl)phenyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(4-hydroxyphenyl)-4-(methylamino)quinazolin-2(1H)-one 2-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)benzonitrile 7-chloro-1-(2-fluoro-3-hydroxyphenyl)-4-(methylamino)quinazolin-2(1H)-one 1-(3-aminophenyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one 2-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl-) cyclopropane-1-carbonitrile 2-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)-cyclobutan-1-carbonitrile 4-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)-cyclohexane-1-carbonitrile 7-chloro-1-cyclohexyl-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(3-hydroxycyclohexyl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(4-hydroxycyclohexyl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(cyclohex-1-en-1-yl)-4-(dimethylamino)quinazolin-2(1H)-one 7-chloro-1-(cyclopent-1-en-1-yl)-4-(dimethylamino)quinazolin-2(1H)-one 7-chloro-1-cyclohexyl-4-(dimethylamino)quinazolin-2(1H)-one 7-chloro-1-cyclopentyl-4-(dimethylamino)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(3-(3-phenylpropyl)phenyl)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(3-phenetoxyphenyl)quinazolin-2(1H)-one 1-(3-((benzyloxy)methyl)phenyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one N-benzyl-3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)benzamide N-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)-2-phenylacetamide 4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)-7-(trifluoromethyl)quinazolin-2(1H)-one 7-chloro-1-(3-(2-(3-(hydroxymethyl)phenoxy)-ethyl)phenyl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(3-(2-(pyridin-2-yloxy)ethyl)phenyl)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(3-(2-(pyridin-3-yloxy)ethyl)phenyl)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(3-(2-(pyrimidin-4-yloxy)ethyl)phenyl)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(3-(2-(thiazol-2-yloxy)ethyl)phenyl)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(3-(2-(thiazol-2-ylamino)ethyl)phenyl)quinazolin-2(1H)-one 7-chloro-1-(3-(2-((1-methyl-1H-pyrazol-5-yl)amino)ethyl)phenyl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(3-(2-((1-methyl-1H-pyrazol-5-yl)oxy)ethyl)phenyl)-4-(methylamino)quinazolin-2(1H)-one 4-(dimethylamino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one 1-(2-chlorophenyl)-4-(dimethylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one 4-(azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-(azetidin-1-yl)-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazolin-2(1H)-one 4-(pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one 1-(2-chlorophenyl)-4-(pyrrolidin-1-yl)-7-(trifluoromethyl)-quinazolin-2(1H)-one 4-(3-hydroxypyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one 1-(2-chlorophenyl)-4-(3-hydroxypyrrolidin-1-yl)-7-(trifluoromethyl)-quinazolin-2(1H)-one 4-(azetidin-1-yl)-7-cyclopropyl-1-(o-tolyl)quinazolin-2(1H)-one 4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one 7-isopropyl-4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)-quinazolin-2(1H)-one 7-cyclopropyl-4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)-quinazolin-2(1H)-one 7-cyclopropyl-4-(pyrrolidin-1-yl)-1-(o-tolyl)quinazolin-2(1H)-one 2-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)acetonitrile methyl 2-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)acetate 2-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)-N-methylacetamide 4-cyclopropoxy-7-cyclopropyl-1-phenylquinazolin-2(1H)-one 7-cyclopropyl-4-isopropoxy-1-phenylquinazolin-2(1H)-one 7-cyclopropyl-1-phenyl-4-(2,2,2-trifluoroethoxy)quinazolin-2(1H)-one 7-cyclopropyl-4-(oxetan-3-ylmethoxy)-1-phenylquinazolin-2(1H)-one 7-cyclopropyl-4-(cyclopropylmethoxy)-1-phenylquinazolin-2(1H)-one 7-cyclopropyl-4-methoxy-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 1-(2-chlorophenyl)-4-isopropoxy-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 1-(2-chlorophenyl)-4-(2,2,2-trifluoroethoxy)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 1-(2-chlorophenyl)-4-(oxetan-3-ylmethoxy)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 1-(2-chlorophenyl)-4-(cyclopropylmethoxy)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 1-(2-chlorophenyl)-7-cyclopropyl-4-(3-hydroxy-3-methylpyrrolidin-1-yl)quinazolin-2(1H)-one 1-(2-chlorophenyl)-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-7-methylpyrido[2,3-d]pyrimidin-2(1H)-one 7-chloro-5-(difluoromethoxy)-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one (R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one 7-chloro-5-methoxy-4-(methylamino)-1-(pyridin-3-yl)quinazolin-2(1H)-one 7-chloro-5-methoxy-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 7-cyclopropyl-5-methoxy-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 7-chloro-5-ethyl-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one 7-chloro-5-methyl-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-(o-tolyl)-5-(trifluoromethoxy)quinazolin-2(1H)-one 4-amino-7-cyclopropyl-1-(o-tolyl)quinazolin-2(1H)-one 1-(2-chlorophenyl)-4-(((1R,2R)-2-methoxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 1-(2-chlorophenyl)-4-(((1S,2S)-2-methoxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 7-chloro-1-((2-methoxy-1H-imidazol-4-yl)methyl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-4-(methylamino)-1-((2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one 1-((1H-pyrazol-3-yl)methyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one 1-((1H-pyrazol-4-yl)methyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one 1-(azetidin-3-ylmethyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one 1-(1H-benzo[d]imidazol-6-yl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one 1-(1H-benzo[d]imidazol-4-yl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(1H-indazol-4-yl)-4-(methylamino)quinazolin-2(1H)-one 1-(benzo[d]oxazol-6-yl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one 1-(benzo[d]thiazol-6-yl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(1-methyl-1H-benzo[d]imidazol-5-yl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(1-methyl-1H-benzo[d]imidazol-6-yl)-4-(methylamino)quinazolin-2(1H)-one 7-chloro-1-(imidazo[1,2-a]pyridin-8-yl)-4-(methylamino)quinazolin-2(1H)-one (R)-7-chloro-5-(2-hydroxypropoxy)-4-(methylamino)-1-phenylquinazolin-2(1H)-one (S)-7-chloro-5-(2-hydroxypropoxy)-4-(methylamino)-1-phenylquinazolin-2(1H)-one 7-chloro-5-(2-methoxyethoxy)-4-(methylamino)-1-phenylquinazolin-2(1H)-one 7-chloro-4-(methylamino)-5-(oxetan-3-ylmethoxy)-1-phenylquinazolin-2(1H)-one 5-methoxy-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one 7-cyclopropyl-4-((2,2-difluoroethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 1-(2-chlorophenyl)-7-cyclopropyl-4-((2,2-difluoroethyl)amino)quinazolin-2(1H)-one 7-cyclopropyl-1-phenyl-4-((2,2,2-trifluoroethyl)amino)pyrido[2,3-d]pyrimidin-2(1H)-one 7-cyclopropyl-4-((2,2-difluoroethyl)amino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one 4-amino-7-cyclopropyl-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one 7-cyclopropyl-4-methoxy-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one 7-cyclopropyl-4-(methylamino)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one 7-ethyl-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 7-ethyl-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one 1-(2-chlorophenyl)-7-ethyl-4-(methylamino)quinazolin-2(1H)-one

Implementation options

In the following embodiments 1-34, the present invention includes:

1A. Embodiment 1A describes a compound having the formula (IA'), (IA), (IIA'), or (IIA), or a pharmaceutically acceptable salt thereof, wherein w, x, y, z, R ¹ and R ² have the meanings described below in the Summary of the Invention. In a first subembodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has the structure (IA). In a second subembodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has the structure (IIA). In a third subembodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has the structure (IA'). In a fourth subembodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has the structure (IIA').

1. Embodiment 1 describes a compound having the formula (I), (IA), (IA'), (II), (IIA), (IIA'); or a pharmaceutically acceptable salt thereof, wherein w, x, y, z, R ¹ and R ² have the meanings described below in the Summary of the Invention. In a first sub-embodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has the structure (I). In a second sub-embodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has the structure (II).

2. In embodiment 2, a compound according to any one of embodiments 1A or 1 and subvariants thereof, or a pharmaceutically acceptable salt thereof, is described, wherein

R ¹ is R ⁷ , where R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, phenyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein aryl, heteroaryl and heterocyclyl are unsubstituted or substituted with R ^d , R ^e and/or R ^f ; and

R ² is alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR ⁸ , -NR ⁹ R ¹⁰ or -X ^b -R ¹¹ . In a first subvariant of embodiment 2, R ² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR ⁸ , -NR ⁹ R ¹⁰ or R ¹¹ .

3. Embodiment 3 describes a compound according to any one of embodiments 1A or 1 and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein

R ¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl or aminosulfonylalkyl; and

R ² is alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR ⁸ , -NR ⁹ R ¹⁰ or -X ^b -R ¹¹ . In a first subvariant of embodiment 3, R ² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR ⁸ , -NR ⁹ R ¹⁰ or R ¹¹ .

4. In embodiment 4, a compound of any one of embodiments 1A or 1 and subvariants thereof, or a pharmaceutically acceptable salt thereof, is described, wherein R ¹ is R ⁷ , wherein R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl, or spiroheterocyclyl, wherein the aryl, heteroaryl, or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f .

5. In embodiment 5, the compound of any one of embodiments 1A and 1-4 and subvariants thereof, or a pharmaceutically acceptable salt thereof, has a structure represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), or (IIIg):

, , , ,

(IIIa) (IIIb) (IIIc) (IIId)

, , or

(IIIe) (IIIf) (IIIg)

In a first sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (IIIa). In a second sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (IIIb). In a third sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (IIIc). In a fourth sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (IIId). In a fifth sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (IIIe). In a sixth sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (IIIf). In a seventh sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure represented by formula (IIIg).

6. Embodiment 6 is a compound according to any one of embodiments 1A and 1-5 and subvariants thereof (e.g., compounds having formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), and (IIIg)), or a pharmaceutically acceptable salt thereof, wherein R ² is -NR ⁹ R ¹⁰ .

7. Embodiment 7 is a compound according to any one of embodiments 1A and 1-5 and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is -OR ⁸ .

8. Embodiment 8 is a compound according to any one of embodiments 1A and 1-5 and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is R ¹¹ .

9. Embodiment 9 provides a compound according to any one of embodiments 1A and 1-5 and subembodiments thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is -(alkylene)-R ¹¹ . In a first subembodiment of embodiment 9, the alkylene is methylene or ethylene. In a second subembodiment of embodiment 9, the alkylene is methylene.

10. Embodiment 10 is a compound according to any one of embodiments 1A and 16 and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is a hydrogen atom, methyl, ethyl, cyclopropyl or trideuteromethyl. In a first subvariant of embodiment 10, R ⁹ is a hydrogen atom, methyl, ethyl or cyclopropyl. In a second subvariant of embodiment 10, R ⁹ is a hydrogen atom, methyl or cyclopropyl. In a third subvariant of embodiment 4, R ⁹ is a hydrogen atom. In a fourth subvariant of embodiment 10, R ⁹ is methyl. In a fifth subvariant of embodiment 10, R ^{9 is cyclopropyl. In a sixth subvariant of embodiment 10, R 9 is} a hydrogen atom or methyl. In a seventh subvariant of embodiment 10, R ⁹ is trideuteromethyl.

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

12. Embodiment 12 provides a compound according to any one of Embodiments 1A, 1-5, and 7, and subembodiments thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl. In a first subembodiment of embodiment 12, R 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 sub-variant of embodiment 12, R ⁸ is alkoxyalkyl, preferably methoxyethyl, ethoxyethyl, methoxypropyl or ethoxypropyl.

13. Embodiment 13 provides a compound according to any one of embodiments 1A, 1-7 and 10, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are independently cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, conjugated cycloalkyl, spirocycloalkyl or spirocycloalkylalkyl. In a first subvariant of embodiment 13, R ⁸ and R ¹⁰ are independently cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, each ring independently optionally being unsubstituted or substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxy or cyano. In a second sub-variant of embodiment 13, R ⁸ and R ¹⁰ are independently cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, each ring independently may be unsubstituted or substituted with one or two substituents independently selected from methyl, fluoro or cyano. In a third sub-variant of embodiment 13, R ⁸ and R ¹⁰ are independently cycloalkylalkyl, preferably cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl, the ring in each group independently may be unsubstituted or substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxy or cyano. In a fourth sub-variant of embodiment 13, R ⁸ and R ¹⁰ are independently cycloalkyloxyalkyl, preferably cyclopropyloxyethyl, cyclobutyloxyethyl, cyclopentyloxyethyl or cyclohexyloxyethyl, preferably cyclopropyloxyethyl, the ring in each group independently optionally being unsubstituted or substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxy or cyano. In a fifth sub-variant of embodiment 13, R ⁸ and R ¹⁰ are independently bridged cycloalkyl or bridged cycloalkylalkyl. In a sixth sub-variant of embodiment 13, R ⁸ and R ¹⁰ are independently spirocycloalkyl or spirocycloalkylalkyl. In a seventh sub-variant of embodiment 13, R ⁸ and R ¹⁰ are independently cycloalkyl or cycloalkylalkyl, preferably cyclopropyl or cyclopropylmethyl, each ring independently optionally being unsubstituted or substituted with one or two substituents independently selected from alkyl, halogen or cyano. In an eighth sub-variant of embodiment 13, R ⁸ and R ¹⁰ are independently cyclopropyl or cyclopropylmethyl, each ring independently optionally being unsubstituted or substituted with one or two substituents independently selected from methyl, fluoro or cyano. In a ninth sub-embodiment of embodiment 13, R ⁸ and R ¹⁰ are independently cyclopropyl, cyclobutyl, 1-methylcyclopropyl, (cis)-3-hydroxy-3-methylcyclobutyl, (cis)-3-hydroxy-2,2-dimethylcyclobutyl, 1-cyanocyclobutyl, cyclopropylmethyl, 1-hydroxycyclopropylmethyl, 1-fluorocyclopropylmethyl, (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, 1-fluorocyclopropylmethyl, (1S,2R)-2-fluorocyclopropyl, (1R,2S)-2-fluorocyclopropyl, (1S,2S)-2-fluorocyclopropyl, 2,2-difluorocyclopropyl, (R)-1-cyclopropylethyl or 2,2-difluorocyclopropylmethyl. In a tenth sub-embodiment of embodiment 13, R ⁸ and R ¹⁰ are 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 sub-variant of embodiment 13, R ⁸ and R ¹⁰ are independently cyclopropylmethyl, 1-hydroxycyclopropylmethyl, 1-fluorocyclopropylmethyl, 1-fluorocyclopropylmethyl, (R)-1-cyclopropylethyl or 2,2-difluorocyclopropylmethyl.

14. Embodiment 14 provides a compound according to any one of embodiments 1A, 1-7 and 10 and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein ^R8 and ^R10 are independently phenyl or phenylalkyl (preferably benzyl or phenethyl) wherein phenyl, alone or as part of an aralkyl, is unsubstituted or substituted with ^Rj , ^Rk and/or ^Rl .

15. Embodiment 15 describes a compound according to any one of embodiments 1-7 and 10 and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are independently heteroaryl or heteroaralkyl, wherein heteroaryl, alone or as part of heteroaralkyl, is unsubstituted or substituted with R ^j , R ^k and/or R ^l . In a first sub-embodiment of embodiment 15, R ⁸ and R ¹⁰ are 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, each ring being unsubstituted or substituted with R ^j , R ^k and/or R ^l . In a second sub-embodiment of embodiment 15, R ⁸ and R ¹⁰ are 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, preferably 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, each ring being unsubstituted or substituted with R ^j , R ^k and/or R ^l . In a third sub-embodiment of embodiment 15, R ⁸ and R ¹⁰ are 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-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.

16. Embodiment 16 provides a compound according to any one of Embodiments 1A, 1-7, and 10, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are independently heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein heterocyclyl, alone or as part of another group, is unsubstituted or substituted with R ^j , R ^k and/or R ^l . In a first subvariant of embodiment 16, R ⁸ and R ¹⁰ are independently heterocyclyl, preferably oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, each ring being unsubstituted or substituted with R ^j , R ^k and/or R ^l . In a second sub-embodiment of embodiment 16, R ⁸ and R ¹⁰ are independently heterocyclylalkyl, preferably oxetanylmethyl, oxetanylethyl, azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl or morpholinylethyl, each ring being unsubstituted or substituted with R ^j , R ^k and/or R ^l . In a third sub-embodiment of embodiment 16, R ⁸ and R ¹⁰ are independently heterocyclyloxyalkyl which is unsubstituted or substituted with R ^j , R ^k and/or R ^l . In a fourth sub-embodiment of embodiment 16, R ⁸ and R ¹⁰ are independently bridged heterocyclyl, bridged heterocyclylalkyl. In a fifth sub-variant of embodiment 16, R ⁸ and R ¹⁰ are independently spiroheterocyclyl or spiroheterocyclylalkyl.

17. Embodiment 17 is a compound according to any one of embodiments 1A, 1-5, 8 and 9, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is heterocyclyl that is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o . In a first sub-variant 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, each ring being unsubstituted or substituted with R ^m , R ⁿ and/or R ^o . In a second sub-embodiment 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. In a third sub-variant of embodiment 17, R ¹¹ is 3-hydroxypyrrolidin-1-yl.

18. Embodiment 18 provides a compound according to any one of embodiments 1A, 1-5, 8 and 9, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is cycloalkyl. In a first subvariant of embodiment 18, R ¹¹ is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, each ring independently optionally being unsubstituted or substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxy or cyano.

19. Embodiment 19 provides a compound of any one of Embodiments 1A, 1-5, 8, and 9, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is heteroaryl that is unsubstituted or substituted with R ^j , R ^k and/or R ^l . In a first subvariant 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 substituted with R ^j , R ^k and/or R ^l . In a second sub-embodiment 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.

20. Embodiment 20 is a compound according to any one of embodiments 1A, 1-5, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is hydroxyalkyl, aminoalkyl, aminocarbonylalkyl.

21. Embodiment 21 provides a compound according to any one of embodiments 1A, 1-20, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁶ are independently selected from hydrogen, methyl, chloro, fluoro, bromo, methoxy, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, or dimethylaminocarbonyl. In a first subvariant of embodiment 21, R ⁴ is hydrogen, fluoro, methoxy, cyano, and R ⁶ is hydrogen. In a second subvariant of embodiment 21, R ⁴ and R ⁶ are hydrogen. In a third sub-variant of embodiment 21, R ⁴ and R ⁶ are independently selected from hydrogen, methyl, chloro, fluoro, methoxy, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl or dimethylaminocarbonyl. In a fifth sub-variant of embodiment 21, R ⁴ is hydrogen, fluoro, bromo, methyl, methoxy or cyano, and R ⁶ is hydrogen.

22. Embodiment 22 provides a compound of any one of Embodiments 1A, 1-21, and subembodiments thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is alkyl, alkoxy, alkylsulfonyl, halogen, 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, preferably R ⁵ is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl, heteroaryl, heterocyclyl, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted with R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. In a first sub-variant of embodiment 22, R ⁵ is methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclopentyl, cyano, methylsulfonyl, methylamino or dimethylamino. In a second sub-variant of embodiment 22, R ⁵ is hydroxymethyloxy, hydroxyethyloxy, hydroxymethylamino, hydroxyethylamino, aminoethyloxy, methylaminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, aminoethylamino, methylaminoethylamino, dimethylaminoethylamino or diethylaminoethylamino. In a third sub-embodiment of embodiment 22, R ⁵ is a 5- or 6-membered heteroaryl such as pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl or pyrimidinyl, each of which is unsubstituted or substituted with R ^a , R ^b and/or R ^c independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. In a fourth sub-embodiment 22, R ⁵ is 4- or 6-membered heterocyclyl, preferably oxetan-3-yl, pyrrolidin-1-yl, tetrahydrofuranyl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, wherein each ring is unsubstituted or substituted with ^Ra and/or R ^b . In a fifth sub-embodiment 22, R ⁵ is halogen, alkyl, haloalkyl or cycloalkyl. In a sixth sub-embodiment 22, R ⁵ is chloro, methyl, ethyl, trifluoromethyl or cyclopropyl. In a seventh sub-embodiment 22, R ⁵ is trifluoromethyl, 1,1-difluoroethyl or cyclopropyl. In an eighth sub-variant of embodiment 22, R ⁵ is chloro, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl, or cyclopropyl.

23. Embodiment 23 provides a compound according to any one of Embodiments 1A, 1-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen, alkyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted with R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. In a first sub-embodiment of embodiment 23, R ³ is a hydrogen atom. In a second sub-embodiment of embodiment 23, R ³ is methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano, methylsulfonyl, aminocarbonyl, methylamino or dimethylamino. In a third sub-embodiment of embodiment 23, R ³ is hydroxymethyloxy, hydroxyethyloxy, hydroxymethylamino, hydroxyethylamino, aminoethyloxy, methylaminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy, aminoethylamino, methylaminoethylamino, dimethylaminoethylamino or diethylaminoethylamino. In a fourth sub-embodiment of embodiment 23, R ³ is heteroaryl, preferably a 5- or 6-membered heteroaryl, such as pyrazolyl, imidazolyl, triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl or pyrimidinyl, each ring being unsubstituted or substituted with R ^a , R ^b and/or R ^c . In a fifth sub-embodiment of embodiment 23, R ³ is heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted with ^Ra , R ^b and/or R ^c . In a sixth sub-embodiment of embodiment 3, R ³ is oxopyrrolidinyl, morpholin-4-yl or 2-morpholin-4-ylethyloxy. In a seventh sub-embodiment of embodiment 23, R ³ is hydrogen or methoxy. In an eighth sub-variant of embodiment 23, when R ³ is a group from the second, third, fourth, fifth or sixth sub-variant, then R ² is amino or methylamino, R ⁴ and R ⁶ are a hydrogen atom, and R ⁵ is other than a hydrogen atom.

24. Embodiment 24 is a compound according to any one of embodiments 1A, 1, 3, 5-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is alkyl, preferably methyl, ethyl or isopropyl.

25. Embodiment 25 is a compound according to any one of embodiments 1A, 1, 3, 5-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is haloalkyl, preferably trifluoromethyl.

26. Embodiment 26 is a compound according to any one of embodiments 1A, 1, 3, 5-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, or aminosulfonylalkyl.

27. Embodiment 27 provides a compound according to any one of embodiments 1A, 1, 2, 4-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, or spirocycloalkyl. In a first subvariant of embodiment 27, R ⁷ is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which is unsubstituted or substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, cyano, or halogen. In a first sub-embodiment of embodiment 27, R ⁷ is cycloalkenyl, cyclopentenyl, or cyclohexenyl, which is unsubstituted or substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, cyano, or halogen.

28. Embodiment 28 provides a compound of any one of Embodiments 1A, 1, 2, 4-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is aryl that is unsubstituted or substituted with R ^d , R ^e and/or R ^f , wherein R ^f is selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In a first subvariant of embodiment 28, R ⁷ is phenyl that is unsubstituted or substituted with R ^{d ,} R ^e and/or R ^f . In a second sub-embodiment of embodiment 28, R ⁷ is phenyl that is unsubstituted or substituted with R ^d , R ^e and/or R ^f , wherein R ^d and R ^e are 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 sub-embodiment of embodiment 28, R ⁷ is phenyl that is substituted with R ^d , R ^e and/or R ^f , wherein R ^d and R ^e are 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 are attached to carbon atoms of the phenyl ring that are located in an ortho or meta position to a carbon atom of the phenyl ring attached to the quinazolone nitrogen. In a fourth sub-embodiment of embodiment 28, R ⁷ is phenyl that is unsubstituted or substituted with R ^e and/or R ^f , wherein R ^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 wherein R ^f is attached to a carbon atom of the phenyl ring that is located in an ortho position to the carbon atom of the phenyl ring attached to the quinazolone nitrogen. In a fifth sub-embodiment of embodiment 28, R ⁷ is phenyl that is unsubstituted or substituted with R ^f , wherein R ^f is fluoro, chloro, bromo, or methyl, and wherein R ^f is attached to a carbon atom of the phenyl ring that is located in an ortho position to the carbon atom of the phenyl ring attached to the quinazolone nitrogen.

29. Embodiment 28 provides a compound of any one of embodiments 1A, 1, 2, and 4-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is heteroaryl that is unsubstituted or substituted with R ^d , R ^e and/or R ^f , wherein R ^f is selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In a first sub-embodiment of embodiment 29, R ⁷ is a 5 or 6-membered heteroaryl ring such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, which is unsubstituted or substituted with R ^d , R ^e and/or R ^f . In a second sub-embodiment of embodiment 29, R ^d and R ^e are 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 sub-variant of embodiment 29, R ^d and R ^e are independently selected from methyl, ethyl, fluoro, chloro, bromine, 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 R ^d , R ^e and/or R ^f are attached to carbon atoms of the heteroaryl ring that are located in an ortho or meta position to a carbon atom of the heteroaryl ring attached to the quinazolone nitrogen. In a fourth sub-embodiment of embodiment 29, R ⁷ is pyridinyl or pyrimidinyl, preferably pyridin-3-yl or pyrimidin-4-yl, which is unsubstituted or substituted with R ^e and/or R ^f , wherein R ^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 wherein R ^f is attached to a carbon atom of the pyridinyl or pyrimidinyl ring that is located in the ortho position to the carbon atom of the phenyl ring attached to the quinazolone nitrogen. In a fifth sub-embodiment of embodiment 29, R ⁷ is pyridinyl, preferably pyridin-2-yl or pyridin-3-yl, which is unsubstituted or substituted with R ^f , wherein R ^f is fluoro, chloro or methyl, and wherein R ^f is attached to a carbon atom of the pyridinyl ring that is located in an ortho position to the carbon atom of the phenyl ring attached to the quinazolone nitrogen.

30. Embodiment 30 provides a compound of any one of embodiments 1A, 1, 2, and 4-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl, or spiroheterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f , wherein R ^f is selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In a first sub-embodiment of embodiment 30, R ⁷ is pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl or morpholinyl, each ring independently unsubstituted or substituted with R ^d , R ^e and/or R ^f . In a second sub-embodiment of embodiment 30, R ⁷ is pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl or morpholinyl, each ring independently unsubstituted or substituted with R ^d , R ^e and/or R ^f , independently selected from methyl, ethyl, fluoro, chloro, bromine, methoxy, ethoxy, hydroxy, methylsulfonyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl.

31. Embodiment 31 is a compound according to any one of embodiments 1A, 1, 2, and 4-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R¹represents R⁷, where R⁷is an aryl substituted with R^d, R^eand/or R^f, where R^frepresents -X^c-R¹², where X^cis alkylene or heteroalkylene, and R¹² is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In the first sub-embodiment of embodiment 28, R⁷is phenyl substituted by R^d, R^eand/or R^f. In the second sub-embodiment of embodiment 28, R⁷is phenyl which is unsubstituted or substituted by R^d, R^eand/or R^f, where R^dand R^eindependently selected from methyl, ethyl, fluoro, chlorine, bromine, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, and R^fselected 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 subvariant of embodiment 31, R^fattached to a carbon atom of the phenyl ring that is located in the ortho or meta position to the carbon atom of the phenyl ring attached to the quinazolone nitrogen.

32. Embodiment 32 provides a compound of any one of Embodiments 1A, 1, 2, and 4-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is heteroaryl substituted with R ^d , R ^e and/or R ^f , wherein R ^f is -X ^c -R ¹² , wherein X ^c is alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In a first subvariant of embodiment 32, R ⁷ is a 5 or 6-membered heteroaryl ring such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl that is unsubstituted or substituted with R ^d , R ^e and/or R ^f . In a second sub-embodiment of embodiment 32, R ^d and R ^e are independently selected from methyl, ethyl, fluoro, chloro, bromine, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, and R ^f 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 sub-embodiment of embodiment 32, R ^f is attached to a carbon atom of the heteroaryl ring that is located in an ortho or meta position to a carbon atom of the heteroaryl ring attached to the quinazolone nitrogen.

33. Embodiment 33 provides a compound of any one of Embodiments 1A, 1, 24-23, and subvariants thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is -X ^a -R ⁷ , wherein X ^a is alkylene, and R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl, or spiroheterocyclyl, wherein the aryl, heteroaryl, or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f .

The embodiments listed above include all combinations of the listed embodiments and sub-variants. For example, the group R ¹ listed in embodiment 30 and/or its first and/or second sub-variant can be independently combined with one or more of embodiments 1-28 and 31-33 and/or their sub-variants.

The present invention includes additional embodiments 35-90 described below.

35. A compound having the formula (IA):

(IA),

Where:

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 represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁵ represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is R ⁷ , wherein R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl, deuteroalkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , ^Rh , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, amino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl; or

its pharmaceutically acceptable salt; provided that:

(1) when represents , where: (a) when R ² is piperazin-1-yl, 2-methylpiperazin-1-yl or 1H-benzo[d][1,2,3]triazol-1-yl, R ³ and R ⁶ represent a hydrogen atom, R ⁴ is chlorine, and R ⁵ is bromo or 5-methylindazol-4-yl, then R ¹ is not 2-isopropylphenyl; (b) when R ² and R ⁶ are methyl, and R ³ , R ⁴ and R ⁵ represent a hydrogen atom; or ^R2 and ^R3 are methyl, and ^R4 , ^R5 and ^R6 are a hydrogen atom, then ^R1 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) when ^R2 is amino or acetylamino, ^R4 is dimethylamino, and ^R3 , ^R5 and ^R6 are a hydrogen atom, then ^R1 is not 4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (d) when R ⁵ is fluorine, R ³ , R ⁴ and R ⁶ represent a hydrogen atom, and R ² is 4-aminocarbonylmethyl-2-methylphenylamino, then 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) when R ⁶ is fluorine, R ³ , R ⁴ and R ⁵ represent a hydrogen atom, and R ² is 4-aminocarbonylmethyl-2-methylphenylamino, then R ¹ is not 4-fluoro-2-methoxyphenyl; (f) when R ¹ is 4-chloro-2-ethoxyphenyl, R ⁵ is fluoro, and R ³ , R ⁴ and R ⁶ are a hydrogen atom, then R ² is not 3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino;

(2) when represents , then when R ¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, R ⁵ is amino, and R ³ is methoxy; then R ² is not amino; and

(3) when represents , then when R ¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, one of R ⁴ and R ⁵ is a hydrogen atom, and the second of R ⁴ and R ⁵ is methyl, or R ⁴ and R ⁵ are both methyl, then R ² is not amino.

36. The compound of embodiment 35, wherein the compound has a structure represented by formula (I):

(I),

Where:

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:

^R3 and ^R5 independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by ^Ra , ^Rb and/or ^Rc , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is R ⁷ , where R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, phenyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , ^Rh , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; or

its pharmaceutically acceptable salt.

37. A compound of embodiment 35 or 36, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIg):

, , , ,

(IIIa) (IIIb) (IIIc) (IIId)

, , or

(IIIe) (IIIf) (IIIg)

38. The compound of embodiment 35 or 36, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIa).

39. The compound of embodiment 35 or 36, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIb).

40. The compound of embodiment 35 or 36, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIc).

41. The compound of embodiment 35 or 36, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIId).

42. The compound of embodiment 35 or 36, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIe).

43. The compound of embodiment 35 or 36, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIf).

44. The compound of embodiment 35 or 36, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIg).

45. A compound according to any one of embodiments 35-44 wherein R ² is -NR ⁹ R ¹⁰ .

46. A compound according to any one of embodiments 35-44 wherein R ² is -OR ⁸ .

47. A compound according to any one of embodiments 35-44 wherein R ² is R ¹¹ .

48. A compound according to any one of embodiments 35-45, wherein R ⁹ is deuteroalkyl, preferably trideuteromethyl.

49. A compound according to any one of embodiments 35-45, wherein R ⁹ is a hydrogen atom.

50. A compound according to any one of embodiments 35-45, wherein R ⁹ is alkyl, preferably methyl or ethyl.

51. A compound according to any one of embodiments 35-45, wherein R ⁹ is cycloalkyl, preferably cyclopropyl.

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

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

54. The compound of embodiment 46 or 52, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are alkyl, preferably methyl.

55. The compound of embodiment 52 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, preferably methylaminocarbonylmethyl or dimethylaminocarbonylmethyl.

56. A compound according to any one of embodiments 35-46 and 49-51, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are independently phenyl or phenylalkyl, preferably benzyl or phenethyl, wherein phenyl, alone or as part of benzyl and phenethyl, is unsubstituted or substituted with R ^j , R ^k and/or R ^l .

57. A compound according to any one of embodiments 35-46 and 49-51, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are independently cycloalkyl or cycloalkylalkyl, each ring independently optionally being unsubstituted or substituted with one or two substituents independently selected from alkyl, halogen or cyano.

58. A compound according to any one of embodiments 35-46 and 49-51, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are independently heteroaryl or heteroaralkyl, wherein heteroaryl, alone or as part of heteroaralkyl, is unsubstituted or substituted with R ^j , R ^k and/or R ^l .

59. A compound of embodiment 58 or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are heteroaryl independently selected from pyrazolyl, imidazolyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl and indazolyl, each ring being unsubstituted or substituted with R ^j , R ^k and/or R ^l .

60. A compound of embodiment 58, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are 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, each ring being unsubstituted or substituted with R ^j , R ^k and/or R ^l .

61. A compound according to any one of embodiments 35-46 and 49-51, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are independently heterocyclyl, preferably oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, each ring being unsubstituted or substituted with R ^j , R ^k and/or R ^l .

62. A compound according to any one of embodiments 35-46 and 49-51, or a pharmaceutically acceptable salt thereof, wherein R ⁸ and R ¹⁰ are independently heterocyclylalkyl, preferably oxetanylmethyl, oxetanylethyl, azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl or morpholinylethyl, each ring being unsubstituted or substituted with R ^j , R ^k and/or R ^l .

63. A compound according to any one of embodiments 35-44 and 47, or a pharmaceutically acceptable salt thereof, wherein R ² is R ¹¹ , wherein R ¹¹ is heterocyclyl that is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o .

64. The compound of embodiment 63, or a pharmaceutically acceptable salt thereof, wherein 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, each ring being unsubstituted or substituted with R ^m , R ⁿ and/or R ^o , preferably R ¹¹ is azetidin-1-yl, 4-hydroxyazetidin-1-yl, 4-methylaminocarbonylazetidin-1-yl, 4-dimethylaminocarbonyl azetidin-1-yl, 2-hydromethyl azetidin-1-yl, 2-methyl azetidin-1-yl, 2-oxo azetidin-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.

65. A compound according to any one of embodiments 35-44 and 47, or a pharmaceutically acceptable salt thereof, wherein R ² is R ¹¹ , wherein R ¹¹ is heteroaryl which is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o , 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 substituted with R ^m , R ⁿ and/or R ^o .

66. A compound according to any one of embodiments 35-44, or a pharmaceutically acceptable salt thereof, wherein R ² is hydroxyalkyl, aminoalkyl, or aminocarbonylalkyl.

67. A compound according to any one of embodiments 35-66, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl, heteroaryl, heterocyclyl, wherein heterocyclyl or heteroaryl is unsubstituted or substituted with ^Ra , R ^b and/or R ^c independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl.

68. A compound of Embodiment 67, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl, ethyl, isopropyl, t-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 the heterocyclyl or heteroaryl rings are unsubstituted or substituted with R ^a , R ^b , and/or R ^c independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl.

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

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

71. The compound of any one of embodiments 35-70, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁶ are independently selected from hydrogen, methyl, chloro, fluoro, methoxy, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, or dimethylaminocarbonyl.

72. The compound of any one of embodiments 35-70, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, fluoro, methoxy, cyano, and R ⁶ is a hydrogen atom.

73. The compound of any one of embodiments 35-70, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom or bromine, and R ⁶ is a hydrogen atom.

74. The compound of any one of embodiments 35-70, or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁶ represent a hydrogen atom.

75. The compound of any one of embodiments 35-74, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, alkyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl.

76. The compound of embodiment 75 or a pharmaceutically acceptable salt thereof, wherein

R ³ represents a hydrogen atom.

77. The compound of embodiment 75 or a pharmaceutically acceptable salt thereof, wherein R ³ is methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano, methylsulfonyl, aminocarbonyl, methylamino or dimethylamino.

78. A compound according to any one of embodiments 35-74, or a pharmaceutically acceptable salt thereof, wherein R ³ is heteroaryl, preferably a 5- or 6-membered heteroaryl, such as pyrazolyl, imidazolyl, triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl or pyrimidinyl, each ring being unsubstituted or substituted with R ^a , R ^b and/or R ^c .

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

80. A compound according to any one of embodiments 35-79, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each ring being unsubstituted or substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, cyano or halogen.

81. A compound of any one of embodiments 35-79, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is phenyl that is unsubstituted or substituted with R ^d , R ^e and/or R ^f , wherein R ^d and R ^e are 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 and methyl.

82. A compound of any one of embodiments 35-79, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is phenyl that is unsubstituted or substituted with R ^f , wherein R ^f is fluoro, chloro, bromo, or methyl, and wherein R ^f is attached to a carbon atom of the phenyl ring that is located in an ortho position to the carbon atom of the phenyl ring attached to the quinazolone nitrogen.

83. A compound according to any one of embodiments 35-79, or a pharmaceutically acceptable salt thereof, wherein R¹represents R⁷, where R⁷is a 5 or 6-membered heteroaryl ring such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, which is unsubstituted or substituted by R^dand/or R^e, independently chosen from methyl, ethyl, fluorine, chlorine, bromine, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, and/or R^f, selected from hydroxy, fluorine, chlorine, cyano and methyl.

84. A compound of any one of embodiments 35-79, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is phenyl that is substituted with R ^d , R ^e and/or R ^f , wherein R ^d and R ^e are 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 -X ^c R ¹² , wherein X ^c is alkylene or heteroalkylene, preferably heteroalkylene.

85. A compound of any one of Embodiments 35-79, or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is a 5 or 6-membered heteroaryl ring such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl substituted with R ^d , Re ^and /or R ^f , wherein R ^d and ^Re are 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 -X ^c R ¹² , wherein X ^c is alkylene or heteroalkylene, preferably heteroalkylene.

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

87. A method of treating a MAT2A-mediated disease in a patient, comprising administering to the patient a therapeutically effective amount of:

(a) a compound having the formula (IIA):

(IIA),

Where:

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 represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁵ represents a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by R ^a , R ^b and/or R ^c , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is R ⁷ , where R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl, deuteroalkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, 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, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , R ^h , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, amino, cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl;

(b) a compound having the formula (II):

(II),

Where:

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:

^R3 and ^R5 independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, 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, wherein heterocyclyl or heteroaryl, alone or as part of another group, is unsubstituted or substituted by ^Ra , ^Rb and/or ^Rc , independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl;

R ⁴ and R ⁶ independently represent a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; provided that: (i) no more than two of w, x, y and z can represent N, and (ii) at least one of R ³ , R ⁴ , R ⁵ and R ⁶ is other than a hydrogen atom;

R ¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl or -X ^a -R ⁷ , where X ^a is a bond or alkylene, and R ⁷ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, where aryl, heteroaryl or heterocyclyl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ;

R ² represents a hydrogen atom, alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR ⁸ , -NR ⁹ R ¹⁰ or -X ^b -R11, where:

R ⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^g , ^Rh and/or R ⁱ ;

R ⁹ represents a hydrogen atom, alkyl or cycloalkyl; and

R ¹⁰ represents a hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, conjugated cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, conjugated heterocyclyl, conjugated heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl, alone or as part of another group, is unsubstituted or substituted by R ^j , R ^k and/or R ^l ;

X ^b represents a bond or alkylene; and

R ¹¹ is cycloalkyl, bridged cycloalkyl, conjugated cycloalkyl, spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, conjugated heterocyclyl or spiroheterocyclyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and

R ^d , R ^e , R ^g , ^Rh , R ^j , R ^k , R ^m and R ⁿ are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, 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 are independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano or -X ^c -R ¹² , where X ^c is a bond, alkylene or heteroalkylene, and R ¹² is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; or

its pharmaceutically acceptable salt; or

(c) a compound according to any one of embodiments 35-85, or a pharmaceutically acceptable salt thereof.

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

89. A method of treating MTAP-null cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound having formula (IIA) or (II) according to claim 87, a pharmaceutically acceptable salt thereof; or

a compound according to any one of embodiments 35-85, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

90. A method of treating cancer in a patient, wherein the cancer is characterized by a decrease or absence of MTAP gene expression, an absence of the MTAP gene, or a decrease in MTAP protein function, comprising administering to the subject a therapeutically effective amount of a compound having formula (IIA) or (II) of embodiment 87, a pharmaceutically acceptable salt thereof; or

a compound according to any one of embodiments 35-85, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

Synthesis

The compounds of the present invention can be prepared by the methods shown in the reaction schemes below.

The starting materials and reagents used to prepare the compounds were either available from commercial sources such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.), or were prepared by methods known to those skilled in the art using procedures described in such works 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 Supplementals (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). The presented schemes are illustrations of some of the methods by which the compounds of the present invention can be synthesized, and various modifications in these schemes are possible, which will be apparent to those skilled in the art. The starting materials, intermediates and final products of the reactions can be isolated and purified, if necessary, using well-known methods, including (but not limited to) filtration, distillation, crystallization, chromatography, etc. The substances can be characterized by commonly used methods, including determination of physical constants and spectral data.

Unless otherwise stated, the reactions described herein are carried out at atmospheric pressure in a temperature range from about -78°C to about 150°C, such as from about 0°C to about 125°C, such as at room temperature (or ambient temperature), such as at about 20°C.

Compounds having formula (I) and (II), and the subvariants described in this text, where w, x, y and z are not nitrogen, R ² is other than a hydrogen atom, and the remaining groups have the meanings indicated in the brief description of the invention, can be prepared by the method illustrated and described below in Scheme 1.

Scheme 1

2,4-dioxoquinazoline compound having formula 1, where R¹, R³, R⁴, R⁵and R⁶have the meanings specified in the Summary of the Invention, or represent a precursor group thereof, can be easily converted into a compound having the formula (I), where R²is a halogen, by methods known in the art. For example, the reaction of compound 1 with P°Cl₃in the presence of an organic base such as triethylamine in an inert organic solvent yields a compound having the formula (I), where R²is chlorine, which can then be converted into compounds having the formula (I), where R²other than halogen, by methods known in the art. For example, compounds having the formula (I), where R²represents -NR⁹R¹⁰, a heterocycle containing at least one nitrogen atom, or a heteroaryl with a basic nitrogen atom, can be obtained by reacting a corresponding compound having the formula (I), where R²is chlorine, with an amine having the formula -NR⁹R¹⁰, a heterocycle containing at least one nitrogen atom and a heteroaryl with a basic nitrogen atom, in the presence of a base such as triethylamine, pyridine, diisopropylamine, in an organic solvent such as DMF, etc. An amine having the formula -NR⁹R¹⁰, or a heterocycle containing at least one 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-pyridineamine, 3-pyridineamine, 3-pyridineamine and cyclopropylmethylamine are available from commercial sources.

Alternatively, compounds containing -NR9R10 can be prepared from compounds of formula (I) wherein ^R2 is _-NH2 , under alkylation or arylation conditions known in the art.

A compound having formula (I), wherein R ² is R ¹¹ , wherein R ¹¹ is heteroaryl, can be prepared from compounds having formula (I), wherein R ² is halogen, under Suzuki reaction conditions.

Compounds having formula 1 can be prepared by methods known in the art. Some such methods are described and illustrated below.

Synthesis from 2-halobenzamides:

Method (a)

Reaction of a compound having formula 2, wherein X is a halogen such as chlorine and the remaining groups are as defined in the Summary of the Invention or are a precursor group thereof, with an amine having formula R ¹ NH ₂ , wherein R ¹ is as defined in the Summary of the Invention or are a precursor group thereof, in the presence of an inorganic base such as potassium carbonate, cesium carbonate, etc., and copper yields a compound having formula 3. Compounds having formula 2 are commercially available or can be prepared by methods known in the art. Compounds having formula 2 are converted to compounds having formula 1 by treatment with a base such as sodium hydride in the presence of N,N-carbonyldiimidazole under conditions known in the art.

Alternatively, compounds having formula 1 can be prepared from compound 2 as shown below in method b.

Method (b)

Reaction of a compound having formula 2, wherein X is a halogen, preferably chlorine, and the remaining groups are as defined in the Summary of the Invention or are a precursor group thereof, with an amine having formula R ¹ NH ₂ , in the presence of oxalyl chloride in a chlorinated organic solvent, or with an isocyanate having formula R ¹ NC°, wherein R ¹ is as defined in the Summary of the Invention or is a precursor group thereof, yields an acyl ureido compound having formula 4, which is then cyclized to yield a compound having formula 1, in the presence of a base such as sodium hydride or KHMDS, etc., under conditions well known in the art.

Synthesis from 2-halobenzoic acids

Method (c)

Reaction of benzoic acid having formula 5, wherein X is halogen, preferably chlorine, and the remaining groups are as defined in the Summary of the Invention or are a precursor group thereof, with an amine having formula R ¹ NH ₂ , wherein R ¹ is as defined in the Summary of the Invention or is a precursor group thereof, in the presence of an inorganic base such as potassium carbonate, cesium carbonate, etc., and copper yields a compound having formula 6. Alternatively, the amination reaction can be carried out in the presence of LDA in THF at -78°C. Compounds having formula 5 are commercially available or can be prepared by methods known in the art. Compounds having formula 6 are converted to compounds having formula 1 by reaction with urea under conditions well known in the art.

Alternatively, compounds having formula 6 can be converted into amide compounds having formula 3 by reacting compound 6 with HATU or EDCI/H°Bt and ammonium chloride in the presence of an organic base such as diisopropylethylamine in an organic solvent such as THF, etc. Compound 6 is then converted into compound 1, which can be prepared as shown above in method a or method b.

Synthesis from 2-aminobenzoic acids

Method (d)

The reaction of 2-aminobenzoic acid having the formula 7, wherein the groups R ³ -R ⁶ have the meanings specified in the Summary of the Invention or represent a precursor group thereof, with a halide R ¹ Br, wherein R ¹ has the meaning specified in the Summary of the Invention or represent a precursor group thereof, in the presence of copper acetate and a base such as triethylamine, pyridine, etc., gives compound 6, which can then be converted to the compound having the formula 1 described above.

Synthesis from 2-aminobenzamide

Method (e)

Reaction of 2-aminobenzamide having formula 8, wherein groups R ³ -R ⁶ have the meanings specified in the summary of the invention or represent a precursor group thereof, with a boronic acid having formula R ¹ B(°H) ₂ , wherein R ¹ has the meaning specified in the summary of the invention or represent a precursor group thereof, in the presence of copper(I) chloride and in the presence of a base such as triethylamine, pyridine, etc., gives a compound having formula 3, which can then be converted to a compound having formula 1 described above.

The compounds of formula (I) and (II) and the sub-embodiments described herein can be converted into other compounds of formula (I) and (II), respectively, by methods known in the art. For example, a compound of formula (I) or (II), wherein R ⁵ is a halogen (precursor group), can be converted into the corresponding compound of formula (I) or (II), respectively, wherein R ⁵ is methoxy, by reaction with sodium methoxide in the presence of CuI in DMF. A compound of formula (I) or (II), wherein R ⁵ is a halogen (precursor group), can be converted into the corresponding compound of formula (I) or (II), respectively, wherein R ⁵ is cyano, by reacting it with zinc cyanide in the presence of a Pd catalyst, such as Pd(PH ₃ ) ₄ , in DMF. A compound having formula (I) wherein R ⁵ is halogen (precursor group) can be converted into the corresponding compound having formula (I) wherein R ⁵ is trifluoromethyl by reaction with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of CuI in DMF.

Application

Overexpression of the MAT2A enzyme is known to cause some types of cancer. In one embodiment, the cancer is neuroblastoma, colorectal cancer (such as rectal cancer, colon cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, renal carcinoma, renal parenchymal carcinoma, ovarian cancer, cervical cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumor (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neurodermal tumors), Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, vascular melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

In another embodiment, the cancer is lung cancer, non-small cell lung cancer, bronchioalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous melanoma or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, bowel cancer, breast cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney or urethral cancer, renal cell carcinoma, renal pelvis cancer, mesothelioma, renal cell carcinoma, bile duct cancer, chronic or acute leukemia, lymphocytic lymphoma, central nervous system (CNS) neoplasms, spinal axis tumors, brainstem glioma, glioblastoma multiforme, astrocytoma, schwannoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, eosinophilic adenoma, including difficult-to-treat versions of the above cancers or combinations of one or more of the above cancers.

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 recycled to produce adenosine monophosphate, and 5-methylthioribose-1-phosphate is converted to methionine and formate. Through the recycled pathway, MTA can act as an alternative source of purine when de n°v° purine synthesis is blocked, for example by antimetabolites such as L-alanosine.

MTAP activity is absent in many human and rodent tumor cells. MTAP deficiency is not only found in tissue cultures, but is also observed in primary leukemias, gliomas, melanomas, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcomas, non-Hodgkin lymphoma, and mesotheliomas. K. Marjn et al., Cell Reports 15 (2016) 574–587, the contents of which are incorporated herein by reference, reported that proliferation of cancer cells lacking MTAP activity (MTAP-null) is suppressed by shRNA-mediated knockdown of MAT2A expression. MTAP-null cancer is a cancer in which the MTAP gene is deleted or lost or otherwise inactivated, or a cancer in which the function of the MTAP protein is reduced or impaired.

Accordingly, in one embodiment, the present invention provides a method of treating an MTAP-null cancer in a patient, wherein the cancer is characterized by reduced or absent MTAP expression, or an absent MTAP gene, or reduced MTAP protein function, as 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), (IIA'), or a subvariant described herein, or a pharmaceutically acceptable salt thereof. In another embodiment, a method of treating an MTAP-null cancer in a patient is provided, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) (IA), (IA'), (II), (IIA), (IIA'), or a subvariant described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the MTAP-null 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 lymphoma, or mesothelioma. In another embodiment, the MTAP-null cancer is pancreatic cancer. In 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 another embodiment, the MTAP-null cancer is gastric cancer. In another embodiment, the cancer is colon cancer. In another embodiment, the MTAP-null cancer is liver cancer. In another embodiment, the MTAP-null cancer is glioblastoma multiforme (GBM). In another embodiment, the MTAP-null cancer is bladder cancer. In another embodiment, the MTAP-null cancer is esophageal cancer. In another embodiment, the MTAP-null cancer is breast cancer. In another embodiment, the MTAP-null cancer is non-small cell lung cancer. In another embodiment, the MTAP-null cancer is mononuclear cell lymphoma. In another embodiment, the MTAP-null cancer is DLBCL. In another embodiment, the MTAP-null cancer is ALL.

Genome analysis of MTAP-null cancer cell lines showed that cell lines that also contained a KRAS mutation or a p53 mutation were sensitive to MAT2A inhibition.

Accordingly, the present invention also describes a method of treating a cancer in a patient, wherein the cancer is characterized by a decrease or absence of MTAP expression, or an absence of the MTAP gene, or a decreased function of the MTAP protein (i.e., an MTAP-null cancer), and is further characterized by the presence of a KRAS mutation and/or a p53 mutation, and this method comprises administering to the patient a therapeutically effective amount of a compound having formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant 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 another embodiment, the cancer is MTAP-null and KRAS-mutant and p53-mutant.

The term “KRAS mutation” or “KRAS mutant” refers to a KRAS protein (or the gene encoding the protein) comprising an activating mutation that alters its normal function. For example, a mutant KRAS protein may comprise a single amino acid substitution at position 12 or 13. In a particular embodiment, the mutant KRAS comprises a G12X or G13X substitution, where X is any amino acid substitution at the specified position. In a particular embodiment, the substitution is G12V, G12R, G12C, or G13D. In another embodiment, the substitution is G13D. The term “p53 mutation” or “p53 mutant” refers to a p53 protein (or the gene encoding the protein) comprising a mutation that suppresses or disables its tumor suppressor function. In one embodiment, 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 one embodiment, the cancer is non-small cell lung cancer, pancreatic cancer, head and neck cancer, gastric cancer, colon cancer, or ovarian cancer.

Testing

The ability of the compounds of the present invention to inhibit MAT2A can be tested as described below in Biological Example 1.

Pharmaceutical composition

Compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a pharmaceutically acceptable salt thereof, can be in the form of compositions suitable for administration to a subject. In general, such compositions are pharmaceutical compositions comprising a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable or physiologically acceptable excipients. In some embodiments, a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a pharmaceutically acceptable salt thereof, is present in a therapeutically effective amount. The pharmaceutical compositions can be used in the methods of the present invention; for example, the pharmaceutical compositions can be administered ex vivo or in vivo to a subject to practice the therapeutic methods and uses described herein.

The pharmaceutical compositions can be formulated in formulations compatible with the intended route or mode of administration; examples of routes of administration are provided herein. In addition, the pharmaceutical compositions can be used in combination with other pharmaceutically active agents or compounds as described herein for the treatment of diseases, disorders, and pathological conditions encompassed by the present invention.

Pharmaceutical compositions containing the active substance (e.g., a compound having the formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a pharmaceutically acceptable salt thereof) can be in a form suitable for oral administration, such as tablets, capsules, lozenges, rhomboid tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microgranules or elixirs. Pharmaceutical compositions for oral administration can be prepared according to any methods known in the art of producing pharmaceutical compositions, and such compositions can contain one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and preservatives, to create pharmaceutically advantageous and attractive preparations. Tablets, capsules, etc. contain the active substance in a mixture with non-toxic pharmaceutically acceptable auxiliary substances which are suitable for the production of tablets, capsules etc. Such auxiliary substances may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc.

Tablets, capsules, etc. suitable for oral administration may be uncoated or may be coated by known methods to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged action. For example, a retarding agent such as glyceryl monostearate or glyceryl distearate may be used. Tablets may also be coated by methods known in the art to produce osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or polymeric substances such as polyesters, polyamino acids, hydrogel, 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, to control the delivery of the administered composition. The oral agent can be enclosed in microcapsules obtained by coacervation or interfacial polymerization techniques using hydroxymethylcellulose or gelatin microcapsules or poly(methyl methacrylate) microcapsules, respectively, or can be administered as a colloidal drug delivery system. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the above preparations are known in the art.

Oral preparations may also be in the form of hard gelatin capsules in which the active substance is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin or microcrystalline cellulose, or in the form of soft gelatin capsules in which the active substance is mixed with an aqueous or oily medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active substances in a mixture with auxiliary substances suitable for their manufacture. Such auxiliary substances may be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; dispersing or wetting agents, for example natural phosphatides (e.g. lecithin), or condensation products of alkylene oxide with fatty acids (e.g. polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g. heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (e.g. polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g. polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

Oily suspensions can be prepared by suspending the active substance 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 a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those described above, and flavoring agents may be added to provide a palatable oral preparation.

Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water contain the active substance in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents are given in the present text.

The pharmaceutical compositions may also take the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifiers may be natural gums, such as acacia or tragacanth, natural phosphatides, such as soya lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

Pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, 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, methylparabens, ethyl or n-propyl p-hydroxybenzoate), emulsifiers, suspending agents, dispersing agents, solvents, fillers, bulking agents, surfactants, buffers, carriers, diluents and/or adjuvants. For example, a suitable carrier may be physiological saline or citrate buffered saline, to which other substances customary for pharmaceutical compositions intended for parenteral administration may be added. Neutral buffered saline or saline mixed with serum albumin are also examples of the carrier. A person skilled in the art will recognize a variety of buffer solutions that can be used in the pharmaceutical compositions and dosage forms encompassed by the present invention. Typical buffer solutions 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 compounds such as phosphoric acid, tartaric acids, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts. Suitable 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 (MPS) and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

After the preparation of the pharmaceutical composition, it can be stored in sterile vials in the form of a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such preparations can be stored in the form of a ready-to-use form, a lyophilized form requiring dilution before use, a liquid form requiring dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is contained in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector (similar to, for example, an EpiPen®)), and in other embodiments, a multiple-use container is described (e.g., a multiple-use vial).

The preparations may also contain carriers to protect the composition from rapid degradation or elimination from the body, such as sustained release preparations, including liposomes, hydrogels, prodrugs and microencapsulated delivery systems. For example, retarding agents such as glyceryl monostearate or glyceryl stearate, alone or in combination with a wax, may be used. Any drug delivery device may be used to administer a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, including implants (e.g., implantable pumps) and catheter systems, pumps and devices for slow administration, all of which are well known to those skilled in the art.

Delayed absorption injections, which are usually administered subcutaneously or intramuscularly, can also be used to release a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, over a period of time. Delayed absorption injections are usually on a solid or oil base, and usually contain at least one of the components for preparing the preparations described in this text. A person skilled in the art is familiar with the possible types of preparations and the use of delayed absorption injections.

The pharmaceutical compositions can be in the form of sterile injectable aqueous or oleaginous suspensions. Such a suspension can be prepared according to the methods of the prior art using the suitable dispersing or wetting agents and suspending agents enumerated herein. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Suitable diluents, solvents and dispersion media that can be employed include water, Ringer's solution, isotonic sodium chloride solution, Cremiphr EL™ (BASF, Parsippany, NJ) or sodium phosphate buffered saline (PBS), ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile fixed oils are widely employed as a solvent or suspending medium. Any grade of fixed oil may be employed for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid have found use in injectables. Prolonged absorption of certain injectables can be brought about by the inclusion of an agent which delays absorption (e.g., aluminum monostearate or gelatin).

A compound having the formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, may be administered in the form of suppositories for rectal administration or in the form of sprays for nasal administration or inhalation. Suppositories may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and therefore melts in the anus to release the drug. Such substances include, but are not limited to, cocoa butter and polyethylene glycols.

Routes of administration

The compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, as well as compositions containing them, can be administered by any suitable route. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intra-articular, intraperitoneal, intracerebral (intraparenchymatous), and intracerebroventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Delayed absorption injections, which are usually administered subcutaneously or intramuscularly, can also be used to administer compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, over a period of time. Particular embodiments of the present invention include oral administration.

Combination therapy

The present invention encompasses the use of compounds having the formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or with other prophylactic or therapeutic means (e.g., radiation). In such combination therapy, the different active substances often have different mechanisms of action. Such combination therapy may be particularly advantageous in that it allows a reduction in the dosage of one or more of the agents, thereby reducing or eliminating the side effects associated with these one or more agents. In addition, such combination therapy may have a synergistic therapeutic or prophylactic effect on a disease, disorder, or pathological condition.

As used in this text, the term “combination” includes therapies that can be administered separately, such as in different dosage forms and taken separately (e.g., in a kit), and therapeutic agents that can be administered simultaneously as part of a single preparation (i.e., incorporation of agents into a single preparation).

In some embodiments, compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, are administered or used sequentially, such as when one agent is administered before one or more other agents are administered. In other embodiments, compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, are administered simultaneously, such as when two or more agents are administered at the same or about the same time; the two or more agents may be included in two or more formulations, or may be combined in a single formulation. Regardless of whether two or more agents are administered sequentially or simultaneously, they are considered to be administered in combination in the context of the present invention.

The compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, can be used in combination with at least one other (active) substance in any manner suitable under the selected conditions. In one embodiment, the treatment with at least one active substance and at least one compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, is carried out for a period of time. In another embodiment, the administration of at least one active substance is reduced or stopped (e.g., when the patient's condition is stable), while the administration of the compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof is continued with a constant administration regimen. In another embodiment, the administration of at least one active substance is reduced or discontinued (e.g., when the patient is stable) while the administration of the compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, is reduced (e.g., lower dosage, less frequent administration, or a shorter treatment period). In another embodiment, the administration of at least one active substance is reduced or discontinued (e.g., when the patient is stable) while the administration of the compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, is increased (e.g., higher dosage, more frequent administration, or a longer treatment period). In another embodiment, the administration of at least one active substance is maintained and the administration of a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, is reduced or discontinued (e.g., a lower dosage, less frequent administration, or a shorter treatment period). In another embodiment, the administration of at least one active substance and the administration of a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, are reduced or discontinued (e.g., a lower dosage, less frequent administration, or a shorter treatment period).

The present invention describes methods of treating cancer using a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, and at least one additional therapeutic or diagnostic agent.

In some embodiments, a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, is administered in combination with at least one additional therapeutic agent selected from temozolomide, pemetrexed, pegylated liposomal doxorubicin (Doxil), eribulin (Halaven), ixabepilone (Ixempra), protein-bound paclitaxel (Abraxane), oxaliplatin, irinotecan, venatoclax (a bcl2 inhibitor), 5-azacitadine, anti-CD20 therapeutic agents such as rituxan and obinutuzumab, hormonal agents (anastrozole, exemestand, letrozole, zoladex, lupron, eligard), CDK4/6 inhibitors, palbociclib, abemaciclib, cysteine proteinases (avelumab, cemiplimab-rwlc and bevacizumab).

In some embodiments, the present invention provides methods of treating cancer comprising administering a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, in combination with a signal transduction inhibitor (STI) to achieve additive or synergistic tumor growth inhibition. As used herein, the term "signal transduction inhibitor" means an agent that selectively inhibits one or more steps in signal transduction. Examples of signal transduction inhibitors (STIs) that may be used in the methods of the present invention 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) inhibitors of cell cycle kinases (e.g., flavopiridol); and (vi) inhibitors of phosphatidyl inositol kinase. Agents involved in immunomodulation can also be used in combination with one or more compounds having the formula (I), (IA), (IA'), (II), (IIA), (IIA'), or their subvariants, or salts thereof, to suppress tumor growth in patients suffering from cancer.

In some embodiments, the present invention features methods of treating cancer comprising administering a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, in combination with chemotherapeutic agents. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines including altretamine, thiethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorphosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterine, prednimustine, trofosfamide, uramustine; nitrosoureas such as carmustine, chlorzotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycins, actinomycins, autramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, saminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; Anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); Folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; Purine analogues such as fludarabine, 6-mercaptopurine, triampirine, thioguanine; Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; Androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; Adrenal suppressants such as aminoglutethimide, mitotane, trilostane; Folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elformitin; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamole; nitracrine; pentostatin; fenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosin; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids such as paclitaxel and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum-palladium 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; esperamicins; capecitabine and pharmaceutically acceptable salts, acids or bases of any of the above. In a particular embodiment, the compounds of the present invention are co-administered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C. In a particular embodiment, the cytostatic compound is doxorubicin.

Chemotherapeutic agents also include antihormonal agents that regulate or suppress the action of hormones on tumors, such as antiestrogens, including, for example, tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and antiandrogen agents, such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, levprolide, and goserelin; and pharmaceutically acceptable salts, acids, or bases of any of the foregoing. In some embodiments, combination therapy includes administration of a hormone or related hormonal agent.

The present invention also encompasses the use of compounds having the formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, in combination with immune checkpoint inhibitors. The vast number of genetic and epigenetic alterations characteristic of all cancers provide a diverse array of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the maximum strength (e.g., level of cytokine production or proliferation) and quality (e.g., type of immune response generated, such as pattern of cytokine production) of the response initiated through T cell receptor antigen recognition is regulated by the balance between costimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are critical for preventing autoimmunity (i.e., maintaining self-tolerance) and for protecting tissues from damage when the immune system responds to a pathogenic infection. The expression of immune checkpoint proteins can be dysregulated by tumors as an important mechanism of immunoresistance. Examples of immune checkpoint inhibitors include, but are not limited to, CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, X40, 41BB, VISTA, CD96, TGFβ, CD73, CD39, A2AR, A2BR, ID1, TD2, arginase, B7-H3, B7-H4. Cellular modulators of anti-cancer immunity are also encompassed by the present invention. Examples of such modulators include (but are not limited to) chimeric antigen receptor T cells, tumor infiltrating T cells, and dendritic cells.

The present invention encompasses the use of compounds having the formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subvariants thereof, or salts thereof, in combination with inhibitors of the above immune checkpoints and ligands, such as ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab and durvalumab.

Additional treatments that can be used in combination with a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subvariants thereof, or salts thereof, include radiation therapy, monoclonal antibodies against tumor antigens, a complex of a monoclonal antibody and a toxin, a T-cell adjuvant, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy).

The present invention encompasses the use of compounds having the formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subvariants thereof, or salts thereof, for the treatment of glioblastoma, either alone or in combination with radiation therapy and/or temozolomide (TMZ), avastin or lomustine.

The present invention encompasses pharmaceutically acceptable salts, acids or derivatives of any of the above compounds.

Dosage

The compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, can be administered to a patient in an amount that depends on, for example, the purpose of administration (e.g., the desired degree of partitioning); age; body weight; sex and the health and physical condition of the patient to whom a particular preparation is administered; the route of administration; and the nature of the disease, disorder, pathological condition, or symptom thereof. The administration regimen may also take into account the presence, nature, and severity of any adverse effects associated with the agent(s) administered. Effective dosages and administration regimens can be readily determined, for example, from the results of safety and dose-response studies; in vivo tests (e.g., in animal models), and other methods known in the art.

In general, dosing parameters require that the dosage be below the amount that may cause irreversible toxicity to the patient (maximum tolerated dose (MTD)) and not below the amount needed to achieve a measurable effect in the patient. Such amounts are determined, for example, by pharmacokinetic and pharmacodynamic parameters related to ADME, taking into account the route of administration and other factors.

An effective dosage (ED) is the dose or amount of a drug that produces a therapeutic response or desired effect at a specified site in the body of a patient receiving the drug. The "median effective dose" or ED50 for a drug is the dose or amount of a drug that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although the ED50 is widely accepted as a measure of the reasonable expectation of an effect in a patient, it is not necessarily the dose that a physician would consider appropriate, taking into account all factors involved. Thus, in some situations, the effective amount is greater than the calculated ED50 value, in other situations the effective amount is less than the calculated ED50 value, and in other situations the effective amount is the same as the calculated ED50 value.

In addition, an effective dosage of a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, may be an amount that, when administered as one or more dosages to a patient, provides a desired result, relative to a healthy subject. For example, for a subject with a certain disorder, an effective dosage may be a dosage that improves a diagnostic parameter, measure, marker, etc. of the disease 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 the value of the diagnostic parameter, measure, marker, etc., characteristic of a healthy patient.

In some embodiments, compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, can be administered (e.g., orally) at a dosage of from about 0.01 mg/kg to about 50 mg/kg, or from about 1 mg/kg to about 25 mg/kg of the patient's body weight per day, one or more times per day, to achieve the desired therapeutic effect.

For oral administration, the compositions can be produced in the form of tablets, capsules, etc., containing from 1.0 to 1000 milligrams of the active substance, in particular 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 milligrams of the active substance.

In some embodiments, a dose of a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, is contained in a "unit dosage form." The term "unit dosage form" refers to physically discrete units, each of which contains a predetermined quantity of a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, alone or in combination with one or more additional agents, sufficient to provide the desired effect. It should be understood that the parameters of the unit dosage form depend on the particular agent and the effect to be achieved.

Sets

The present invention also encompasses kits containing a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, and pharmaceutical compositions thereof. The kits typically take the form of a physical structure in which the various components are located, as described below, and can be used, for example, in practicing the methods described above.

The kit may comprise one or more compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or subvariants thereof, or salts thereof, (e.g., in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a patient. A compound of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, may be available in a form that is ready for use (e.g., a tablet or capsule), or in a form that requires, for example, dissolution or dilution (e.g., a powder) before administration. When the compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof, are in a form that requires dissolution or dilution by the user, the kit may also further include diluents (e.g., sterile water), buffer additives, pharmaceutically acceptable excipients, and the like, packaged together with or separately from the compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a subvariant thereof, or a salt thereof. When a combination therapy is used, the kit may contain several agents separately, or they may already be combined into a kit. Each component of the kit may be enclosed in an individual container, and all the various containers may be contained within a common package. The kit of the present invention may be designed for conditions necessary for proper storage of the components included in it (e.g., in a refrigerator or freezer).

The kit may contain a label or insert containing identifying information about the components included therein and instructions for use (e.g., dosing parameters, clinical pharmacology of the active substance(s), including the mechanism of action, pharmacokinetics and pharmacodynamics, side effects, contraindications, etc.). Labels or inserts may contain manufacturer's information, such as a batch number and expiration date. Labels or inserts may, for example, be integrated into the physical structure containing the components, may be contained separately within said physical structure, or may be fixed to the components of the kit (e.g., to an ampoule, tube, or vial).

The labels or inserts may further comprise, or themselves be included in, a computer-readable storage medium such as a disk (e.g., a hard disk, memory card, or disc), an optical disk such as a CD or DVD-RM/RAM, DVD, MP3, magnetic tape, or an electronic storage device such as RAM and RM, or a hybrid of these such as a magnetic/optical storage medium, flash card, or memory card. In some embodiments, the instructions are not present in the kit, but means are provided for receiving the instructions, e.g., from a remote source, e.g., via the Internet.

Examples

The examples and references (intermediates) described below are provided to give a skilled person a complete disclosure and description of how to implement and use the present invention, and are not intended to limit the scope of the invention, nor do they indicate that all of the experiments described below have been performed or that these are all of the experiments that can be performed. It should be understood that the illustrative descriptions provided have not necessarily been performed, but rather mean that such procedures can be performed to obtain the information specified in the text, etc. The authors have made efforts to ensure accuracy in the numbers given (e.g., amounts, temperatures, etc.), but inevitable experimental errors and deviations should be taken into account.

Unless otherwise stated, parts are parts by weight, molecular weights are weight average molecular weight, temperatures are in degrees Celsius (°C), and pressures are at or near atmospheric. Standard abbreviations include the following: µg = microgram; µL = microliter; mM = millimolar; µM = micromolar; aa = amino acid(s); Ac ₂ O = acetic anhydride; AcCl = acetyl chloride; ACN = acetonitrile; AIBN = 2,2'-azobis(2-methylpropionitrile); BID = twice daily; BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc ₂ O or (Boc) ₂ O = di-tert-butyl dicarbonate; bp = base pair; BSA = bovine serum albumin; BW = body weight; d = doublet; dd = doublet of doublets; DEAD = diethyl azodicarboxylate; DIBAL = diisobutylaluminum hydride; DIEA = N,N-diisopropylethylamine; DIPEA = N,N-diisopropylethylamine; dl = deciliter; DMA = dimethylacetamide; 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 = gram; h or hr = hour(s); HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HEPES = 4-(2-hydroxyethyl)-1-piperazine ethyl sulfonic acid; HOAc = acetic acid; HPLC = high performance liquid chromatography; im = intramuscular; ip = intraperitoneal; IHC = immunohistochemistry; IPS = isopropyl alcohol; kb = thousand bases; kDa = kilodalton; kg = kilogram; L = liter; LC = liquid chromatography; LCMS = liquid chromatography-mass spectrometry; m/z = mass/charge ratio; M = molarity; m = multiplet; MeCN = acetonitrile; MeOH = methanol; _MeSO2Cl = methanesulfonyl chloride; mg = milligram; min = minute(s); ml = milliliter; mM = millimolarity; MS = mass spectrometry; MsCl = methanesulfonyl chloride; n. = normality; NADPH = nicotinamide adenine dinucleotide phosphate; NBS = N-bromosuccinamide; ng = nanogram; nm = nanometer; nM = nanomolarity; NMP = N-methylpyrrolidone; NMR = nuclear magnetic resonance; ns = not statistically significant; nt = nucleotide(s); PBS = phosphate-buffered saline; Pd/C = palladium on charcoal; _Pd2 (dba) ₃ = Tris(dibenzylideneacetone) dipalladium; Pd(dppf) _Cl2 = 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride; PE = petroleum ether; QD = once daily; QM = once monthly; QW = once weekly; rac = racemic; Rt = retention time; s = singlet; s or sec = second(s); sat = saturated; SC or SQ = subcutaneous; 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.

Examples of synthesis

Comparative example 1

Synthesis of 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one

Step 1. Synthesis of 4-chloro-2-(phenylamino)benzoic acid

To a stirred solution of 2,4-dichlorobenzoic acid (1 equiv.) in DMF (0.5 M) were 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 mixture was brought to room temperature and filtered through a pad of celite. The resulting filtrate was acidified with 2 N HCl. The resulting precipitate was filtered and dried in vacuo to give 4-chloro-2-(phenylamino)benzoic acid as a brown solid.

Step 2. Synthesis of 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one

A mixture of 4-chloro-2-(phenylamino)benzoic acid (1 equiv.) and urea (5 equiv.) was placed in a round-bottomed flask equipped with a magnetic stirrer and heated at 200°C for 2 h. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (20-30% EtOAc/Hexane) to give the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 11.82 (s, 1H), 8.04 (d, J = 8.3 Hz, 1H), 7.66-7.56 (m, 3H), 7.48-7.44 (m, 2H), 7.31 (dd, J = 8.3, 1.9 Hz, 1H), 6.31 (d, J = 1.8 Hz, 1H). m/z [M+H] ⁺ 273.18.

Comparative example 2

Synthesis of 7-chloro-1-(pyridin-3-yl)quinazolin-2,4(1H,3H)-dione

Step 1. Synthesis of 4-chloro-2-(pyridin-3-ylamino)benzamide

To a stirred solution of 2,4-dichlorobenzamide (1 equiv.) in DMF (0.5 M) were added 3-aminopyridine (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 mixture was warmed to room temperature and filtered through a pad of celite. The resulting filtrate was acidified with 2 N HCl. The resulting precipitate was filtered and dried in vacuo to give the title compound as a brown solid. m/z [M+H] ⁺ 249.1.

Step 2. Synthesis of 7-chloro-1-(pyridin-3-yl)quinazolin-2,4(1H,3H)-dione

A vial was charged with 4-chloro-2-(pyridin-3-ylamino)benzamide (1.0 equiv) and DMF (0.2 M). 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 min. CDI (1.5 equiv) was added to the reaction vessel and the reaction mixture was stirred at room temperature for 20 min. The reaction was quenched by adding MeOH (0.5 mL) and AcOH (0.2 mL). The crude reaction mixture was directly purified by reversed-phase liquid chromatography (20-75% MeCN/water, 0.1% formic acid). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.82 (s, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.61 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.68-7.50 (m, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.32 (s, 1H). m/z [M+H] ⁺ 274.0.

Using a procedure similar to that described in Comparative Example 2, Step 1, 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinamide was prepared using 2-chloroaniline and 2-chloro-6-cyclopropylnicotinamide instead of 3-aminopyridine and 2,4-dichlorobenzamide, respectively.

m/z [M+H] ⁺ 288.0.

Using a procedure similar to that described above for stage 2, the following compounds were obtained:

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

m/z [M+H] ⁺ 274.0.

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

m/z [M+H] ⁺ 314.0.

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.

m/z [M+H] ⁺ 387.9, 385.9.

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.

m/z [M+H] ⁺ 326.0.

3-(7-Chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile was prepared using 4-chloro-2-((3-cyanophenyl)amino)benzamide. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.92 (s, 1H), 8.13-8.00 (m, 3H), 7.85 (dd, J = 8.3, 1.7 Hz, 2H), 7.34 (dt, J = 8.5, 1.7 Hz, 1H), 6.43 (d, J = 1.7 Hz, 1H).

m/z [M+H] ⁺ 298.0.

Comparative example 3

Synthesis of 7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

Step 1. Synthesis of 4-chloro-2-fluoro-6-(phenylamino)benzoic acid

To a stirred solution of aniline (2 equiv.) in THF (1 M) was added LDA (3 equiv.) at -78 °C and the reaction mixture was stirred for 10 min. 4-Chloro-2,6-difluorobenzoic acid (1 equiv.) in THF (1 M) was added at -78 °C and the reaction mixture was stirred for 48 h at room temperature. After completion of the reaction, the mixture was poured into 1 N HCl solution and extracted with ethyl acetate. The combined organic layers were separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired 4-chloro-2-fluoro-6-(phenylamino)benzoic acid as a pale yellow solid.

Step 2. Synthesis of 4-chloro-2-fluoro-6-(phenylamino)benzamide

To a stirred solution of 4-chloro-2-fluoro-6-(phenylamino)benzoic acid (1 equiv.) in DMF (0.4 M) was added HATU (1.5 equiv.), DIPEA (5 equiv.) at room temperature and stirred for 30 min. Ammonium chloride (5 equiv.) was added to the reaction mixture and stirring was continued for 16 h at room temperature. After completion of the reaction, the mixture was poured into ice water and stirred for 30 min, the solid precipitate was filtered and dried in vacuo to give 4-chloro-2-fluoro-6-(phenylamino)benzamide as an off-white solid.

Step 3. Synthesis of 7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

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

Using a procedure similar to that described above in Comparative Example 3, Step 2, the following compounds were prepared:

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

m/z [M+H] ⁺ 255.12.

2,6-dichloro-4-(trifluoromethyl)benzamide was prepared using 2,6-dichloro-4-(trifluoromethyl)benzoic acid.

m/z [M+H] ⁺ 258.15.

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

m/z [M+H] ⁺ 286.1.

Comparative example 4

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

Step 1. Synthesis of 4-chloro-2-((3-(methoxymethyl)phenyl)amino)benzamide

2-Amino-4-chlorobenzamide (1.0 equiv), copper chloride (0.15 equiv), 3-(methoxymethyl)phenylboronic acid (1.5 equiv), and triethylamine (0.5 equiv) were placed in a vial under air. MeOH (0.4 M) was added to the reaction vessel and the 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 give the title compound. m/z [M+H] ⁺ 291.1.

Step 2. Synthesis of 7-chloro-1-[3-(methoxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione

4-Chloro-2-((3-(methoxymethyl)phenyl)amino)benzamide (1.0 equiv) and DMF (0.2 M) were placed in a vial under nitrogen atmosphere. NaH (60% in mineral oil, 3.0 equiv) was added to the reaction mixture at 0 °C and the mixture was stirred at room temperature for 10 min. CDI (1.5 equiv) was added and the mixture was stirred at room temperature for 20 min. The reaction was quenched by adding MeOH and AcOH. The crude reaction mixture was directly purified by reversed-phase liquid chromatography (20-75% MeCN/water, 0.1% formic acid) to give the title compound. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.80 (s, 1H), 8.03 (dd, J = 8.4, 1.3 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.41-7.34 (m, 2H), 7.30 (dt, J = 8.4, 1.7 Hz, 1H), 6.30 (t, J = 1.6 Hz, 1H), 4.50 (s, 2H) m/z [M+H] ⁺ 317.1.

The following compounds were obtained using the method described above:

7-Chloro-1-(3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-hydroxyphenylboronic acid with 3-(methoxymethyl)phenylboronic acid

m/z [M+H] ⁺ 289.0

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

m/z [M+H] ⁺ 317.1

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

m/z [M+H] ⁺ 291.1

7-Chloro-1-(3-methylphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing m-tolylboronic acid with 3-(methoxymethyl)phenylboronic acid

m/z [M+H] ⁺ 287.0

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

m/z [M+H] ⁺ 331.1

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

m/z [M+H] ⁺ 307.0

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

m/z [M+H] ⁺ 303.0

3-(7-Chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile was prepared by replacing (3-cyanophenyl)boronic acid with 3-(methoxymethyl)phenylboronic acid

m/z [M+H] ⁺ 298.0

tert-butyl (3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzyl)carbamate was prepared by replacing 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid with 3-(methoxymethyl)phenylboronic acid

m/z [M+Na] ⁺ 424.0

7-Chloro-1-(3-methoxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing (3-methoxyphenyl)boronic acid with 3-(methoxymethyl)phenylboronic acid

m/z [M+H] ⁺ 303.0

7-Chloro-1-(5-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-fluoro-5-hydroxyphenylboronic acid with 3-(methoxymethyl)phenylboronic acid

m/z [M+H] ⁺ 307.0

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

m/z [M+H] ⁺ 291.0

7-Chloro-1-(2-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 2-fluoro-3-hydroxyphenylboronic acid with 3-(methoxymethyl)phenylboronic acid

m/z [M+H] ⁺ 307.0

7-Chloro-1-(4-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 4-fluoro-3-hydroxyphenylboronic acid with 3-(methoxymethyl)phenylboronic acid

m/z [M+H] ⁺ 307.0

Comparative example 5

Synthesis of 1-[3-(aminomethyl)phenyl]-7-chloro-1,3-dihydroquinazoline-2,4-dione

Tert-butyl (3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzyl)carbamate (1.0 equiv) and MeCN (0.2 M) were placed in a vial under nitrogen atmosphere, 4N HCl in 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 chromatography (10-45% MeCN/water, 0.1% formic acid) to give the title compound. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.30 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 7.3 Hz, 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.

Comparative example 6

Synthesis of 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

Step 1. Synthesis of 2,4-dichloro-N-(o-tolylcarbamoyl)benzamide

To a suspension of 2,4-dichlorobenzamide (1 equiv.) in DCE (0.5 M) was added oxalyl chloride (1.35 equiv.) dropwise at room temperature. The reaction mixture was then heated at 55 °C for 1 h and then refluxed for 20 h. The reaction mixture was evaporated in vacuo to give the crude product as a yellow oil. A solution of the resulting crude isocyanate in DCE (1.2 M) at 0 °C was added dropwise to a cooled solution of o-toluidine in DCE (0.4 M). The ice bath was removed and the reaction mixture was stirred at room temperature for 45 min. The solid precipitate was filtered, washed with dichloromethane and dried to give the title compound as a white solid. m/z [M+H] ⁺ 324.0.

Step 2. Synthesis of 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

A suspension of 2,4-dichloro-N-(o-tolylcarbamoyl)benzamide in DME:toluene (0.06 M, 1:1 v/v) was cooled to 0°C and NaH (60% dispersion in oil, 3.1 equiv) was added portionwise. After complete addition, the ice bath was removed and the mixture was refluxed for 18 h. The reaction mixture was cooled to room temperature and poured into 20% aqueous HCl. The resulting mixture was stirred vigorously, the off-white precipitate was filtered, washed with ether and dried to give the crude product, which was used in the next step without further purification. m/z [M+H] ⁺ 287.0.

Using a procedure similar to that described above for stage 1, the following compounds were obtained:

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

m/z [M+H] ⁺ 363.0.

5-Cyano-4-cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide was prepared using 5-cyano-4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide.

m/z [M+Na] ⁺ 360.0.

N-((2-Chlorophenyl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide was prepared by replacing 2-chloroaniline with o-toluidine and using 4-(1,1-difluoroethyl)-2-fluorobenzamide instead of 2,4-dichlorobenzamide (Pharmablock, PBU1050).

m/z [M+H] ⁺ 357.1.

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

m/z [M+H] ⁺ 333.0

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

m/z [M+H] ⁺ 333.0.

N-((2-Chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was synthesized using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-chloroaniline instead of o-toluidine.

m/z [M+H] ⁺ 333.00

2,4-Dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide was prepared by using 2,4-dichlorobenzamide instead of 2,4-dichlorobenzamide and pyrimidin-2-amine.

m/z [M+H] ⁺ 311.0.

4-Cyclopropyl-2-fluoro-N-((3-methylpyrazin-2-yl)carbamoyl)benzamide was synthesized using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 3-methylpyrazin-2-amine instead of o-toluidine.

m/z [M+H] ⁺ 315.20

4-Cyclopropyl-2-fluoro-N-(pyrazin-2-ylcarbamoyl)benzamide was synthesized using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and pyrazin-2-amine instead of o-toluidine.

m/z [M+H] ⁺ 301.00.

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

m/z [M+H] ⁺ 339.00

N-((3-chloropyridin-2-yl)carbamoyl)-4-ethyl-2-fluorobenzamide was prepared using 3-chloropyridin-2-amine instead of o-toluidine and 4-ethyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide.

m/z [M+H] ⁺ 322.0.

N-((3-chloropyridin-2-yl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide was prepared using 3-chloropyridin-2-amine instead of o-toluidine and 4-(1,1-difluoroethyl)-2-fluorobenzamide instead of 2,4-dichlorobenzamide.

m/z [M+H] ⁺ 358.0.

4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide was prepared using imidazo[1,2-a]pyridin-7-amine instead of o-toluidine and 4-(1,1-difluoroethyl)-2-fluorobenzamide instead of 2,4-dichlorobenzamide.

m/z [M+H] ⁺ 363.0.

2-Fluoro-N-(pyrazin-2-ylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2-fluoro-4-(trifluoromethyl)benzamide instead of 2,4-dichlorobenzamide and pyrazin-2-amine instead of o-toluidine.

m/z [M+H] ⁺ 329.05

2-Fluoro-N-(pyridazin-3-ylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2-fluoro-4-(trifluoromethyl)benzamide instead of 2,4-dichlorobenzamide and pyridazin-3-amine instead of o-toluidine.

m/z [M+H] ⁺ 329.05

2-Fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared using 2-fluoro-4-(trifluoromethoxy)benzamide instead of 2,4-dichlorobenzamide and imidazo[1,2-a]pyridin-5-amine instead of o-toluidine.

m/z [M+H] ⁺ 383.0

2-Chloro-4-cyclopropyl-N-((3-(trifluoromethyl)pyrazin-2-yl)carbamoyl)benzamide was prepared using 2-chloro-4-cyclopropylbenzamide instead of 2,4-dichlorobenzamide and 3-(trifluoromethyl)pyrazin-2-amine instead of o-toluidine.

5-Bromo-2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared using 5-bromo-2-fluoro-4-(trifluoromethoxy)benzamide instead of 2,4-dichlorobenzamide.

m/z [M+Na] ⁺ 456.0, 454.0

5-Bromo-2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared using 5-bromo-2-fluoro-4-(trifluoromethoxy)benzamide instead of 2,4-dichlorobenzamide and aniline instead of o-toluidine.

4-Bromo-N-((2-chlorophenyl)carbamoyl)-2,5-difluorobenzamide was prepared using 4-bromo-2,5-difluorobenzamide instead of 2,4-dichlorobenzamide and 2-chloroaniline instead of o-toluidine.

2,6-difluoro-4-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide was prepared using 2,6-difluoro-4-(trifluoromethyl)benzamide instead of 2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine instead of o-toluidine.

4-Cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide was prepared using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and imidazo[1,2-a]pyridin-7-amine instead of o-toluidine.

2-Chloro-N-((2-chloropyridin-3-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide instead of 2,4-dichlorobenzamide and 2-chloropyridin-3-amine instead of o-toluidine

m/z [M+H] ⁺ 379.3.

2-Chloro-6-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide instead of 2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine instead of o-toluidine.

m/z [M+H] ⁺ 413.11.

5-Bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)phenyl)carbamoyl)benzamide was prepared using 5-bromo-4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-(trifluoromethyl)aniline instead of o-toluidine.

m/z [M+H] ⁺ 447.2.

5-Bromo-4-cyclopropyl-N-((2-cyclopropylphenyl)carbamoyl)-2-fluorobenzamide was prepared using 5-bromo-4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-cyclopropylaniline instead of o-toluidine.

m/z [M+H] ⁺ 417.36.

5-Bromo-N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared using 5-bromo-4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-bromoaniline instead of o-toluidine.

5-Bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide was prepared using 5-bromo-4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine instead of o-toluidine.

m/z [M+H] ⁺ 446.3.

5-Bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared using 5-bromo-2-fluoro-4-(trifluoromethyl)benzamide instead of 2,4-dichlorobenzamide and 2-chloroaniline instead of o-toluidine.

5-Bromo-N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared using 5-bromo-4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-chloropyridin-3-amine instead of o-toluidine.

m/z [M+H] ⁺ 412.3.

N-((2-Chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide was prepared using 4-cyclopropyl-2-fluoro-6-methoxybenzamide instead of 2,4-dichlorobenzamide and 2-chloropyridin-3-amine instead of o-toluidine.

m/z [M+H] ⁺ 364.30.

N-((2-Chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-chloropyridin-3-amine instead of o-toluidine.

m/z [M+H] ⁺ 334.2.

2-Fluoro-4-(trifluoromethyl)-N-((1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)carbamoyl)benzamide was prepared using 2-fluoro-4-(trifluoromethyl)benzamide instead of 2,4-dichlorobenzamide and 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-amine instead of o-toluidine.

m/z [M+H] ⁺ 475.54.

2-Fluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2-fluoro-4-(trifluoromethyl)benzamide instead of 2,4-dichlorobenzamide and aniline instead of o-toluidine.

m/z [M+H] ⁺ 327.24.

N-((3-Chloropyridin-2-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 3-chloropyridin-2-amine instead of o-toluidine.

m/z [M+H] ⁺ 334.2.

4-Cyclopropyl-2-fluoro-N-(pyrimidin-5-ylcarbamoyl)benzamide was prepared using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and pyrimidin-5-amine instead of o-toluidine.

4-Cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide was prepared using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide.

m/z [M+H] ⁺ 313.29.

2-Fluoro-4-(trifluoromethyl)-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide was prepared using 2-fluoro-4-(trifluoromethyl)benzamide instead of 2,4-dichlorobenzamide and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine instead of o-toluidine.

m/z [M+H] ⁺ 461.4.

4-Cyclopropyl-2-fluoro-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide was prepared using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine instead of o-toluidine.

m/z [M+H] ⁺ 433.4.

N-((2-Bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-bromoaniline instead of o-toluidine.

m/z [M+H] ⁺ 377.23.

4-Cyclopropyl-2-fluoro-6-methoxy-N-(pyridin-3-ylcarbamoyl)benzamide was prepared using 4-cyclopropyl-2-fluoro-6-methoxybenzamide instead of 2,4-dichlorobenzamide and pyridin-3-amine instead of o-toluidine.

m/z [M+H] ⁺ 330.36.

4-Cyclopropyl-2-fluoro-6-methoxy-N-(o-tolylcarbamoyl)benzamide was prepared using 4-cyclopropyl-2-fluoro-6-methoxybenzamide instead of 2,4-dichlorobenzamide.

m/z [M+H] ⁺ 343.34.

4-chloro-N-((2-chlorophenyl)carbamoyl)-2,6-difluorobenzamide was prepared using 4-chloro-2,6-difluorobenzamide instead of 2,4-dichlorobenzamide and 2-chloroaniline instead of o-toluidine.

m/z [M+H] ⁺ 345.2.

4-Chloro-2,6-difluoro-N-(o-tolylcarbamoyl)benzamide was prepared using 4-chloro-2,6-difluorobenzamide instead of 2,4-dichlorobenzamide.

m/z [M+H] ⁺ 325.22.

N-(Benzylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide instead of 2,4-dichlorobenzamide and benzylamine instead of o-toluidine.

m/z [M+H] ⁺ 358.0.

4-Cyclopropyl-2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide was prepared using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-methylpyridin-3-amine instead of o-toluidine.

m/z [M+H] ⁺ 314.2.

2-Chloro-N-((2-chloro-6-fluorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide instead of 2,4-dichlorobenzamide and 2-chloro-6-fluoroaniline instead of o-toluidine.

Using a procedure similar to that described above for stage 2, the following compounds were obtained:

7-Chloro-1-(2-fluorophenyl)quinazoline-2,4(1H,3H)-dione was prepared using 2-fluoroaniline instead of -toluidine.

m/z [M+H] ⁺ 291.0

1-(3-Bromophenyl)-7-chloroquinazoline-2,4(1H,3H)-dione was prepared using 3-bromoaniline instead of o-toluidine.

m/z [M+H] ⁺ 351.0

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.

m/z [M+H] ⁺ 343.0.

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.

m/z [M+H] ⁺ 318.0.

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.

m/z [M+H] ⁺ 313.0.

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.

m/z [M+H] ⁺ 313.0.

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

m/z [M+H] ⁺ 313.00.

Comparative example 7

Synthesis of 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

Step 1. Synthesis of 4-cyclopropyl-2-fluorobenzamide

To a vial were placed 4-bromo-2-fluorobenzamide (1 equiv.), cyclopropylboronic acid (3 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.1 equiv.). A 1:1 mixture of toluene: tert-butanol (0.1 M) was added, followed by aqueous potassium carbonate solution (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 evaporated under reduced pressure. The residue was purified by flash column chromatography (0-100% ethyl acetate/hexane) to give the title compound.

Step 2. Synthesis of 5-bromo-4-cyclopropyl-2-fluorobenzamide

4-Cyclopropyl-2-fluorobenzamide (1 equiv.) and N-bromosuccinimide (1.2 equiv.) were placed in a vial. 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 isolated by filtration.

Step 3. Synthesis of 5-bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide

To a suspension of 5-bromo-4-cyclopropyl-2-fluorobenzamide (1 equiv.) in DCE (0.5 M) was added oxalyl chloride (1.35 equiv.) dropwise at room temperature. The reaction mixture was then heated at 55 °C for 1 h and then refluxed for 20 h. The reaction mixture was evaporated in vacuo to give the crude product as a yellow oil. A solution of the resulting crude isocyanate in DCE (1.2 M) at 0 °C was added dropwise to a cooled solution of 2-chloroaniline in DCE (0.4 M). The ice bath was removed and the reaction mixture was stirred at room temperature for 45 min. The solid precipitate was filtered, washed with dichloromethane and dried to give the title compound as a white solid.

Step 4. Synthesis of 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

A suspension 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 NaH (60% dispersion in oil, 3.1 equiv) was added portionwise. After complete addition, the ice bath was removed and the mixture was refluxed for 18 h. The reaction mixture was cooled to room temperature and poured into 20% aqueous HCl. The resulting mixture was stirred vigorously and the off-white solid was filtered off, washed with ether and dried to give the crude product, which was used in the next step without further purification. m/z [M+H] ⁺ 392.0.

Comparative example 8

Synthesis of 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide

To a suspension of 2,4-dichlorobenzamide (1 equiv.) in DCE (0.5 M) was added oxalyl chloride (1.35 equiv.) dropwise at room temperature. The reaction mixture was then heated at 55 °C for 1 h and then refluxed for 20 h. The mixture was evaporated in vacuo to give the crude product 2,4-dichlorobenzoyl isocyanate as a yellow oil. A solution of this crude product in DCE (1.2 M) at 0 °C 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 precipitate was filtered, washed with dichloromethane and dried to give the title compound as a white solid. m/z [M+H] ⁺ 311.0.

The following compounds were obtained using the method described above.

2,4-dichloro-N-(pyridin-2-ylcarbamoyl)benzamide

m/z [M+H] ⁺ 312.0

2,4-dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyridin-2-amine.

m/z [M+H] ⁺ 312.0.

2,4-dichloro-N-(pyridazin-3-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyridazin-3-amine.

m/z [M+H] ⁺ 311.0

2,4-dichloro-N-(pyrimidin-5-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyrimidin-5-amine.

m/z [M+H] ⁺ 311.0

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

m/z [M+H] ⁺ 299.0

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

m/z [M+H] ⁺ 299.0

2,4-dichloro-N-(thiazol-2-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and thiazol-2-amine.

m/z [M+H] ⁺ 316.0

2,4-dichloro-N-(thiazol-5-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and thiazol-5-amine.

m/z [M+H] ⁺ 316.0

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

m/z [M+H] ⁺ 299.0

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

m/z [M+H] ⁺ 377.98.

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

m/z [M+H] ⁺ 359.24

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

m/z [M+H] ⁺ 379.22

2-Chloro-6-isopropyl-N-(phenylcarbamoyl)nicotinamide was prepared using 2-chloro-6-isopropylnicotinamidenicotinamide and aniline.

m/z [M+H] ⁺ 318.1

2,6-difluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2,6-difluoro-4-(trifluoromethyl)benzamide and aniline.

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

N-((2-Chlorophenyl)carbamoyl)-2-fluoro-4-(trifluoromethoxy)benzamide was prepared using 2-fluoro-4-(trifluoromethoxy)benzamide and 2-methylpyridin-3-amine.

m/z [M+H] ⁺ 377.27.

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

m/z [M+H] ⁺ 406.9 (major).

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.

m/z [M+H] ⁺ 368.0.

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

m/z [M+H] ⁺ 366.1.

Comparative example 9

Synthesis of 7-chloro-1-(pyrazin-2-yl)quinazolin-2,4(1H,3H)-dione

KHMDS (3 equiv) was added dropwise to a suspension of 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide in DMF (0.06 M) at room temperature. The reaction mixture was heated at 95 °C for 18 h. Water was added to the reaction mixture after completion of the reaction until the product was completely dissolved, and purification was immediately performed by reversed-phase liquid chromatography (20-60% MeCN/water, 0.1% formic acid) to give the title compound. m/z [M+H] ⁺ 276.0.

According to the method described above, the following compounds were obtained, replacing 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide:

7-Chloro-1-(pyridin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(pyridin-2-ylcarbamoyl)benzamide

m/z [M+H] ⁺ 274.0.

7-Chloro-1-(pyrimidin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide

m/z [M+H] ⁺ 276.0

7-Chloro-1-(pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(pyridazin-3-ylcarbamoyl)benzamide

m/z [M+H] ⁺ 276.0

7-Chloro-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(pyrimidin-5-ylcarbamoyl)benzamide

m/z [M+H] ⁺ 276.0

7-Chloro-1-(1H-pyrazol-4-yl)quinazoline-2,4(1H,3H)-dione was prepared using N-((1H-pyrazol-4-yl)carbamoyl)-2,4-dichlorobenzamide

m/z [M+H] ⁺ 263.0

7-Chloro-1-(1H-imidazol-2-yl)quinazoline-2,4(1H,3H)-dione was prepared using N-((1H-imidazol-2-yl)carbamoyl)-2,4-dichlorobenzamide

m/z [M+H] ⁺ 263.0

7-Chloro-1-(thiazol-2-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(thiazol-2-ylcarbamoyl)benzamide

m/z [M+H] ⁺ 280.0

7-Chloro-1-(thiazol-5-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(thiazol-5-ylcarbamoyl)benzamide

m/z [M+H] ⁺ 280.0

7-Chloro-1-(1H-pyrazol-5-yl)quinazoline-2,4(1H,3H)-dione was prepared using N-((1H-pyrazol-5-yl)carbamoyl)-2,4-dichlorobenzamide

m/z [M+H] ⁺ 263.0

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

m/z [M+H]+ 342.31

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

m/z [M+H] ⁺ 343.03

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

m/z [M+H] ⁺ 323.29

7-Isopropyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 2-fluoro-6-isopropyl-N-(phenylcarbamoyl)nicotinamide

m/z [M+H] ⁺ 282.1

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

m/z [M+H] ⁺ 325.3.

1-(2-Methylpyridin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared using 2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)-4-(trifluoromethyl)benzamide

m/z [M+H] ⁺ 322.33.

1-(2-Chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione was prepared using N-((2-chlorophenyl)carbamoyl)-2-fluoro-4-(trifluoromethoxy)benzamide

m/z [M+H] ⁺ 357.24.

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

m/z [M+H] ⁺ 384.9

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

m/z [M+H] ⁺ 348.1

7-Cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared using 4-cyclopropyl-N-((2-(difluoromethoxy)pyridin-3-yl)carbamoyl)-2-fluorobenzamide

m/z [M+H] ⁺ 346.1

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione was prepared using N-((2-chlorophenyl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide

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

m/z [M+H] ⁺ 292.0

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

m/z [M+H] ⁺ 308.0

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

m/z [M+H] ⁺ 288.05.

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

m/z [M+H] ⁺ 374.05

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

m/z [M+H] ⁺ 275.0

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

m/z [M+H] ⁺ 402.9, 400.9

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

m/z [M+H] ⁺ 416.9, 414.9

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

m/z [M+H] ⁺ 349.0.

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

m/z [M+H] ⁺ 363.0.

1-(Pyridazin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared using 2-fluoro-N-(pyridazin-3-ylcarbamoyl)-4-(trifluoromethyl)benzamide.

m/z [M+H] ⁺ 309.05.

1-(Pyrazin-2-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared using 2-fluoro-N-(pyrazin-2-ylcarbamoyl)-4-(trifluoromethyl)benzamide.

m/z [M+H] ⁺ 309.05.

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

m/z [M+H] ⁺ 319.00.

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

m/z [M+H] ⁺ 394.00.

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

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

m/z [M+H] ⁺ 281.00.

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

m/z [M+H] ⁺ 295.00.

1-(3-Chloropyridin-2-yl)-7-ethylquinazoline-2,4(1H,3H)-dione was prepared using N-((3-chloropyridin-2-yl)carbamoyl)-4-ethyl-2-fluorobenzamide

m/z [M+H] ⁺ 302.0.

1-(3-Chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione was prepared using N-((3-chloropyridin-2-yl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide.

m/z [M+H] ⁺ 338.0.

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

m/z [M+H] ⁺ 343.0.

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.

m/z [M+H] ⁺ 366.0.

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

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

m/z [M+H] ⁺ 343.1

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

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

m/z [M+H] ⁺ 425.27.

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

m/z [M+H] ⁺ 397.36.

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

m/z [M+H] ⁺ 435.24.

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

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

m/z [M+H] ⁺ 355.29.

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

m/z [M+H] ⁺ 344.33.

1-(2-Chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared using N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide

m/z [M+H] ⁺ 314.3.

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

m/z [M+H] ⁺ 455.53.

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

m/z [M+H] ⁺ 307.34.

1-(3-Chloropyridin-2-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared using N-((3-chloropyridin-2-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide.

m/z [M+H] ⁺ 314.2.

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

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

m/z [M+H] ⁺ 441.34.

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

m/z [M+H] ⁺ 413.47.

1-(2-Bromophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared using N-((2-Bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide.

m/z [M+H] ⁺ 357.24.

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

m/z [M+H] ⁺ 310.28.

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

m/z [M+] ⁺ 323.38.

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

m/z [M+H] ⁺ 305.20.

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

m/z [M+H] ⁺ 322.2.

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

m/z [M+H] ⁺ 294.2.

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

m/z [M+H] ⁺ 360.2.

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

m/z [M+H] ⁺ 338.26.

Comparative example 10

Synthesis of 7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

Step 1. Synthesis of 4-chloro-2,5-difluorobenzamide

To a stirred solution of 4-chloro-2,5-difluorobenzoic acid (1 equiv.) in THF (0.9 M) was added DIPEA (5 equiv.), HATU (1.2 equiv.) and _NH3 (0.4 M solution in THF, 3 equiv.) in a sealed flask at 0 °C. The resulting mixture was stirred at room temperature for 16 h and the reaction progress 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.

Step 2. Synthesis of 4-chloro-2,5-difluoro-N-(phenylcarbamoyl)benzamide.

Phenyl isocyanate (1 equiv) was added to a stirred solution of 4-chloro-2,5-difluorobenzamide (1 equiv) in toluene (0.5 M), and the resulting mixture was refluxed for 16 h. The reaction mixture was diluted with ethyl acetate, then washed with water. The combined organic layers were separated, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography (10% Et°Ac/Hexane) to afford the title compound as an off-white solid.

Step 3. Synthesis of 7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

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 solution in THF, 1 equiv.) at 0 °C. The resulting mixture was warmed to room temperature and 18-crown-6 (0.01 g, cat.) was added. After heating at 75 °C for 4 h, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layers were dried over sodium sulfate and evaporated. The solid residue 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-d ₆ ) δ ppm. 12.13-11.95 (m, 1 H), 7.96 (d, J = 8.61 Hz, 1 H), 7.77-7.55 (m, 3 H), 7.46 (m, 2 H), 6.43 (d, J = 5.89 Hz, 1 H). m/z [M+H] ⁺ 291.13.

Using a procedure similar to that described above for comparative example 10, step 2, the following compounds were obtained:

2,6-dichloro-N-((2-fluorophenyl)carbamoyl)nicotinamide was prepared using 1-fluoro-2-isocyanatobenzene and 2,6-dichloronicotinamide

m/z [M+H] ⁺ 329.0

2,6-dichloro-N-((2-chlorophenyl)carbamoyl)nicotinamide was prepared using 1-chloro-2-isocyanatobenzene and 2,6-dichloronicotinamide

m/z [M+H] ⁺ 345.95, 343.95

2,6-Dichloro-N-(o-tolylcarbamoyl)nicotinamide was prepared using 1-isocyanato-2-methylbenzene and 2,6-dichloronicotinamide

m/z [M+H] ⁺ 324.0

2,6-dichloro-N-(phenylcarbamoyl)nicotinamide was prepared using 2,6-dichloronicotinamide

m/z [M+H] ⁺ 310.0
2,6-dichloro-N-(pyridin-3-ylcarbamoyl)nicotinamide was prepared using 3-isocyanatopyridine and 2,6-dichloronicotinamide

m/z [M+H] ⁺ 312.2

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

m/z [M+H] ⁺ 391.35.

2-chloro-4-methoxy-N-(phenylcarbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinamide and phenyl isocyanate.

m/z [M+H] ⁺ 374.23.

Using a procedure similar to that described above for comparative example 10, step 3, the following compounds were obtained:

7-Cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

m/z [M+H] ⁺ 293.25

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

m/z [M+H] ⁺ 384.9.

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

m/z [M+H] ⁺ 418.8.

Comparative example 11

Synthesis of 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione

Step 1. Synthesis of 3,4-dichloro-2-(phenylamino)benzoic acid

A flask was charged with 2-amino-3,4-dichlorobenzoic acid (1 equiv), triethylamine (4 equiv), and bromobenzene (1 equiv). Dioxane (1 M) and copper(II) acetate (1 equiv) were added and the reaction mixture was heated at 110 °C for 18 h. The reaction mixture was cooled, additional bromobenzene (1 equiv) was added, and then heated at 110 °C for 24 h. The crude reaction mixture was diluted with saturated aqueous ammonium chloride and extracted with dichloromethane. The organic layer was washed with 1 N HCl and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography (0-50% ethyl acetate/hexane) to give the title compound.

Step 2. Synthesis of 3,4-dichloro-2-(phenylamino)benzamide

To a stirred solution of 3,4-dichloro-2-(phenylamino)benzoic acid (1 eq.) in THF (0.9 M) was added DIPEA (5 eq.), HATU (1.2 eq.), then _NH3 (0.4 M solution in THF, 3 eq.) was added in a sealed flask at 0 °C. The resulting 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 give the title compound as a white solid.

Step 3. Synthesis of 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione

3,4-Dichloro-2-(phenylamino)benzamide (1.0 equiv) and DMF (0.2 M) were placed in a vial under nitrogen atmosphere. 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 min. CDI (1.5 equiv) was added and the mixture was stirred at room temperature for 20 min. The reaction was quenched by adding MeOH (0.5 mL) and AcoH (0.2 mL). The crude reaction mixture was directly purified by reversed-phase liquid 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 = 8.5 Hz, 1H), 7.48-7.43 (m, 3H), 7.29 (d, J = 7.8 Hz, 2H). m/z [M+H] ⁺ 307.0

Comparative example 12

Synthesis of 7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione

Step 1. Synthesis of 4-chloro-2-fluoro-3-methylbenzamide

In a flask were placed 4-chloro-2-fluoro-3-methylbenzoic acid (1 equiv), hydroxybenzotriazole (0.2 equiv) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.5 equiv). DMF (0.5 M) was added followed by diisopropylethylamine (2 equiv). The reaction mixture was stirred for 15 min and ammonium chloride (5 equiv) was added. The reaction mixture was stirred at room temperature for 2 h. The crude reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with 1N HCl solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated under reduced pressure to give the title compound.

Step 2. Synthesis of 4-chloro-2-fluoro-3-methyl-N-(phenylcarbamoyl)benzamide

To a suspension of 4-chloro-2-fluoro-3-methylbenzamide (1 equiv.) in DCE (0.5 M) was added oxalyl chloride (1.35 equiv.) dropwise at room temperature. The reaction mixture was then heated at 55 °C for 1 h and then refluxed for 20 h. The reaction mixture was evaporated in vacuo to give the crude product as a yellow oil. A solution of the resulting crude 4-chloro-2-fluoro-3-methylbenzoyl isocyanate in DCE (1.2 M) at 0 °C was added dropwise to a cooled solution of aniline in DCE (0.4 M). The ice bath was removed and the reaction mixture was stirred at room temperature for 45 min. The solid precipitate was filtered, washed with dichloromethane and dried to give the title compound as a white solid.

Step 3. Synthesis of 7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione

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

Using the method described above, the following compounds were obtained, replacing 4-chloro-2-fluoro-3-methylbenzamide:

2-Fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using o-toluidine and 2-fluoro-4-(trifluoromethyl)benzamide

m/z [M+H] ⁺ 341.00

1-(o-tolyl)-7-trifluoromethylquinazoline-2,4(1H,3H)-dione was prepared using 2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide.

m/z [M+H] ⁺ 321.00

Comparative example 13

Synthesis of 1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Step 1. Synthesis of 2-(phenylamino)-6-(trifluoromethyl)nicotinamide

The round bottom flask was purged with nitrogen and a solution of KHMDS (2.5 equiv, 1 M solution in THF) was added to a 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 the volume to remove THF. The solid phase was filtered, washed with additional toluene and dried in vacuo to give the title compound. m/z [M+H] ⁺ 282.1.

Step 2. Synthesis of 1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

By a procedure similar to that described above for Comparative Example 2, but replacing 4-chloro-2-(pyridin-3-ylamino)benzamide with 2-(phenylamino)-6-(trifluoromethyl)nicotinamide, the title compound was obtained.

Using a procedure similar to that described above for comparative example 13, step 1, the following compounds were obtained:

2-((2-Fluorophenyl)amino)-6-(trifluoromethyl)nicotinamide was obtained by replacing aniline with 2-fluoroaniline.

m/z [M+H] ⁺ 300.0.

2-((2-Bromophenyl)amino)-6-(trifluoromethyl)nicotinamide was obtained by replacing aniline with 2-bromoaniline.

m/z [M+H] ⁺ 360.0, 362.0

Comparative example 14

Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile

A vial was charged with 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione (1 equiv) and copper cyanide (2 equiv). Dimethylformamide (0.5 M) was added and the reaction mixture was heated at 120°C for 18 h, then cooled. The reaction mixture was filtered and purified by reverse phase chromatography (30-60% MeCN/water, 0.1% formic acid) to give the title compound. m/z [M+H] ⁺ 338.0.

Using a procedure similar to that described above for Comparative Example 14, the following compounds were obtained:

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.

m/z [M+H] ⁺ 339.0.

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.

m/z [M+H] ⁺ 362.0.

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.

m/z [M+H] ⁺ 372.3.

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.

m/z [M+H] ⁺ 344.46.

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.

m/z [M+H] ⁺ 382.28.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using 6-bromo-1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-hydroxyquinazoline-2(1H)-one.

m/z [M+H] ⁺ 339.4.

Comparative example 15

Synthesis of 7-chloro-1-(3-vinylphenyl)quinazoline-2,4(1H,3H)-dione

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 were added potassium fluoride (3 equiv.) and tributyl(vinyl)stannane (1.5 equiv.) at room temperature. The reaction mixture was degassed by bubbling argon for 20 min. Pd(OAc) ₂ (10 mol%) was added and the reaction mixture was degassed again for 5 min. The resulting mixture was stirred at 100 °C for 16 h. After completion of the reaction, the mixture was filtered through a pad of celite. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layer was washed _with water, saturated aqueous sodium chloride solution and dried over _Na2SO4 . The organic layer was then filtered and evaporated under reduced pressure to give the crude product. It was purified by column chromatography (1:6 EtOAc/hexane) to give the title compound as a yellow solid. m/z [MH] ⁺ 298.73.

Comparative example 16

Synthesis of 7-cyclopropyl-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

Step 1. Synthesis of 2-bromo-4,6-dichlorobenzoic acid

Butyl nitrite (2 equiv.) was added dropwise at 0 °C to a suspension of CuBr ₂ (1.2 equiv.) in acetonitrile (0.25 M). The reaction mixture was stirred for 10 min and 2-amino-4,6-dichlorobenzoic acid (1 equiv.) was added portionwise. The mixture was stirred at 0 °C for 2 h, then allowed to warm to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C and 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 evaporated under reduced pressure to give 2-bromo-4,6-dichlorobenzoic acid as an off-white solid.

Step 2. Synthesis of 2,4-dichloro-6-vinylbenzoic acid

To a stirred solution of 2-bromo-4,6-dichlorobenzoic acid (1 equiv.) in DMSO: _H2O (3:1, 0.2 M) was added vinyl boronic acid pinacol ester (1.2 equiv.), _K2CO3 (3 equiv.) _, and Pd(dppf) _Cl2 (5 mol%) at room temperature. The reaction mixture was purged with argon for 10 min, then heated to 120°C and stirred for 16 h. The reaction mixture was diluted with 1N HCl and EtOAc, then washed with saturated aqueous sodium chloride. The combined organic layers were separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography (20% EtOAc/Hexane) and then evaporated under reduced pressure to give 2,4-dichloro-6-vinylbenzoic acid as an off-white semi-solid.

Step 3. Synthesis of 2,4-dichloro-6-ethylbenzoic acid

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 hydrogen atmosphere (1 atm.) for 16 h, then filtered through a pad of celite and washed several times with ethyl acetate. The filtrate was evaporated under reduced pressure to give 2,4-dichloro-6-ethylbenzoic acid as a viscous liquid, which was used in the next step without further purification.

Step 4. Synthesis of 2,4-dichloro-6-ethylbenzamide

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.), and then _NH4Cl (5 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 16 h, then diluted with ethyl acetate and washed with water. The combined organic layers were separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The resulting crude product was purified by column chromatography (30% EtOAc/Hexane) and evaporated under reduced pressure to give the title compound as an off-white solid.

Step 5. Synthesis of 2,4-dichloro-6-ethyl-N-(o-tolylcarbamoyl)benzamide

To a stirred solution of 2,4-dichloro-6-ethylbenzamide (1 eq.) in DCE (0.3 M) was added oxalyl chloride (1.9 eq.) at room temperature. The reaction mixture was stirred at 100 °C for 16 h and evaporated to give crude 2,4-dichloro-6-ethylbenzoyl isocyanate as a sticky liquid. To a stirred solution of o-toluidine (1.2 eq.) in DCE (1.4 M) at 0 °C was slowly added the resulting crude isocyanate as a suspension in DCE (1.5 M) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and evaporated in vacuo. The solid residue was washed with pentane and dried in vacuo to give the title compound as an off-white solid.

Step 6. Synthesis of 7-chloro-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

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 slowly added KHMDS (2 equiv., 1.0 M solution in THF) dropwise at 0 °C. The reaction mixture was stirred at 100 °C for 1 h, then diluted with water and 1 N HCl was slowly added. The precipitate that formed was filtered and washed with water, dried in vacuo to give the title compound as a pale yellow solid.

Step 7. Synthesis of 7-cyclopropyl-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

To a stirred solution of 7-chloro-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one (1 equiv.) in toluene: _H2O (8:2, 0.6 M) was added cyclopropylboronic acid (10 equiv.), _K3PO4 (3 equiv.) at room temperature. The reaction mixture was purged with _argon for 5 min and Pd( _PPh3 ) ₄ (10 mol%) was added. The reaction mixture was stirred at 150°C in a microwave oven for 1 h, then diluted with water and extracted with ethyl acetate. The combined organic layers were separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (10-20% EtOAc/Hexane) and evaporated under reduced pressure to give the title compound as an off-white solid. m/z [M+H] ⁺ 321.41.

Comparative example 17

Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione

Step 1. Synthesis of 4-bromo-2-fluoro-6-hydroxybenzoic acid

To a stirred solution of 4-bromo-2,6-difluorobenzoic acid (1 eq.) in N-methyl-2-pyrrolidone (0.85 M) was added sodium hydroxide (4 eq.) at room temperature. The reaction mixture was stirred for 45 min at 120°C, then cooled to room temperature and ice water was added. The mixture was acidified with 2N HCl (100 mL) to approximately pH 1, the precipitate formed was filtered and washed with water to give the title compound as an off-white solid.

Step 2. Synthesis of methyl 4-bromo-2-fluoro-6-hydroxybenzoate

To a stirred solution of 4-bromo-2-fluoro-6-hydroxybenzoic acid (1 eq.) in methanol (0.4 M) was added thionyl chloride (0.36 eq.) at 0 °C. The reaction mixture was stirred at 90 °C for 72 h and then evaporated under reduced pressure. The residue was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over _{anhydrous Na2SO4} , filtered, evaporated under reduced pressure to give the title compound as an off-white solid.

Step 3. Synthesis of methyl 4-bromo-2-(difluoromethoxy)-6-fluorobenzoate

To a stirred solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1 eq.) in acetonitrile/water (1:1, 0.2 M) was added potassium hydroxide (20 eq.) at room temperature. The solution was cooled to -78 °C and diethyl (bromodifluoromethyl) phosphonate (2 eq.) was added. The reaction mixture was stirred for 20 min at room temperature, diluted with water and extracted with ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over _{anhydrous Na2SO4} , filtered and evaporated under reduced pressure to give the crude product. Purification by column chromatography (5% EtOAC/Hexane) gave the title compound as a colorless liquid.

Step 4. Synthesis of methyl 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoate

To a stirred solution of methyl 4-bromo-2-(difluoromethoxy)-6-fluorobenzoate (1 equiv.) in toluene/water (1:1, 0.2 M) were added cyclopropylboronic acid (1.5 equiv.) and _Na2CO3 (3 equiv.). The resulting mixture was degassed for 20 min under argon and _PdCl2 ( _dppf )DCM (10 mol %) was added. The reaction mixture was stirred at 120 °C for 16 h, then filtered through _celite and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous _Na2SO4 , filtered and evaporated under reduced pressure to give the crude product. Purification by column chromatography on silica gel (5% EtOAc/Hexane) and evaporation under reduced pressure gave the title compound as a colorless liquid.

Step 5. Synthesis of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoic acid

To a stirred solution of methyl 4-cyclopropyl 2-(difluoromethoxy)-6-fluorobenzoate (1 eq.) in MeOH/THF/ _H2O (2:2:1, 0.17 M) was added _LiOH.H2O (2 eq.) at room temperature. The reaction mixture was stirred for 16 h at room temperature. The methanol was removed under reduced pressure, water was added to the residue, and the solution was acidified with 2N HCl to about pH 1. The solid precipitate was filtered and dried to give the title compound as an off-white solid.

Step 6. Synthesis of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide

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 room temperature. The reaction mixture was stirred at room temperature for 16 h, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with cold water and saturated aqueous sodium chloride _solution . The organic layer was dried over anhydrous _Na2SO4 , filtered and evaporated under reduced pressure to give the title compound as a light yellow solid.

Step 7. Synthesis of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide

To a stirred solution of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide (1 eq.) in DCE (0.4 M) was added oxalyl chloride (1.4 eq.), and the reaction mixture was stirred at 100 °C for 20 h. The mixture was evaporated under reduced pressure to give crude 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoyl isocyanate. A stirred solution of 2-chloroaniline (1 eq.) in DCE (0.7 M) was added to a solution of the crude isocyanate in THF (1 M) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous _Na2SO4 , filtered and evaporated. The resulting crude product was purified by column chromatography (10% EtOAc/ _Hexane ) and evaporated under reduced pressure to give the title compound as a light brown solid.

Step 8. Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione

To a stirred solution of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-(difluoro-methoxy)-6-fluorobenzamide (1 equiv.) in DMF (0.5 M) was added KHMDS (2 equiv., 1 M solution in THF) dropwise at 0 °C. The reaction mixture was stirred at 100 °C for 2 h, then cooled to room temperature and acidified with 2 N HCl to approximately pH 1. The white precipitate was filtered, washed with water and dried to give the title compound as a yellow solid. m/z [M+H] ⁺ 379.3.

Comparative example 18

Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione

Step 1. Synthesis of 4-bromo-2-fluoro-6-methoxybenzamide

To a stirred solution of 4-bromo-2,6-difluorobenzamide (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 mixture was evaporated under reduced pressure, the residue was diluted with water and extracted with ethyl acetate. The combined organic layers were separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate. The solution was filtered and evaporated under reduced pressure to give the crude product. It was purified by column chromatography (40% EtOAc/Hexane) and evaporated under reduced pressure to give the title compound as a white solid.

Step 2. Synthesis of 4-cyclopropyl-2-fluoro-6-methoxybenzamide

To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzamide (1 _eq .) in toluene/water (4:1, 0.3 M) were added cyclopropylboronic acid (1.5 eq.), _K2CO3 (3 eq.), tributylphosphine (20 mol%), _Pd2 (dba) ₃ (10 mol%), and the reaction mixture was stirred at 115°C for 16 h. The mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solution was then filtered and evaporated under reduced pressure to give a crude product which was purified by column chromatography (30% EtOAc/Hexane) and evaporated under reduced pressure to give the title compound as an off-white solid.

Step 3. Synthesis of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide

To a stirred solution of 4-cyclopropyl 2-fluoro-6-methoxybenzamide (1 eq.) in DCE (0.25 M) was added oxalyl chloride (1.3 eq.) at 0 °C, 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 eq.) in DCE (0.7 M) at 0 °C under nitrogen atmosphere and stirred at room temperature for 2 h. The solid precipitate was filtered, washed with diethyl ether and dried in vacuo to give the title compound as a brown solid.

Step 4. Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-4-hydroxy-5-methoxyquinazolin-2(1H)-one

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 solution in THF, 2.5 eq.) dropwise at 0 °C and the reaction mixture was stirred at 100 °C for 4 h. The mixture was diluted with water and acidified to approximately pH 1 with 2 N HCl. The solid precipitate was filtered and dried in vacuo to give the title compound as an off-white solid. m/z [M+H] ⁺ 343.34.

Comparative example 19

Synthesis of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine

A vial under nitrogen was charged with 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile (1.0 equiv) and THF (0.5 M). LAH (2.0 equiv) was added and the reaction mixture was stirred at 70 °C for 2 h. The mixture was cooled to 0 °C and quenched with wet Na ₂ SO _4. The reaction mixture was filtered through a pad of celite, washing with ethyl acetate. The filtrate was dried over Na ₂ SO ₄ , filtered and evaporated to give the title compound; m/z [M+H] ⁺ 228.28.

Comparative example 20

Synthesis of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-amine

Step 1. 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one

1-(1H-imidazol-4-yl)ethan-1-one (1.0 equiv) and THF (0.5 M) were placed in a vial under nitrogen atmosphere. 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 reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with ice water and diluted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by silica gel chromatography (20-25% EtOAc/Hexane) gave the title product; m/z [M+H] ⁺ 241.4.

Step 2. Synthesis of 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one oxime

In a vial under nitrogen atmosphere were placed 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one (1 equiv) and methanol (0.5 M). Hydroxylamine hydrochloride (1.2 equiv) and K ₂ CO ₃ (3 equiv) were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was passed through a pad of celite, washing with methanol. The filtrate was dried over Na ₂ SO ₄ , filtered and evaporated to give the title product; m/z [M+H] ⁺ 256.39.

Step 3. 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-amine

1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one oxime (1 equiv) was placed in a vial under nitrogen, EtOH, zinc (15 equiv) and ammonium chloride (10 equiv) were added at room temperature and the reaction mixture was stirred at 80°C for 48 h. The reaction mixture was filtered through a pad of celite, washing with ethanol. The filtrate was dried over Na ₂ SO ₄ , filtered and evaporated. Purification by reverse phase chromatography (30% ACN/water) gave the title compound; m/z [M+H] ⁺ 242.38.

Comparative example 21

Synthesis of 5-cyano-4-cyclopropyl-2-fluorobenzamide

5-Bromo-4-cyclopropyl-2-fluorobenzamide (1 equiv) and copper cyanide (2 equiv) were placed in a vial. Dimethylformamide (0.5 M) was added 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 chromatography (30-60% MeCN/water, 0.1% formic acid) to give the title compound. m/z [M+H] ⁺ 205.0.

Comparative example 22

Synthesis of 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinic acid

Step 1. Ethyl 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinate

To a vial containing ethyl 2,4-dichloro-6-(trifluoromethyl)nicotinate (1.0 equiv.) in DMF (0.9 M) under nitrogen flow was added MeOH (1.0 equiv.) at room temperature. The reaction mixture was cooled to 0 °C and NaH (60%) (1.0 equiv.) was added slowly portionwise. The reaction mixture was stirred at the same temperature for 1 h, then quenched with cold water and extracted with ethyl acetate. The combined organic layers were separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the title compound; m/z [M+H] ⁺ 284.23.

Step 2. 2-Chloro-4-methoxy-6-(trifluoromethyl)nicotinic acid

To a stirred solution of ethyl 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinate (1.0 equiv.) in MeOH:THF: _H2O (2:7:1, 0.5 M) was added LiOH (5.0 equiv.) at room temperature. The reaction mixture was heated to 80°C and stirred for 16 h. The reaction mixture was diluted with water, adjusted to pH 4 with 1N HCl, extracted with ethyl acetate. The combined organic layers were separated and washed with saturated aqueous sodium chloride, dried over _{anhydrous Na2SO4} , filtered, and evaporated under reduced pressure to give the title compound; m/z [M+H] ⁺ 256.11.

Comparative example 23

Synthesis of 6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione

To a solution of 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione (1 equiv.) in trifluoroacetic acid (0.3 M) were added N-bromosuccinimide (1.2 equiv.) and sulfuric acid (18 M, 0.1 equiv.). The reaction mixture was heated at 40 °C for 4 h, then cooled. The mixture was poured into water, the precipitate formed was filtered and dried in vacuo to give the title compound as a white solid. m/z [M+H] ⁺ 415.0/416.9.

According to the above-described method, 6-bromo-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was obtained using 1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 391.9/393.9.

Comparative example 24

Synthesis of 7-ethyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

In a vial were placed 7-chloro-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1 equiv), potassium ethyl trifluoroborate (3 equiv), potassium tert-butoxide (3 equiv), and chloro(crotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II) (0.1 equiv). A 9:1 mixture of toluene:water (0.1 M) was added. The reaction mixture was heated at 100 °C for 2 h, then cooled. The crude reaction mixture was diluted with ethyl acetate, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC (40-65% MeCN/water, 0.1% formic acid) to give the title compound. m/z [M+H] ⁺ 374.05.

Using a procedure similar to that described above for Comparative Example 24, the following compounds were prepared by replacing 7-chloro-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

7-Ethyl-1-(o-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 7-chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

m/z [M+H] ⁺ 282.1

1-(2-Chlorophenyl)-7-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 7-chloro-1-(2-chlorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

m/z [M+H] ⁺ 302.1

7-Ethyl-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 7-chloro-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

m/z [M+H] ⁺ 286.1

7-Ethyl-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 7-chloro-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

m/z [M+H] ⁺ 269.1

Comparative example 25

Synthesis of 1-(2-Chlorophenyl)-7-(trifluoromethyl)-6-vinylquinazoline-2,4(1H,3H)-dione

The vial was flushed with nitrogen and charged with 6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (1.0 equiv), vinyl boronic acid pinacol ester (4 equiv), and K ₂ CO ₃ (5 equiv). Toluene:H ₂ ° (4:1, 0.4 M) was added to the reaction vessel, followed by the addition of Pd(dppf)Cl ₂ DCM complex (0.1 equiv). The reaction mixture was heated at 100 °C for 16 h. The mixture was then diluted with water and extracted with ethyl acetate. The combined organic layers were separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure to give the crude product. The crude reaction mixture was directly purified by column chromatography on silica gel (10-20% EtOAc/Hexane). The desired fractions were combined to give the title compound as a yellow solid. m/z [M+H] ⁺ 367.12.

Using a procedure similar to that described above for Comparative Example 25, the following compounds were prepared by replacing 6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione and pinacol vinyl boronic ester:

1-(2-Chlorophenyl)-7-cyclopropyl-6-vinylquinazoline-2,4(1H,3H)-dione was prepared using 6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 339.15.

m/z [M+H] ⁺ 6-Chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared using 7-bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione and cyclopropylboronic acid.

347.0.

1-(2-Chlorophenyl)-6-methyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared using 6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione and methylboronic acid.

m/z [M+H] ⁺ 355.3.

1-(2-Chlorophenyl)-7-cyclopropyl-6-methylquinazoline-2,4(1H,3H)-dione was prepared using 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione and methylboronic acid.

m/z [M+H] ⁺ 327.2.

Comparative example 26

Synthesis of 1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde

In a vial under nitrogen atmosphere was placed 1-(2-chlorophenyl)-7-(trifluoromethyl)-6-vinylquinazoline-2,4(1H,3H)-dione (1.0 equiv) in THF: _H2O (10:3, 0.5 M), _OsO4 (0.1 M solution in _H2O ) (2.0 equiv) was added followed by _NaIO4 (4.0 equiv) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through celite, the filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were separated, washed with saturated aqueous sodium chloride solution, dried over _{anhydrous Na2SO4} , filtered and evaporated under reduced pressure to give the title compound. m/z [M+H] ⁺ 369.04.

By a procedure similar to that described above for Comparative Example 26, 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde was prepared by replacing 1-(2-chlorophenyl)-7-(trifluoromethyl)-6-vinylquinazoline-2,4(1H,3H)-dione with 1-(2-chlorophenyl)-7-cyclopropyl-6-vinylquinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 341.1.

Comparative example 27

Synthesis of 1-(2-Chlorophenyl)-6-(difluoromethyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

A vial under nitrogen atmosphere was charged with 1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde (1.0 equiv.) in DCM (0.7 M), DAST (10 equiv.) was added at 0 °C, then ethanol (catalytic amount) and heated at 60 °C for 16 h. The reaction mixture was quenched with saturated NaHCO ₃ solution and extracted with ethyl acetate. The combined organic layers were separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the crude product. It was purified by column chromatography (10-20% EtOAc/Hexane). The pure fractions were combined and evaporated under reduced pressure to give the title compound. m/z [M+H] ⁺ 391.11.

By a procedure similar to that described above for Comparative Example 27, 1-(2-chlorophenyl)-7-cyclopropyl-6-(difluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared by replacing 1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde with 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde.

m/z [M+H] ⁺ 363.5.

Comparative example 28

Synthesis of 5-methoxy-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

5-Fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (1.0 equiv), MeOH (0.6 M), and MeONa (5.4 N in MeOH, 10 equiv) were added to a 20 mL vial under nitrogen atmosphere. The reaction mixture was stirred for 60 min at room temperature. The reaction mixture was acidified by adding AcOH. The resulting solution was purified by reverse-phase chromatography (20-60% MeCN/water, with 0.1% formic acid). m/z [M+H] ⁺ 337.0.

Example 1

Synthesis of 4,7-dichloro-1-phenylquinazolin-2(1H)-one

To a stirred solution of 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one (1 eq.) in ACN (0.1 M) was added DIPEA (5 eq.) and _POCl3 (2 eq.) at 0°C. The reaction mixture was stirred at 100°C for 4 h, then poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with _NaHCO3 solution, dried over sodium sulfate, filtered and evaporated under reduced pressure below 10°C to give the title compound as a brown solid.

Example 2

Synthesis of 7-chloro-4-(methylamino)-1-phenylquinazolin-2(1H)-one

To a stirred solution of 4,7-dichloro-1-phenylquinazolin-2(1H)-one (0.3 g, 1.03 mmol) in DMF (10 mL) was added TEA (2 eq.) and methylamine (5 eq.), and the reaction mixture was stirred at 70 °C for 2 h. The crude product was purified by column chromatography (50-90% EtOAc/Hexane). The pure fractions were evaporated to give the title compound as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.64-8.53 (m, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.62-7.56 (m, 2H), 7.54-7.48 (m, 1H), 7.33-7.22 (m, 3H), 6.32-6.27 (m, 1H), 2.98 (d, J = 4.2 Hz, 3H). m/z [M+H] ⁺ 286.23.

The following compounds were obtained using the method described above, replacing 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one and methylamine as necessary:

7-Bromo-4-(methylamino)-1-phenylquinazoline-2(1H)-one was prepared using 7-bromo-1-phenylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, CD _3OH ) δ 7.90 (d, J = 8.7 Hz, 1H), 7.65 (t, J = 7.5 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H), 6.68 (s, 1H), 3.13 (s, 3H). m/z [M+H] ⁺ 330.0.

7-Fluoro-4-(methylamino)-1-phenylquinazoline-2(1H)-one was prepared using 7-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, CD ₃ OH) δ 8.06 (dd, J = 8.7, 5.9 Hz, 1H), 7.64 (t, J = 7.5 Hz, 2H), 7, 58 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 7.7 Hz, 2H), 7.02 (t, J = 8.4 Hz, 1H), 6.21 (d, J = 10.7 Hz, 1H), 3.13 (s, 3H). m/z [M+H] ⁺ 270.0.

7-chloro-1-(3-fluoro-5-hydroxyphenyl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.42 (s, 1H), 8.64 (d, J = 4.1 Hz, 1H), 8.10 (d, J = 8.6 Hz , 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 10.7 Hz, 1H), 6.65 (d, J = 9.1 Hz, 1H), 6.52 (s, 1H), 6.44 (s, 1H), 2.96 (s, 4H). m/z [M+H] ⁺ 320.0.

7-Chloro-6-fluoro-4-(methylamino)-1-phenylquinazoline-2(1H)-one was prepared using 7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.62-8.57 (m, 1 H), 8.21 (d, J = 9.9 Hz, 1 H), 7.62-7.57 (m, 2 H), 7.56-7.50 (m, 1 H), 7.36-7.30 (m, 2 H), 6.40 (d, J = 6.0 Hz, 1 H), 3.33 (s, 3 H). m/z [M+H] ⁺ 304.08.

7-Chloro-5-fluoro-4-(methylamino)-1-phenylquinazoline-2(1H)-one was prepared using 7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.08-7.96 (m, 1H), 7.64-7.49 (m, 3H), 7.35-7.24 (m, 3H), 6.11 (s, 1 H), 3.03-2.93 (m, 3H). m/z [M+H] ⁺ 304.1.

7-Chloro-4-(methylamino)-1-(pyridin-4-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(pyridin-4-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 287.1

7-Chloro-4-(methylamino)-1-(pyridin-3-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 287.1

7-Chloro-4-(methylamino)-1-(pyridin-2-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(pyridin-2-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 287.1

7-Chloro-4-(methylamino)-1-(pyrimidin-2-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(pyrimidin-2-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 288.1

7-Chloro-4-(methylamino)-1-(pyrazin-2-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 288.1

7-Chloro-4-(methylamino)-1-(pyridazin-3-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 288.1

7-Chloro-4-(methylamino)-1-(pyrimidin-5-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 288.1

7-Chloro-4-(methylamino)-1-(1H-pyrazol-4-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(1H-pyrazol-4-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 276.1

7-Chloro-1-(1H-imidazol-2-yl)-4-(methylamino)quinazolin-2(1H)-one was prepared using 7-chloro-1-(1H-imidazol-2-yl)quinazolin-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 276.1

7-Chloro-4-(methylamino)-1-(thiazol-2-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(thiazol-2-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 293.1.

7-Chloro-4-(methylamino)-1-(thiazol-5-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(thiazol-5-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 293.1

7-Chloro-4-(methylamino)-1-(1H-pyrazol-5-yl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(1H-pyrazol-5-yl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 276.1

7-Chloro-4-(cyclopropylamino)-1-phenylquinazolin-2(1H)-one was prepared using cyclopropylamine.

^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.46 (d, J = 3.9 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.63 -7.57 (m, 2H), 7.55-7.49 (m, 1H), 7.33-7.30 (m, 2H), 7.28-7.25 (m, 1H), 6.29 (d, J = 2.0 Hz, 1H), 3.11-3.04 (m, 1H), 0.84-0 .77 (m, 2H), 0.73-0.67 (m, 2H). m/z [M+H] ⁺ 312.20.

7-Chloro-4-(oxetan-3-ylamino)-1-phenylquinazolin-2(1H)-one was prepared using oxetan-3-amine.

^1H NMR (400 MHz, DMSO- _d6 ) δ = 9.02 (d, J = 5.0 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.63- 7.57 (m, 2H), 7.55-7.49 (m, 1H), 7.35-7.26 (m, 3H), 6.30 (d, J = 1.8 Hz, 1H), 5.18-5.08 (m, 1H), 4.88-4.84 (m, 2H), 4.70-4 .65 (m, 2H). m/z [M+H] ⁺ 328.19.

7-Chloro-1-phenyl-4-((tetrahydrofuran-3-yl)amino)quinazolin-2(1H)-one was prepared using tetrahydrofuran-3-amine.

^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.44 (d, J = 6.1 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.57 -7.63 (m, 2H), 7.54-7.50 (m, 1H), 7.33-7.27 (m, 3H), 6.29 (d, J = 1.8 Hz, 1H), 4.71-4.79 (m, 1H), 3.96-3.90 (m, 2H), 3.79-3 .70 (m, 2H), 2.30-2.21 (m, 1H), 2.06 (td, J = 12.2, 6.2 Hz, 1H). m/z [M+H] ⁺ 342.12.

4-(Benzylamino)-7-chloro-1-phenylquinazolin-2(1H)-one was prepared using benzylamine.

^1H NMR (400 MHz, DMSO- _d6 ): δ = 9.13 (t, J = 5.7 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 7.63 -7.57 (m, 2H), 7.54-7.47 (m, 1H), 7.27-7.42 (m, 8H), 6.31 (d, J = 1.8 Hz, 1H), 4.76 (d, J = 5.7 Hz, 2H). m/z [M+H] ⁺ 362.12.

7-Chloro-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one was prepared using dimethylamine.

¹ H NMR (CDCl ₃ , 400 MHz): δ (ppm) 7.76 (d, J = 8.8 Hz, 1H), 7.55-7.59 (m, 2H), 7.47-7.51 (m, 1H), 7.26-7.29 (m, 2H), 7.06 (dd, J = 8.7, 2.1 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 3.38 (s, 6H). m/z [M+H] ⁺ 300.21.

4-(Azetidin-1-yl)-7-chloro-1-phenylquinazolin-2(1H)-one was prepared using azetidine.

^1H NMR (400 MHz, DMSO- _d6 ): δ = 7.82 (d, J = 8.8 Hz, 1H), 7.62-7.57 (m, 2H), 7.54-7, 49 (m, 1H), 7.28 (d, J = 7.2 Hz, 2H), 7.19 (dd, J = 8.7, 2.1 Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 4.53-4.02 (m, 4H), 2.45-2.41 (m , 2H). m/z [M+H] ⁺ 312.20.

7-Chloro-4-(3-hydroxypyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one was prepared using pyrrolidin-3-ol

^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.16 (d, J = 8.8 Hz, 1H), 7.62-7.58 (m, 2H), 7.49-7, 54 (m, 1H), 7.32-7.29 (m, 2H), 7.20 (dd, J = 8.8, 2.1 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 5.12 (d, J = 3.1 Hz, 1H), 4.41 (brs, 1H) , 3.84-4.02 (m, 3H), 3.69-3.64 (m, 1H), 1.92-2.08 (m, 2H). m/z [M+H] ⁺ 342.12.

7-Chloro-4-(4-methylpiperazin-1-yl)-1-phenylquinazolin-2(1H)-one was prepared using 1-methylpiperazine

¹ H NMR (400 MHz, CDCl ₃ ): δ = 8.25 (d, J = 1.8 Hz, 1H), 7.57-7.65 (m, 3H), 7.54-7.50 (m, 1H), 7.30-7.27 (m, 2H), 7.10 (dd, J = 8.6, 2.0 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 4.08-3.85 (m, 8H), 2.84-2.79 (m, 4H), 2.48 (s, 3H). m/z [M+H] ⁺ 355.18.

7-Chloro-4-morpholino-1-phenylquinazolin-2(1H)-one was prepared using morpholine.

^1H NMR (400 MHz, CDCl ₃ ): δ = 7.64-7.57 (m, 3H), 7.53-749 (m, 1H), 7.29 (d, J = 7.2 Hz, 2H), 7.08 (dd, J = 8.7, 1.9 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H), 3.88 (s, 8H). m/z [M+H] ⁺ 342.12.

7-Chloro-1-phenyl-4-(1H-pyrazol-1-yl)quinazolin-2(1H)-one was prepared using pyrazole.

¹ H NMR (400 MHz, CDCl ₃ ); δ = 9.49 (d, J = 9.0 Hz, 1H), 8.87 (d, J = 2.6 Hz, 1H), 7.94 (d, J = 0.9 Hz, 1H), 7.67-7.62 (m, 2H), 7.61-7.55 (m, 1H), 7.36-7.32 (m, 2H), 7.25 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 6.58-6.56 (m, 1H). m/z [M+H] ⁺ 323.13.

7-Chloro-4-(ethylamino)-1-phenylquinazolin-2(1H)-one was prepared using ethylamine.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 8.57 (t, J = 5.3 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.62-7.57 (m, 2H), 7.55-7.48 (m, 1H), 7.33-7.26 (m, 3H), 6.29 (d, J = 2.0 Hz, 1H), 3.57-3.49 (m, 2H), 1.25-1.21 (m, 3H). m/z [M+H] ⁺ 300.21.

7-Chloro-4-((2,2-difluoroethyl)amino)-1-phenylquinazolin-2(1H)-one was prepared using 2,2-difluoroethane-1-amine.

^1H NMR (400 MHz, DMSO- _d6 ): δ = 8.90 (bs, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.63-7.58 ( m, 2H), 7.55-7.50 (m, 1H), 7.34-7.29 (m, 3H), 6.42-6.25 (m, 2H), 3.98-3.89 (m, 2H). m/z [M+H] ⁺ 336.13.

7-Chloro-1-phenyl-4-(pyridin-2-ylamino)quinazolin-2(1H)-one was prepared using pyridin-2-amine.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 13.84 (br s, 1H), 8.51 (br d, J = 3.3 Hz, 1H), 8.42 (d, J = 8.3 Hz, 1H), 7.94-7.89 (m, 1H), 7.66-7.48 (m, 5H), 7.39-7.33 (m, 2H), 7.22 (dd, J = 5.5, 6.8 Hz, 1H), 6.31 (br s, 1H). m/z [M+H] ⁺ 349.12.

7-Chloro-1-phenyl-4-(pyridin-4-ylamino)quinazolin-2(1H)-one was prepared using pyridin-4-amine.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.16 (d, J = 9.4 Hz, 1H), 8.54-8.44 (m, 3H), 7.97 (dd, J = 3.5, 16.9 Hz, 2H), 7.65-7.60 (m, 2H), 7.58-7.52 (m, 1H), 7.42-7.35 (m, 3H), 6.37 (br s, 1H). m/z [M+H] ⁺ 349.12.

7-Bromo-4-(dimethylamino)-1-phenylquinazoline-2(1H)-one was prepared using 7-bromo-1-phenylquinazoline-2,4(1H,3H)-dione and dimethylamine.

^1H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 8.7 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.28 (s, 2H), 7.21 (d, J = 8.7 Hz, 1H), 6.72 (s, 1H), 3.38 (s, 6H). m/z [M+H] ⁺ 344.0.

4-(Dimethylamino)-7-fluoro-1-phenylquinazoline-2(1H)-one was prepared using 7-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione and dimethylamine.

^1H NMR (400 MHz, Chloroform-d) δ 7.89-7.82 (m, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.47 (t, J = 7 .3 Hz, 1H), 7.28 (s, 2H), 6.81 (t, J = 8.3 Hz, 1H), 6.23 (d, J = 10.6 Hz, 1H), 3.39 (s, 6H). m/z [M+H] ⁺ 284.1.

7-chloro-4-(dimethylamino)-1-(4-fluorophenyl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(4-fluorophenyl)quinazoline-2,4(1H,3H)-dione and dimethylamine.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (d, J = 8.7 Hz, 1H), 7.41 (dt, J = 17.4, 8.5 Hz, 4H), 7.21 (d, J = 8.7 Hz, 1H), 6.38 (s, 1H), 3.31 (s, 8H). m/z [M+H] ⁺ 318.0.

4-(Dimethylamino)-7-chloro-1-(5-fluoro-3-hydroxyphenyl)hydroquinazolin-2-one was prepared using 7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazolin-2,4(1H,3H)-dione and dimethylamine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.40 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz , 1H), 6.73 (d, J = 10.9 Hz, 1H), 6.66 (d, J = 8.9 Hz, 1H), 6.53 (s, 1H), 6.48 (s, 1H), 3.30 (s, 6H). m/z [M+H] ⁺ 334.0.

4-(azetidin-1-yl)-7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione and azetidine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 7.82 (d, J = 8.6 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 6.73 (d , J = 10.7 Hz, 1H), 6.63 (d, J = 9.3 Hz, 1H), 6.50 (s, 1H), 6.45 (s, 1H), 4.96-4.53 (m, 3H), 4.53-4.12 (m, 3H), 3.83 (s, 1H), 2.46-2.39 (m, 2H). m/z [M+H] ⁺ 346.0.

7-chloro-4-(cyclopropyl(methyl)amino)-1-(3-fluorophenyl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(3-fluorophenyl)quinazoline-2,4(1H,3H)-dione and N-methylcyclopropanamine

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.44 (d, J = 8.8 Hz, 1H), 7.64 (q, J = 7.7 Hz, 1H), 7.39 (t , J = 8.4 Hz, 1H), 7.30 (d, J = 9.7 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 6.37 (s, 1H), 3.52 (s, 1H), 3.22 (s, 3H), 0.91 (d, J = 6, 3 Hz, 2H), 0.68 (s, 2H). m/z [M+H] ⁺ 344.0.

4-Amino-7-chloro-1-(5-fluoro-3-hydroxyphenyl)hydroquinazoline-2-one was prepared using 7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione and ammonia (7 M solution in MeOH).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H), 8.07 (s, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 10.9 Hz, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.52 (s, 1H), 6.44 (s, 1H). m/z [M+H] ⁺ 306.0.

4-Amino-7-chloro-1-(4-fluorophenyl)hydroquinazolin-2-one was prepared using 7-chloro-1-(4-fluorophenyl)quinazolin-2,4(1H,3H)-dione and ammonia (7 M solution in MeOH).

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.16 (t, J = 8.5 Hz, 2H), 8.08 (s, 1H), 7.40 (p, J = 8.2, 7.7 Hz, 4H), 7.27 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H). m/z [M+H] ⁺ 290.0.

7,8-dichloro-4-(dimethylamino)-1-phenylquinazoline-2(1H)-one was prepared using 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione and dimethylamine.

¹ H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J = 35.1, 8.6 Hz, 1H), 7.47-7.41 (m, 1H), 7.41-7.36 (m, 2H), 7.32 (q, J = 8.9, 7.5 Hz, 3H), 3.36 (s, 6H). m/z [M+H] ⁺ 334.0.

7-Chloro-4-(dimethylamino)-8-methyl-1-phenylquinazoline-2(1H)-one was prepared using 7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione and dimethylamine.

¹ H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 8.7 Hz, 1H), 7.44-7.37 (m, 2H), 7.33 (dd, J = 15.5, 7.8 Hz, 3H), 7.20 (d, J = 8.8 Hz, 1H), 3.35 (s, 6H), 1.71 (s, 3H). m/z [M+H] ⁺ 314.0.

7-Chloro-4-(dimethylamino)-1-(o-tolyl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione and dimethylamine.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (bps, 1H), 8.15 (d, J = 12 Hz 1H), 7.44 (m, 3H), 7.31 (d, J = 8 Hz, 1H), 7.21 (d, J = 8 Hz, 1H), 6.21 (s, 1H), 3.01 (s, 3H).

7-Chloro-4-(dimethylamino)-1-(2-fluorophenyl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(2-fluorophenyl)quinazoline-2,4(1H,3H)-dione and dimethylamine.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (bps, 1H), 8.15 (d, J = 8 Hz 1H), 7.63-7.40 (m, 4H) , 7.34 (d, J = 8 Hz, 1H), 6.38 (s, 1H), 2.99 (s, 3H).

3-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)benzonitrile was prepared using 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile and dimethylamine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.06 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.93 (s , 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.7 Hz, 1H), 6.40 (s, 1H), 3.32 (s, 6H). m/z [M+H] ⁺ 325.1.

4-(Dimethylamino)-7-chloro-1-(3-methoxyphenyl)hydroquinazolin-2-one was prepared using 7-chloro-1-(3-methoxyphenyl)quinazolin-2,4(1H,3H)-dione and dimethylamine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.04 (d, J = 8.7 Hz, 1H), 7.51 (t, J = 8.1 Hz, 1H), 7.21 (d , J = 8.8 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.90 (s, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.39 (s, 1H), 3.79 (s, 3H), 3.30 (s, 8H). m/z [M+H] ⁺ 330.0.

7-Chloro-1-(3-methoxyphenyl)-4-(methylamino)hydroquinazolin-2-one was prepared using 7-chloro-1-(3-methoxyphenyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.65 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 7.50 (t, J = 8.0 Hz , 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.90 (s, 4H), 6.36 (s, 1H), 3.79 (s, 3H), 2.98 (d, J = 4.4 Hz, 3H). m/z [M+H] ⁺ 316.1.

7-Chloro-1-(3-fluorophenyl)-4-(methylamino)hydroquinazoline-2-one was prepared using 7-chloro-1-(3-fluorophenyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.64 (q, J = 7.7 Hz, 1H), 7.39 (t, J = 8.7 Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H), 2.98 (d, J = 4.2 Hz, 3H). m/z [M+H] ⁺ 304.1.

7-Chloro-4-(methylamino)-1-(3-methylphenyl)hydroquinazolin-2-one was prepared using 7-chloro-1-(m-tolyl)quinazolin-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.31-7.24 (m, 1H), 7.11 (s, 1H), 7.08 (d, J = 7.8 Hz, 1H), 6.32 (d, J = 1.9 Hz, 1H), 2.98 (d, J = 4.3 Hz, 3H). m/z [M+H] ⁺ 300.1.

7-Chloro-1-(3-chlorophenyl)-4-(methylamino)hydroquinazoline-2-one was prepared using 7-chloro-1-(3-chlorophenyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 (d, J = 4.9 Hz, 1H), 8.16-8.07 (m, 1H), 7.66-7.57 (m, 2H), 7.51 (t, J = 1.8 Hz, 1H), 7.31 (tt, J = 8.7, 1.8 Hz, 2H), 6.35 (t, J = 1.7 Hz, 1H), 2.98 (dd, J = 4.3, 1.7 Hz, 3H). m/z [M+H] ⁺ 320.0.

1-[7-Chloro-1-(3-fluorophenyl)-2-oxohydroquinazolin-4-yl]azetidine-3-carbonitrile was prepared using 7-chloro-1-(3-fluorophenyl)quinazoline-2,4(1H,3H)-dione and azetidine-3-carbonitrile.

¹ H NMR (400 MHz, MeCN-d ₃ ) δ 7.70 (d, J = 8.7 Hz, 1H), 7.63 (q, J = 7.7 Hz, 1H), 7.32 (t, J = 8.7 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.14 (t, J = 7.6 Hz, 2H), 6.57 (s, 1H), 4.77 (d, J = 34.8 Hz, 4H), 3.91-3.79 (m, 1H). m/z [M+H] ⁺ 355.10.

1-(3-Bromophenyl)-7-chloro-4-(dimethylamino)quinazoline-2(1H)-one was prepared using 1-(3-bromophenyl)-7-chloroquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.04 (d, J = 8.7 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.61 (s , 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 3.31 (s, 6H). m/z [M+H] ⁺ 378.0.

7-Chloro-4-((2-(dimethylamino)ethyl)amino)-1-phenylquinazolin-2(1H)-one was prepared using N ¹ ,N ¹ -dimethylethane-1,2-diamine.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (b.s, 1H), 8.23-8.08 (m, 2H), 7.62-7.40 (m, 3H), 7.29-7.18 (m, 3H), 6.26 (d, J = 1.8 Hz, 1H), 3.57 (br.s, 2H), 2.56 (br.t, J = 6.6 Hz, 2H), 2.23 (s, 6H). m/z [M+H] ⁺ 343.1.

7-Chloro-4-((2-(dimethylamino)ethyl)(methyl)amino)-1-phenylquinazolin-2(1H)-one was prepared using N ¹ ,N ¹ ,N ² -trimethylethane-1,2-diamine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.23 (bps, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.61-7.50 (m, 3H), 7.31 (d, J = 7.2 Hz, 2H), 7.20 (dd, J = 2.0, 8.8 Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H), 3.80 (brt, J = 6.5 Hz, 2H), 3.35 (s, 3H) , 2.64 (t, J = 6.5 Hz, 2H), 2.21 (s, 6H). m/z [M+H] ⁺ 357.1.

7-Methyl-4-(methylamino)-1-phenylpyrido[4,3-d]pyrimidin-2(1H)-one was prepared using 7-methyl-1-phenylpyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.10 (s, 1H), 8.82-8.75 (m, 1H), 7.60-7.55 (m, 2H), 7. 54-7.50 (m, 1H), 7.28 (d, J = 7.2 Hz, 2H), 6.13 (s, 1H), 2.99 (d, J = 4.5 Hz, 3H), 2.35-2.32 (m, 3H). m/z [M+H] ⁺ 267.3.

7-Methyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 7-methyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.59-8.56 (m, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.49-7.44 ( m, 2H), 7.40-7.35 (m, 1H), 7.21-7.17 (m, 2H), 7.11 (d, J = 8.1 Hz, 1H), 2.98 (d, J = 4.5 Hz, 3H), 2.29 (s, 3H). m/z [M+H] ⁺ 267.3.

7-Chloro-1-phenyl-4-(pyrrolidin-1-yl)quinazolin-2(1H)-one was prepared using pyrrolidine.

¹ H NMR (400 MHz, Chloroform-d ) δ 7.92 (d, J = 8.8 Hz, 1H), 7.59-7.54 (m, 2H), 7.50-7.46 (m, 1H), 7.29-7.27 (m, 2H), 7.05 (dd, J = 2.0, 8.8 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H), 3.97 (br t, J = 6.7 Hz, 4H), 2.07-2.02 (m, 4H). m/z [M+H] ⁺ 326.2.

7-Chloro-1-phenyl-4-(piperidin-1-yl)quinazolin-2(1H)-one was prepared using piperidine.

¹ H NMR (400 MHz, Chloroform-d) δ 7.64-7.54 (m, 3H), 7.52-7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.06 (dd, J = 2.0, 8.7 Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 3.79 (br s, 4H), 1.79 (br s, 6H). m/z [M+H] ⁺ 340.2.

4-Amino-7-chloro-1-phenylquinazolin-2(1H)-one was prepared using ammonia (7M solution in MeOH)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.17-8.02 (m, 3H), 7.60-7.47 (m, 3H), 7.33-7.18 (m, 3H), 6.29 (d, J = 1.8 Hz, 1H). m/z [M+H] ⁺ 272.1.

7-Chloro-4-methoxy-1-phenylquinazolin-2(1H)-one was prepared using methanol.

¹ H NMR (400 MHz, Chloroform-d): δ 7.94 (d, J = 8.6 Hz, 1H), 7.63-7.57 (m, 2H), 7.56-7.50 (m, 1H), 7.31-7.27 (m, 2H), 7.18-7.14 (m, 1H), 6.58 (d, J = 1.8 Hz, 1H), 4.21 (s, 3H). m/z [M+H] ⁺ 287.2.

7-Chloro-4-(3-hydroxyazetidin-1-yl)-1-phenylquinazolin-2(1H)-one was prepared using azetidin-3-ol.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.84 (d, J = 8.8 Hz, 1H), 7.62-7.57 (m, 2H), 7.54-7.49 (m, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.19 (dd, J = 2.0, 8.7 Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 5.01-3.69 (m, 5H). m/z [M+H] ⁺ 328.1.

(R)-7-Chloro-4-(3-fluoropyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one was prepared using (R)-3-fluoropyrrolidine.

^1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.59 (t, J = 7.6 Hz, 2H), 7.51 (t, J = 7.3 Hz, 1H), 7.28 (s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.59 (s, 1H), 5.39 (d, J = 52.3 Hz, 1H), 4.31-4.19 (m, 2H) , 4.19-4.09 (m, 2H), 2.48 (td, J = 14.4, 5.4 Hz, 1H), 2.26-2.04 (m, 1H). m/z [M+H] ⁺ 344.0.

7-Chloro-1-(3-fluorophenyl)-4-((3-hydroxypropyl)(methyl)amino)quinazolin-2(1H)-one was prepared using 3-(methylamino)propan-1-ol.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.04 (d, J = 8.8 Hz, 1H), 7.64 (q, J = 7.7 Hz, 1H), 7.39 (t , J = 8.0 Hz, 1H), 7.31 (d, J = 9.6 Hz, 1H), 7.21 (t, J = 8.5 Hz, 2H), 6.39 (s, 1H), 3.79-3.72 (m, 2H), 3.33 (s, 4H), 1.98-1, 87 (m, 2H). m/z [M+H] ⁺ 362.0.

7-Chloro-1-(2-chlorophenyl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 5.0 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 7.84-7.68 (m, 1H), 7.65-7.44 (m, 3H), 7.33 (d, J = 8.6 Hz, 1H), 6.22 (d, J = 2.3 Hz, 1H), 3.00 (d, J = 4.3 Hz, 3H). m/z [M+H] ⁺ 322.00.

1-(2-Bromophenyl)-7-chloro-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-chloro-1-(2-bromophenyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (d, J = 5.0 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.62-7.36 (m, 3H), 7.25 (d, J = 8.5 Hz, 1H), 6.12 (t, J = 1.7 Hz, 1H), 2.99-2.82 (m, 3H). m/z [M+H] ⁺ 366.00.

(R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one was prepared using (R)-3-hydroxypyrrolidine.

^1H NMR (400 MHz, DMSO- _d6 ) δ = 8.16 (d, J = 8.4 Hz, 1H), 7.61-7.58 (m, 2H), 7.54-7.53 (m, 1H), 7.52-7.51 (m, 2H), 7.19 (dd, J = 2.0, 8.8 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 5.11 (bs, 2H), 4.41 (s, 1H), 4.01-3, 85 (m, 3H), 3.66 (d, J = 12 Hz, 1H), 2.03-1.96 (m, 2H). m/z [M+H] ⁺ 342.19.

1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.12 (bps, 1H), 8.80 (d, J = 8.1 Hz, 1H), 7.81 (dd, J = 8, 1, 1.8 Hz, 1H), 7.71-7.58 (m, 1H), 7.47 (m, 3H), 3.04 (s, 3H).

4-(Methylamino)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 321.1

4-((2,2-difluoroethyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using 2,2-difluoroethane-1-amine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.14 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.6 Hz , 1H), 7.57-7.34 (m, 3H), 7.27 (d, J = 7.7 Hz, 1H), 6.60-6.07 (m, 2H), 3.97 (kv, J = 16.3 Hz, 2H), 1.96 (d, J = 2.0 Hz, 3H). m/z [M+H] ⁺ 384.00.

7-Cyclopropyl-4-(methylamino)-1-(o-tolyl)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.4 (d, J = 3.6 Hz, 1H), 7.96 (d, J = 6.8 Hz, 1H), 7.45-7.36 (m, 3H), 7.14 (d, J = 6.8 Hz, 1H), 6.80 (dd, J = 1.2, 6.8 Hz, 1H), 5.99 (d, J = 1.2 Hz, 1H), 2.96 (d, J = 3.6 Hz, 3H), 1.93 (d, J = 8.0 Hz, 3H), 0.91 (dd, J = 1.2, 6.4 Hz, 2H), 0.95-0.93 (m, 2H); LCMS: m/z [M+H] ⁺ 306.33.

6-Bromo-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 6-bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.85 (s, 1H), 8.64 (s, 1H), 7.60 (t, J = 7.4 Hz, 2H), 7.55 -7.50 (m, 1H), 7.33 (d, J = 7.5 Hz, 2H), 6.65 (s, 1H), 2.98 (s, 3H). m/z [M+H] ⁺ 398.0.

6-Bromo-1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.99 (s, 1H), 8.71 (s, 1H), 7.76 (d, J = 9.4 Hz, 1H), 7.62-7.52 (m, 3H), 6.52 (s, 1H), 3.00 (s, 3H). m/z [M+H] ⁺ 432.0.

7-Cyclopropyl-4-((2,2-difluoroethyl)amino)-1-phenylquinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-phenylquinazoline-2,4(1H,3H)-dione and 2,2-difluoroethane-1-amine.

^1H NMR (400 MHz, DMSO- _d6 ) δ = 8.71 (t, J = 4.0 Hz, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.60- 7.57 (m, 2H), 7.52-7.49 (m, 1H), 7.27 (d, J = 6.0 Hz, 2H), 6.84 (d, J = 6.0 Hz, 1H), 6.37-6.11 (m, 2H), 3.93-3.86 (m, 2H), 1.80 -1.77 (m, 1H), 0.95-0.91 (m, 2H), 0.58 (dd, J = 4.0, 4.8 Hz, 2H). m/z [M+H] ⁺ 342.35.

1-(3-Chloropyridin-2-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(3-chloropyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.22 (d, J = 3.2 Hz, 1H), 8.83 (d, J = 6.4 Hz, 1H), 8.59 (dd, J = 1.2, 3.6 Hz, 1H), 8.20 (dd, J = 1.2, 6.4 Hz, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7.59 (dd, J = 3.6, 6.4 Hz, 1H), 3.04 (d, J = 3.6 Hz, 3H). m/z [M+H] ⁺ 356.36.

4-(Methylamino)-1-(3-methylpyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(3-methylpyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ = 8.50 (d, J = 4.0 Hz, 1H), 8.14 (d, J = 6.4 Hz, 1H), 7.77 ( d, J = 5.2 Hz, 1H), 7.52 (b.s, 1H), 7.40-7.38 (m, 1H), 7.28 (s, 1H), 3.14 (d, J = 4.0 Hz, 3H), 2.16 (s, 3H). m/z [M+H] ⁺ 336.37.

7-Isopropyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 7-isopropyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.63 (d, J = 4.8 Hz, 1H), 8.37 (dd, J = 8.2, 2.3 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.41-7.30 (m, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.1, 1H), 2.98 (dd, J = 4.5, 2.3 Hz, 4H), 2.81 (p, J = 7.2 Hz, 1H), 1.00 (dd, J = 7.0, 2.3 Hz, 7H). m/z [M+H] ⁺ 295.1.

5-Fluoro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 5-fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.20 (dd, J = 12.4, 5.5 Hz, 1H), 7.62 (t, J = 7.5 Hz, 2H), 7 .58-7.50 (m, 2H), 7.35 (d, J = 7.6 Hz, 2H), 6.36 (s, 1H), 3.02 (s, 3H). m/z [M+H] ⁺ 338.1.

6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazoline-2(1H)-one was prepared using 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.67 (s, 1H), 8.43 (s, 1H), 7.77-7.67 (m, 1H), 7.56 (dt, J = 7.1, 2.1 Hz, 2H), 7.45 (dt, J = 6.6, 2.6 Hz, 1H), 5.75 (s, 1H), 2.05 (d, J = 8.0 Hz, 1H), 0.97 (d, J = 8.2 Hz, 2H), 0.26 (s, 2H). m/z [M+H] ⁺ 404.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrile was prepared using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile and cyclopropylmethanamine

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.83 (t, J = 5.1 Hz, 1H), 8.76 (s, 1H), 7.74 (d, J = 7.3 Hz , 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.49 (d, J = 7.5 Hz, 1H), 5.73 (s, 1H), 2.18-2.10 (m, 1H), 1.22-1.15 (m, 1H), 1.08 (d, J = 7, 4 Hz, 2H), 0.52 (d, J = 6.8 Hz, 2H), 0.44-0.37 (m, 2H), 0.31 (d, J = 3.9 Hz, 2H). m/z [M+H] ⁺ 391.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((oxetan-2-ylmethyl)amino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrile was prepared by replacing 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile and oxetan-2-ylmethanamine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.93 (s, 1H), 8.78 (s, 1H), 7.79-7.74 (m, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.52-7.46 (m, 1H), 5.74 (s, 1H), 5.01-4.92 (m, 1H), 4.60-4.44 (m, 3H), 3.84 (d, J = 15.7 Hz, 1H), 3.77-3.66 ( m, 1H), 3.50 (s, 1H), 2.14 (s, 1H), 1.07 (s, 2H), 0.40 (d, J = 7.1 Hz, 2H). m/z [M+H] ⁺ 407.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((2-(methylsulfonyl)ethyl)amino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrile was prepared using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile and 2-(methylsulfonyl)ethan-1-amine

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.00 (d, J = 5.9 Hz, 1H), 8.66 (s, 1H), 7.75 (dd, J = 6.6, 3.2 Hz, 1H), 7.63-7.54 (m, 2H), 7.52-7.46 (m, 1H), 5.76 (s, 1H), 3.91 (p, J = 7.3 Hz, 2H), 3.59-3.49 (m, 2H), 3.09 (s, 3H), 2.20-2.09 (m, 1H), 1.09 (d, J = 8.4 Hz, 2H), 0.42 (d, J = 6.4 Hz, 2H). m/z [M+H] ⁺ 443.1.

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1R,2S)-2-fluorocyclopropyl)amino)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione and (1R,2S)-2-fluorocyclopropan-1-amine

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.02 (dd, J = 8.6, 1.9 Hz, 1H), 7.59 (tdt, J = 49.6, 6.1, 2.9 Hz, 4H), 6.95 (d, J = 8.5 Hz, 1H), 6.17 (s, 1H), 4.80-4.55 (m, 1H), 3.10 (dt, J = 9.1, 6.3 Hz, 1H), 1.91-1.75 (m, 1H), 1.40-1.23 (m, 2H), 1.02 (d, J = 8.2 Hz, 2H), 0.62 (dp, J = 4.8, 2.3 Hz, 2H). m/z [M+H] ⁺ 370.0.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1-fluorocyclopropyl)methyl)amino)-5-methoxyquinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione and (1-fluorocyclopropyl)methanamine.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.58 (t, 1H), 7.71-7.69 (m, 1H), 7.55-7.53 (m, 2H), 7. 52-7.42 (m, 1H), 6.44 (d, J = 1.5 Hz, 1H), 5.61 (d, J = 1.5 Hz, 1H), 4.02-3.94 (m, 5H), 1.81-1.77 (m, 1H), 1.10-1.03 (m, 2H ), 0.94-0.92 (m, 4H), 0.62-0.60 (m, 2H). m/z [M+H] ⁺ 414.39.

4-Methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione and methanol

¹ H NMR (500 MHz, DMSO-d ₆ ): δ 8.66 (dd, J = 1.5 Hz, 1H), 8.25 (d, J = 8 Hz, 1H), 7.84 (dd, J = 1.5 Hz, 1H), 7.66 (dd, J = 1.0 Hz, 1H), 7.53-7.50 (m, 1H), 6.58 (s, 1H), 4.15 (s, 3H), 2.20 (s, 3H); LCMS. m/z [M+H] ⁺ 336.40.

1-(2-Chlorophenyl)-4-cyclopropoxy-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and cyclopropanol

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.58 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.71-7.68 (m, 1H), 7.55-7.52 (m, 3H), 4.67-4.64 (m, 1H), 1.02-0.94 (m, 4H). m/z [M+H] ⁺ 382.33.

1-(2-Chlorophenyl)-4-(((c, S)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazolin-2,4(1H,3H)-dione and trans-2-fluorocyclopropan-1-amine

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.59 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.77-7.73 (m, 1H) , 7.64-7.50 (m, 3H), 7.26 (d, J = 10.0 Hz, 1H), 6.10 (s, 1H), 4.96-4.82 (m, 1H), 3.48-3.42 (m, 1H), 1.55-1.47 (m, 1H), 1. 24-1.19 (m, 1H). m/z [M+H] ⁺ 414.39.

1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.74-7.72 (m, 1 H), 7.59-7.55 (m, 3 H), 7.45-7.28 (m, 1H), 6.56 (s, 1 H), 5.87 (s, 1 H), 3.01 (d, J = 4.5 Hz, 3 H), 1.86-1.82 (m, 1 H), 0.97-0.95 (m, 2 H), 0.61-0.59 (m, 2 H). m/z [M+H] ⁺ 392.3.

7-Cyclopropyl-5-ethyl-4-(methylamino)-1-(o-tolyl)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-5-ethyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 7.45-7.35 (m, 3H), 7.19 (s, 1H), 7.13-7.11 (m, 1H), 6.67 (s, 1H), 5.83 (d, J = 1.5 Hz, 1H), 3.13 (kv, J = 7.5 Hz, 2H), 3.00 (s, 3H), 1.91 (s, 3H), 1.74-1.70 (m, 1H), 1.23 (t, J = 7.5 Hz, 3H), 0.90-0.88 (m, 2H) , 0.52-0.50 (m, 2H). m/z [M+H] ⁺ 334.37.

1-(2-Chlorophenyl)-7-cyclopropyl-4-methoxyquinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione and methanol.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, J = 8.5 Hz 1H), 7.78-7.75 (m, 1H), 7.62-7.54 (m, 3H), 6.9 (dd, J = 8.5, 1.5 Hz, 1H), 6.15 (d, J = 1.5 Hz, 1H), 4.08 (s, 3H), 1.92-1.87 (m, 1H), 0.99-0.96 (m, 2H), 0.66-0.64 (m, 2H). m/z [M+H] ⁺ 327.16.

7-chloro-4-(methylamino)-1-(3-vinylphenyl)quinazoline-2(1H)-one was prepared using 7-chloro-1-(3-vinylphenyl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 312.26.

1-(2-Chlorophenyl)-4-(pyridin-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and pyridin-4-amine.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (br s, 1H), 8.57 (d, J = 5.3 Hz, 2H), 8.07-7.77 (m, 3H), 7.68 (m, 1H), 7.52 (m, 3H). m/z [M+H] ⁺ 418.00.

7-Bromo-6-chloro-1-(2-chlorophenyl)-4-(isoxazol-4-ylamino)quinazolin-2(1H)-one was prepared using 7-bromo-6-chloro-1-(2-chlorophenyl)quinazolin-2,4(1H,3H)-dione and isoxazol-4-amine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.71 (s, 1H), 9.46 (s, 1H), 8.89 (s, 1H), 8.66 (s, 2H), 7 .85-7.73 (m, 1H), 7.69-7.51 (m, 3H), 6.63 (s, 1H). m/z [M+H] ⁺ 452.9 (main).

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione and cyclopropylmethanamine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.77 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.07-7.88 (m, 2H) , 7.84 (d, J = 6.7 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 5.91 (s, 1H), 1.73 (s, 1H), 1.05 (s, 1H), 0.81 (d, J = 8.7 Hz, 2H), 0.47 ( m, 2H), 0.35 (d, J = 7.8 Hz, 2H), 0.16 (s, 2H). m/z [M+H] ⁺ 399.1.

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-1-(2-(difluoromethoxy)pyridin-3-yl)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione and cyclopropylmethanamine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.64 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.09 (d, J = 8.3 Hz , 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.74 (t, J = 73.3, Hz, 1H), 7.50 (m, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.15 (s, 1H), 1.88 (s, 1H), 1, 20 (s, 1H), 0.96 (d, J = 8.6 Hz, 2H), 0.63 (d, J = 14.2 Hz, 2H), 0.49 (d, J = 7.8 Hz, 2H), 0.30 (d, J = 4.5 Hz, 2H). m/z [M+H] ⁺ 401.1.

1-(2-chlorophenyl)-4-(((trans)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione and trans-2-fluorocyclopropan-1-amine.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 8.23 (d, J = 9.1 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 2H), 7.51 (s, 1H), 7.24 (d, J = 9.0 Hz, 1H), 6.10 (s, 1H), 1.52 (m, 1H), 1.22 (m, 1H), two missing protons are under the DMSO peak. m/z [M+H] ⁺ 414.0.

1-(2-Chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione and cyclopropylmethanamine.

^1H NMR (400 MHz, Methanol- _d4 ) δ 8.06 (d, J=8.4 Hz, 1H), 7.60-7.48 (m, 1H), 7.40 (dt, J= 6.2, 2.3 Hz, 2H), 7.26 (dd, J = 16.4, 7.1 Hz, 2H), 6.36 (s, 1H), 3.42-3.23 (m, 2H), 1.63 (t, J = 18.4 Hz, 3H), 1.12 (m, 1H), 0.40 (d, J = 7.7 Hz, 2H), 0.19 (d, J = 5.3 Hz, 2H). m/z [M+H] ⁺ 390.1.

4-(((1S,2R)-2-Fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione and (1S,2R)-2-fluorocyclopropan-1-amine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.79 (s, 1H), 8.46 (d, J=8.5 Hz, 1H), 7.69-7.49 (m, 4H) , 7.37 (d, J = 7.2 Hz, 2H), 6.57 (s, 1H), 5.01-4.73 (m, 1H), 1.45-1.17 (m, 2H). m/z [M+H] ⁺ 364.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.51 (s, 1H), 8.07-7.93 (m, 1H), 7.73 (dt, J = 5.9, 2.8 Hz, 1H), 7.62-7.39 (m, 3H), 6.82 (d, J = 8.5 Hz, 1H), 6.02 (s, 1H), 2.97 (t, J = 3.1 Hz, 3H), 1.81 (s, 1H), 0.94 (d, J = 8.4 Hz, 2H), 0.60 (s, 2H). m/z [M+H] ⁺ 326.0.

(R)-4-(2-(Hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using (R)-azetidin-2-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.49 (d, J = 8.1 Hz, 1H), 7.61 (dd, J = 8.2, 2.4 Hz, 1H), 7 .40-7.25 (m, 3H), 7.12 (d, J = 7.5 Hz, 1H), 5.26 (s, 1H), 4.94-4.50 (m, 3H), 3.96 (d, J = 11.5 Hz, 1H), 3.70 (dd, J = 11.9, 3.3 Hz, 2H), 2.57-2.46 (s, 1H), 2.43-2.31 (s, 1H), 1.92 (d, J= 16.3, 3H). m/z [M+H] ⁺ 391.1.

N-Methyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethane-1-sulfonamide was prepared using 2-amino-N-methylethane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.23 (s, 1H), 8.79 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.1 Hz , 1H), 7.38-7.24 (m, 3H), 7.17 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 3.86 (d, J = 20.3 Hz, 2H), 3.52-3.26 (m, 2H), 2.64 (s, 3H), 1, 93 (s, 3H). m/z [M+H] ⁺ 442.1.

N-Methyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)propane-1-sulfonamide was prepared using 3-amino-N-methylpropane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.04 (s, 1H), 8.85 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 8.2 Hz , 1H), 7.35-7.27 (m, 3H), 7.16 (d, J = 7.5 Hz, 1H), 6.98 (s, 1H), 3.74-3.58 (m, 2H), 3.20-3.12 (m, 2H), 2.59 (d, J = 2.5 Hz , 3H), 2.11-2.0 (m, 2H), 1.93 (d, J = 2.5 Hz, 3H). m/z [M+H] ⁺ 456.1.

N-Cyclopropyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethane-1-sulfonamide was prepared using 2-amino-N-cyclopropylethane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.24 (s, 1H), 8.78 (d, J = 7.3 Hz, 1H), 7.81 (d, J = 8.1 Hz , 1H), 7.67 (s, 1H), 7.40-7.25 (m, 3H), 7.16 (d, J = 7.6 Hz, 1H), 3.93-3.81 (m, 2H), 3.55-2.45 (m, 2H), 2.59-2.51 (m, 1H), 1 .93 (d, J = 2.6 Hz, 3H), 0.60 (t, J = 3.3 Hz, 4H). m/z [M+H] ⁺ 468.1.

4-(((1S,2R)-2-Fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using (1S,2R)-2-fluorocyclopropan-1-amine HCl and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.99 (s, 1H), 8.91 (d, J = 7.1 Hz, 1H), 7.79 (d, J = 8.6 Hz , 1H), 7.39-7.27 (m, 3H), 7.18 (t, J = 7.9 Hz, 1H), 4.91 (d, J = 64.8 Hz, 1H), 3.15-3.09 (m, 1H), 1.93 (s, 3H), 1.42-1.22 (m , 2H). m/z [M+H] ⁺ 379.1.

4-(((1R,2S)-2-Fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using (1R,2S)-2-fluorocyclopropan-1-amine HCl and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.99 (s, 1H), 8.91 (d, J = 7.1 Hz, 1H), 7.79 (d, J = 8.6 Hz , 1H), 7.39-7.27 (m, 3H), 7.18 (t, J = 7.9 Hz, 1H), 4.91 (d, J = 64.8 Hz, 1H), 3.15-3.09 (m, 1H), 1.93 (s, 3H), 1.42-1.22 (m , 2H). m/z [M+H] ⁺ 379.1.

N,N-dimethyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propane-1-sulfonamide was prepared using 3-amino-N,N-dimethylpropane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.87 (s, 1H), 8.44 (d, J = 7.7 Hz, 1H), 7.60 (d, J = 8.4 Hz , 1H), 7.53-7.36 (m, 3H), 7.26 (d, J = 7.4 Hz, 1H), 6.45 (s, 1H), 3.75-3.56 (m, 2H), 3.21 (t, J = 7.1 Hz, 2H), 2.80 (d, J = 2 .5 Hz, 6H), 2.15-2.03 (m, 2H), 1.95 (d, J = 2.5 Hz, 3H). m/z [M+H] ⁺ 469.1.

N,N-dimethyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamide was prepared using 2- amino-N,N-dimethylethane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.05 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.4 Hz , 1H), 7.50-7.40 (m, 3H), 7.26 (d, J = 7.5 Hz, 1H), 6.46 (s, 1H), 4.01-3.84 (m, 2H), 3.49-3.42 (m, 2H), 2.83 (s, 6H), 1.96 (d, J = 2.6 Hz, 3H). m/z [M+H] ⁺ 455.1.

Tert-butyl (R)-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)pyrrolidine-1-carboxylate was prepared using tert-butyl (R)-3-aminopyrrolidine-1-carboxylate and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 489.2

4-((2-(Morpholinosulfonyl)ethyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 2-(morpholinosulfonyl)ethan-1-amine and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.06 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.3 Hz , 1H), 7.52-7.38 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 6.46 (s, 1H), 4-3.84 (m, 2H), 3.65 (s, 4H), 3.55-3.46 (m, 2H), 3.25-3 .14 (m, 4H), 1.96 (s, 3H). m/z [M+H] ⁺ 497.1.

N-cyclopropyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamide was prepared using 2-amino-N-cyclopropylethane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.02 (s, 1H), 8.35 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.52-7.38 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 6.46 (s, 1H), 3.95-3.78 (m, 2H), 3.60-3.43 (m, 3H), 2.57 (d , J = 6.4 Hz, 1H), 1.96 (d, J = 2.7 Hz, 3H), 0.60 (t, J = 3.9 Hz, 4H). m/z [M+H] ⁺ 467.1.

(R)-4-(2-(Hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using (R)-azetidin-2-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.15-8.06 (m, 1H), 7.54-7.37 (m, 4H), 7.22 (d, J = 7.3 Hz, 1H), 6.44 (d, J = 7.1 Hz, 1H), 5.29 (s, 1H), 4.98-4.44 (m, 3H), 3.99-3.88 (m, 1H), 3.71 (d, J = 11.8 Hz, 1H), 2.57-2.45 ( m, 1H), 2.40-2.27 (m, 1H), 1.95 (dd, J = 16.3, 2.6 Hz, 3H). m/z [M+H] ⁺ 390.1.

4-(3-(Hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using azetidin-3-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.10 (d, J=8.5 Hz, 1H), 7.53-7.38 (m, 4H), 7.22 (d, J= 7.3 Hz, 1H), 6.44 (s, 1H), 5.07-4.79 (m, 2H), 4.65-4.48 (m, 1H), 4.37-4.23 (m, 1H), 4.13-3.99 (m, 1H), 3.69-3.60 (m, 2H ), 2.96-2.86 (m, 1H), 1.94 (s, 3H). m/z [M+H] ⁺ 390.1.

(R)-4-(2-(Methoxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (R)-2-(methoxymethyl)azetidine and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.08 (d, J=8.5 Hz, 1H), 7.56-7.38 (m, 4H), 7.23 (t, J= 7.6 Hz, 1H), 6.45 (d, J = 7.0 Hz, 1H), 5.03-4.68 (m, 2H), 4.64-4.40 (m, 1H), 3.96-3.86 (m, 1H), 3.71-3.62 (m, 2H), 2.61-2 .50 (m, 1H), 2.45-2.30 (m, 1H), 1.95 (d, J = 17.4 Hz, 3H). m/z [M+H] ⁺ 404.1.

4-((trans)-3,4-dihydroxypyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (3S,4S)-pyrrolidin-3,4-diol and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.51-8.37 (m, 1H), 7.53-7.39 (m, 4H), 7.25 (dd, J = 24.0, 7.5 Hz, 1H), 6.47 (d, J = 16.7 Hz, 1H), 5.40 (s, 2H), 4.54-3.85 (m, 4H), 3.82-3.54 (m, 2H), 1.95 (d, J = 34.0, 3H). m/z [M+H] ⁺ 406.1.

4-(((1R,2S)-2-fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1S,2R)-2-fluorocyclopropan-1-amine HCl and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.83 (s, 1H), 8.51 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.4 Hz , 1H), 7.53-7.38 (m, 3H), 7.28 (t, J = 8.9 Hz, 1H), 6.47 (s, 1H), 4.90 (d, J = 65.0 Hz, 1H), 3.15-3.05 (m, 1H), 1.96 (s, 3H), 1.49-1.18 (m, 2H). m/z [M+H] ⁺ 378.1.

4-(((1S,2R)-2-fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1R,2S)-2-fluorocyclopropan-1-amine HCl and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.83 (s, 1H), 8.51 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.4 Hz , 1H), 7.53-7.38 (m, 3H), 7.28 (t, J = 8.9 Hz, 1H), 6.47 (s, 1H), 4.90 (d, J = 65.0 Hz, 1H), 3.15-3.05 (m, 1H), 1.96 (s, 3H), 1.49-1.18 (m, 2H). m/z [M+H] ⁺ 378.1.

3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propane-1-sulfonamide was prepared using 3-aminopropane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.88 (bps, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8, 4 Hz, 1H), 7.50-7.37 (m, 3H), 7.21 (d, J = 7.5 Hz, 1H), 6.66 (bbs, 2H), 6.44 (s, 1H), 4.00-3.50 (m, 2H), 3.11 (t, J = 8.0 Hz, 2H ), 2.09 (t, J = 8.0 Hz, 2H), 1.92 (s, 3H). m/z [M+H] ⁺ 441.1.

N-Methyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propane-1-sulfonamide was prepared by replacing 3-(methylamino)propane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.88 (bps, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8, 5 Hz, 1H), 7.49-7.37 (m, 3H), 7.21 (d, J = 8.5 Hz, 1H), 6.68 (s, 1H), 6.44 (s, 1H), 4.0-3.5 (m, 2H), 3.13 (t, J = 7.9 Hz, 1H), 2.57 (s, 3H), 2.03 (t, J = 7.9 Hz, 1H), 1.92 (s, 3H). m/z [M+H] ⁺ 455.1.

2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamide was prepared using 2-aminoethane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.95 (bps, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8, 3 Hz, 1H), 7.50-7.39 (m, 3H), 7.21 (d, J = 7.4 Hz, 2H), 7.03 (b.s, 1H), 6.67 (b.s, 1H), 6.45 (s, 1H), 4.00-3.70 (m, 2H), 3.50 -3.35 (m, 2H), 1.93 (s, 3H). m/z [M+H] ⁺ 427.05.

N-methyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamide was prepared using 2-(methylamino)ethane-1-sulfonamide and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.96 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.5 Hz , 1H), 7.52-7.38 (m, 3H), 7.21 (d, J = 7.5 Hz, 1H), 6.67 (b.s, 1H), 6.45 (s, 1H), 4.00-3.75 (m, 2H), 3.48-3.34 (m, 2H), 2 .62 (s, 3H), 1.92 (s, 3H). m/z [M+H] ⁺ 441.1.

(S)-4-(2-(Hydroxymethyl)morpholino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using (S)-morpholin-2-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.14 (d, J = 8.5 Hz, 1H), 7.54-7.38 (m, 4H), 7.31-7.24 ( m, 1H), 6.51 (s, 1H), 4.91 (br.s, 1H), 4.43-4.16 (m, 2H), 4.00-3.93 (m, 1H), 3.79-3.59 (m, 2H), 3.56-3.45 (m, 2H ), 3.34-3.09 (m, 2H), 1.94 (s, 3H). m/z [M+H] ⁺ 420.1.

4-(3-Methoxyazetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 3-methoxyazetidine and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.09 (d, J=8.5 Hz, 1H), 7.52-7.39 (m, 3H), 7.22 (d, J= 7.4 Hz, 1H), 6.45 (s, 1H), 5.14-4.46 (m, 3H), 4.42-4.36 (m, 1H), 4.28-3.98 (m, 1H), 3.32 (s, 3H), 1.94 (s, 3H). m/z [M+H] ⁺ 390.1.

4-(4-methyl-3-oxopiperazin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-methylpiperazin-2-one and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.17 (d, J=8.4 Hz, 1H), 7.56-7.40 (m, 4H), 7.26 (d, J= 7.6 Hz, 1H), 6.50 (s, 1H), 4.49-4.35 (m, 2H), 4.21-4.09 (m, 1H), 4.08-3.99 (m, 2H), 2.93 (s, 3H), 1.95 (s, 3H). m/z [M+H] ⁺ 417.1.

4-(3-Hydroxyazetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using azetidin-3-ol and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.08 (d, J=8.7 Hz, 1H), 7.52-7.37 (m, 4H), 7.22 (d, J= 7.3 Hz, 1H), 6.45 (s, 1H), 6.01 (b.s, 1H), 5.15-4.85 (m, 1H), 4.69-4.39 (m, 3H), 4.22-3.90 (m, 1H), 1.94 (s, 3H). m/z [M+H] ⁺ 376.1.

1-(2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)azetidine-3-carbonitrile was prepared using azetidine-3-carbonitrile and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.02 (d, J=8.3 Hz, 1H), 7.55-7.37 (m, 4H), 7.22 (d, J= 7.4 Hz, 1H), 6.47 (s, 1H), 5.31-4.45 (m, 4H), 4.09-3.98 (m, 1H), 1.94 (s, 3H). m/z [M+H] ⁺ 385.1.

(3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propyl)sulfamide was prepared using 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.79 (s, 1H), 8.42 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 8.4 Hz , 1H), 7.52-7.37 (m, 3H), 7.25 (d, J = 7.5 Hz, 1H), 6.61 (bs, 1H), 6.54 (bs, 2H), 6.44 (s, 1H), 3.67-3.49 (m, 2H), 3.02 -2.97 (m, 2H), 1.95 (s, 3H), 1.89 (t, J = 7.3 Hz, 2H). m/z [M+H] ⁺ 456.1.

(2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethyl)sulfamide was prepared using 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.82 (b, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8, 4 Hz, 1H), 7.52-7.38 (m, 3H), 7.24 (d, J = 7.5 Hz, 1H), 6.74 (bs, 1H), 6.62 (bs, 2H), 6.45 (s, 1H), 3.76-3.60 (m, 2H), 3.27 -3.13 (m, 2H), 1.95 (s, 3H). m/z [M+H] ⁺ 442.1.

3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)propane-1-sulfonamide was prepared using 3-aminopropane-1-sulfonamide and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 6.0, 3.2 Hz, 1H), 7.56 (dt, J = 5.9, 3.0 Hz, 2H), 7.46 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 5.7 Hz, 3H), 6.03 (s, 1H), 3.72-3.50 (m, 2H), 3.09 (t, J = 8.2 Hz, 2H), 2.07 (t, J = 7.9 Hz, 2H), 1.87-1.76 (m, 1H), 0.95 (d, J = 8.4 Hz, 2H), 0.65-0.53 (m, 2H). m/z [M+H] ⁺ 433.1.

3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylpropane-1-sulfonamide was prepared using 3-amino-N-methylpropane-1-sulfonamide and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J = 5.4 Hz, 1H), 8.08-7.98 (m, 1H), 7.73 (dt, J = 6.2, 3.0 Hz, 1H), 7.56 (dt, J = 6.2, 3.1 Hz, 2H), 7.47 (dt, J = 5.8, 3.1 Hz, 1H), 6.96 (d, J = 4.7 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.03 (s, 1H), 3.71-3.50 (m, 2H), 3.17-3.08 (m, 2H), 2.58 (t, J = 3.8 Hz, 3H), 2.03 (kv, J = 7.5 Hz, 2H), 1.88-1.75 (m, 1H), 0.94 (d, J = 8.4 Hz, 2H), 0.66-0.52 (m, 2H). m/z [M+H] ⁺ 447.0.

2-((1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamide was prepared using 2-aminoethane-1-sulfonamide and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.61 (s, 1H), 8.01-7.91 (m, 1H), 7.73 (d, J = 5.9 Hz, 1H) , 7.56 (dd, J = 6.3, 3.3 Hz, 2H), 7.47 (s, 1H), 7.01 (s, 2H), 6.84 (d, J = 8.2 Hz, 1H), 6.04 (s, 1H), 3.96-3.81 (m, 2H), 3.40 (s, 2H), 1.90-1.76 (m, 1H), 0.95 (d, J = 8.3 Hz, 2H), 0.65-0.53 (m, 2H). m/z [M+H] ⁺ 419.0.

2-((1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylethane-1-sulfonamide was prepared using 2-amino-N-methylethane-1-sulfonamide and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 7.0 Hz, 1H), 8.00-7.91 (m, 1H), 7.74 (dt, J = 6.4, 3.0 Hz, 1H), 7.56 (dq, J = 7.0, 3.5 Hz, 2H), 7.47 (dt, J = 6.1, 3.2 Hz, 1H), 7.10 (d, J = 5.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.04 (s, 1H), 3.90-3.72 (m, 2H), 3.42 (t, J = 6.5 Hz, 2H), 2.63 (t, J = 3.8 Hz, 3H), 1.87-1.76 (m, 1H), 0.95 (d, J = 8.4 Hz, 2H), 0.68-0.53 (m, 2H). m/z [M+H] ⁺ 433.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(4-(hydroxymethyl)piperidin-1-yl)quinazoline-2(1H)-one was prepared using piperidin-4-ylmethanol and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 7.76-7.65 (m, 2H), 7.57 (dt, J = 5.9, 2.5 Hz, 2H), 7.47 ( dt, J = 5.8, 2.6 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.06 (s, 1H), 4.63 (s, 1H), 4.39-4.28 (m, 2H), 3.34 (s, 2H), 3.15 (d, J = 15.0 Hz, 2H), 1.87-1.78 (m, 1H), 1.82 (d, J = 13.0 Hz, 3H), 1.75 (s, 1H), 1.36 (q, J = 12.7, 12.3 Hz, 2H), 0.96 (d, J = 8.5 Hz, 2H), 0.65-0.50 (m, 2H). m/z [ M+H] ⁺ 410.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(3-hydroxypiperidin-1-yl)quinazoline-2(1H)-one was prepared using piperidin-3-ol and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 7.80 (t, J = 9.4 Hz, 1H), 7.73 (dt, J = 5.9, 2.6 Hz, 1H), 7 .65-7.53 (m, 2H), 7.50-7.43 (m, 1H), 6.81 (d, J = 8.5 Hz, 1H), 6.06 (s, 1H), 4.04 (t, J = 10.8 Hz, 1H), 3.90-3.68 (m, 2H), 3.37 -3.23 (m, 2H), 2.00-1.78 (m, 3H), 1.56 (dq, J = 19.3, 9.5 Hz, 2H), 0.96 (d, J = 8.6 Hz, 2H), 0.69-0.51 (m, 2H). m/z [M+H] ⁺ 396.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(3-hydroxyazetidin-1-yl)quinazoline-2(1H)-one was prepared using azetidin-3-ol and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 7.72 (dd, J = 6.9, 3.1 Hz, 2H), 7.56 (dt, J = 5.6, 2.5 Hz, 2H), 7.42 (d, J = 2.5 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.03 (s, 1H), 5.96 (bps, 1H), 5.09-4.72 (m, 1H), 4.74-3.88 (m, 3H) , 4.68-4.57 (m, 1H), 1.88-1.73 (m, 1H), 0.95 (d, J = 8.4 Hz, 2H), 0.64-0.46 (m, 2H). m/z [M+H] ⁺ 368.1.

(3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)propyl)sulfamide was prepared using 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (d, J = 5.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.72 (dt, J = 6.1, 2.8 Hz, 1H), 7.56 (dt, J = 5.9, 2.8 Hz, 2H), 7.45 (dt, J = 6.0, 2.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 6.3 Hz, 1H), 6.52 (s, 2H), 6.02 (s, 1H), 3.47-3.27 (m, 2H), 2.98 (d, J = 6.8 Hz, 2H), 1.91-1.76 (m, 3H), 0.94 (d, J = 8.4 Hz, 2H), 0.65-0.52 (m, 2H). m/z [M+H] ⁺ 448.1.

(3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)propyl)sulfamide was prepared using 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.49 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.73 (dt, J = 6.1, 2.8 Hz, 1H), 7.56 (dt, J = 6.0, 2.8 Hz, 2H), 7.50-7.43 (m, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.76 (t, J = 6.3 Hz, 1H), 6.62 (s , 2H), 6.02 (s, 1H), 3.75-3.54 (m, 2H), 3.18 (d, J = 6.5 Hz, 2H), 1.84-1.75 (m, 1H), 0.95 (d, J = 8.3 Hz, 2H), 0.64-0.53 (m, 2H). m/z [M+H] ⁺ 434.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((2-(difluoromethyl)pyridin-4-yl)amino)quinazoline-2(1H)-one was prepared using 2-(difluoromethyl)pyridin-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.61 (t, J = 4.2 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 8.21 (s , 2H), 7.78 (dt, J = 6.1, 3.2 Hz, 1H), 7.64-7.52 (m, 3H), 6.96 (s, 2H), 6.95 (d, J = 112 Hz, 1H), 6.13 (s, 1H), 1.94-1.83 (m, 1H) , 1.00 (d, J = 8.4 Hz, 2H), 0.71-0.59 (m, 2H). m/z [M+H] ⁺ 439.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-cyclopropylpyridin-4-yl)amino)quinazoline-2(1H)-one was prepared using 2-(cyclopropyl)pyridin-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.99 (s, 1H), 8.45-8.29 (m, 2H), 7.95-7.71 (m, 3H), 7. 66-7.49 (m, 3H), 6.95 (d, J = 8.4 Hz, 1H), 6.12 (s, 1H), 2.10-1.99 (m, 1H), 1.94-1.82 (m, 1H), 1.06-0.83 (m, 6H), 0.70-0 .57 (m, 2H). m/z [M+H] ⁺ 429.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-(difluoromethoxy)pyridin-4-yl)amino)quinazoline-2(1H)-one was prepared using 2-(difluoromethoxy)pyridin-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.25 (b, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 5, 7 Hz, 1H), 8.17 (d, J = 212 Hz, 1H), 7.81-7.70 (m, 2H), 7.64-7.48 (m, 3H), 6.96 (d, J = 8.5 Hz, 1H), 6.13 (s, 1H), 1.97-1, 82 (m, 1H), 1.00 (d, J = 8.4 Hz, 2H), 0.72-0.54 (m, 2H). m/z [M+H] ⁺ 455.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3-methyl-1,2,4-oxadiazol-5-yl)amino)quinazoline-2(1H)-one was prepared using 3-methyl-1,2,4-oxadiazol-5-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 12.14 (bps, 1H), 8.26 (dd, J = 8.3, 2.6 Hz, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.71-7.62 (m, 3H), 6.98 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H), 2.36 (d, J = 2.7 Hz, 3H), 1.97-1.84 (m, 1H), 1.02 ( d, J = 8.1 Hz, 2H), 0.73-0.54 (m, 2H). m/z [M+H] ⁺ 394.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((oxazol-5-ylmethyl)amino)quinazolin-2(1H)-one was prepared using oxazol-5-ylmethanamine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.97 (bps, 1H), 8.34 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7 .74 (b.s, 1H), 7.56 (b.s, 2H), 7.48 (b.s, 1H), 7.13 (bbs, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.04 (s, 1H), 4.90-4.63 (m, 2H ), 1.89-1.77 (m, 1H), 0.95 (d, J = 8.3 Hz, 2H), 0.67-0.54 (m, 2H). m/z [M+H] ⁺ 393.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((isoxazol-3-ylmethyl)amino)quinazolin-2(1H)-one was prepared using isoxazol-3-ylmethanamine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (b.s, 1H), 8.88 (s, 1H), 8.08 (dd, J = 8.5, 2.6 Hz, 1H), 7.72 (b.s, 1H), 7.60-7.53 (m, 2H), 7.48 (b.s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.60 (s, 1H), 6.06 (s, 1H), 4.95-4.70 ( m, 2H), 1.87-1.78 (m, 1H), 0.95 (d, J = 8.3 Hz, 2H), 0.69-0.52 (m, 2H). m/z [M+H] ⁺ 393.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((5-methylisoxazol-3-yl)amino)quinazoline-2(1H)-one was prepared using 5-methylisoxazol-3-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (b.s, 1H), 8.32 (b.s, 1H), 7.77 (b.s, 1H), 7.70- 7.51 (m, 3H), 6.90 (d, J = 8.5 Hz, 1H), 6.68 (b.s, 1H), 6.09 (s, 1H), 2.44 (s, 3H), 1.93-1.81 (m, 1H), 0.98 (d, J = 8.4 Hz, 2H), 0.73-0.55 (m, 2H). m/z [M+H] ⁺ 393.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)quinazoline-2(1H)-one was prepared using (1-methyl-1H-pyrazol-4-yl)methanamine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (br.s, 1H), 8.06 (dd, J = 8.6, 2.5 Hz, 1H), 7.73 (br.s., 1H). s, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.60-7.51 (m, 2H), 7.49-7.38 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 6.02 (s, 1H), 4.66-4.41 (m , 2H), 3.80 (s, 3H), 1.85-1.75 (m, 1H), 0.94 (d, J = 8.0 Hz, 2H), 0.64-0.52 (m, 2H). m/z [M+H] ⁺ 406.1.

1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-3-ylamino)quinazolin-2(1H)-one was prepared using isoxazol-3-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.86 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.77 (bps, 1H), 7 .66-7.53 (m, 3H), 6.90 (b.s, 1H), 6.89 (d, J = 8.6 Hz, 1H), 6.08 (s, 1H), 1.91-1.81 (t, J = 6.7 Hz, 1H), 0.97 (d, J = 8.4 Hz, 2H), 0.69-0.56 (m, 2H). m/z [M+H] ⁺ 379.05.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((5-methoxypyridin-3-yl)amino)quinazoline-2(1H)-one was prepared using 5-methoxypyridin-3-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (bs, 1H), 8.68 (bs, 1H), 8.36 (d, J = 8.4 Hz, 1H) , 8.13 (s, 1H), 7.98 (br.s, 1H), 7.76 (b.s, 1H), 7.65-7.51 (m, 3H), 6.94 (d, J = 8.4 Hz, 1H), 6.11 (s, 1H), 3.87 (s, 3H), 1.93-1.81 (m, 1H), 0.99 (d, J = 8.4 Hz, 2H), 0.70-0.57 (m, 2H). m/z [M+H] ⁺ 419.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((6-methylpyridin-3-yl)amino)quinazoline-2(1H)-one was prepared using 6-methylpyridin-3-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.03 (s, 1H), 8.79 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.64-7.46 (m, 3H), 7.31 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.10 (s, 1H), 2.48 (s, 3H), 1.91-1.81 (m, 1H), 0.98 (d, J = 8.3 Hz, 2H), 0.71-0.56 (m, 2H). m/z [M+H] ⁺ 403.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((6-methoxypyridin-3-yl)amino)quinazoline-2(1H)-one was prepared using 6-methoxypyridin-3-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.98 (s, 1H), 8.47 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.75 (dd, J = 6.3, 3.2 Hz, 1H), 7.62-7.46 (m, 3H), 6.92 (t, J = 7.6 Hz, 2H), 6.10 (s, 1H), 3.88 (s, 3H), 1.92-1.81 (m, 1H), 0.98 (d, J = 8.2 Hz, 2H), 0.70-0.55 (m, 2H). m/z [M+H] ⁺ 419.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((pyridin-4-ylmethyl)amino)quinazoline-2(1H)-one was prepared using pyridin-4-ylmethanamine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.13 (s, 1H), 8.54 (s, 2H), 8.13 (dd, J = 8.6, 2.6 Hz, 1H) , 7.76-7.68 (m, 1H), 7.55 (d, J = 3.2 Hz, 2H), 7.52-7.43 (m, 1H), 7.36 (s, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.06 (s, 1H), 4.91 -4.65 (m, 2H), 1.88-1.78 (m, 1H), 0.96 (d, J = 8.3 Hz, 2H), 0.69-0.52 (m, 2H). m/z [M+H] ⁺ 403.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((pyridin-3-ylmethyl)amino)quinazoline-2(1H)-one was prepared using pyridin-3-ylmethanamine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.08 (s, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 8.09 (dd, J = 8, 5, 2.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 3.2 Hz, 1H), 7.61-7.51 (m, 2H), 7.48 (d, J = 3.2 Hz, 1H), 7.42-7.36 ( m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.04 (s, 1H), 4.89-4.65 (m, 2H), 1.87-1.76 (m, 1H), 0.95 (d, J = 8.3 Hz, 2H), 0.66-0.54 (m, 2H). m/z [M+H] ⁺ 403.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((pyridin-2-ylmethyl)amino)quinazoline-2(1H)-one was prepared using pyridin-2-ylmethanamine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.12 (s, 1H), 8.54 (d, J = 3.6 Hz, 1H), 8.15 (dd, J = 8.6, 2.6 Hz, 1H), 7.84-7.68 (m, 2H), 7.58-7.52 (m, 2H), 7.46 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.05 (s, 1H), 4.95-4.72 (m, 2H), 1.89-1.77 (m, 1H), 0.96 (d, J = 8.3 Hz, 2H), 0.66-0.54 (m, 2H). m/z [M+H] ⁺ 403.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(pyrimidin-5-ylamino)quinazoline-2(1H)-one was prepared using pyrimidin-5-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.12 (s, 2H), 8.94 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.81 -7.69 (m, 1H), 7.62-7.55 (m, 2H), 7.56-7.48 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.76 (s, 2H), 6.09 (s, 1H), 1.91-1.82 (m, 1H), 0.99 (d, J = 8.3 Hz, 2H), 0.69-0.58 (m, 2H). m/z [M+H] ⁺ 390.05.

1-(2-Chlorophenyl)-7-isopropyl-4-(methylamino)pyrido[2,3-d]pyrimidine-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-isopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.72 (s, 1H), 8.40 (dd, J = 8.1, 2.2 Hz, 1H), 7.65-7.55 ( m, 1H), 7.50-7.40 (m, 2H), 7.41-7.33 (m, 1H), 7.17 (dd, J = 8.1, 2.3 Hz, 1H), 2.99 (s, 3H), 2.86-2.77 (m, 1H), 1.02-0.99 ( m, 6H). m/z [M+H] ⁺ 329.1.

1-(2-Chlorophenyl)-7-(difluoromethyl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(difluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.81 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.79-7.71 (m, 1H) , 7.61-7.54 (m, 2H), 7.54-7.48 (m, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.00 (td, J = 55.3, 2.2 Hz, 1H), 6.46 (s, 1H), 3.01 (s, 3H) . m/z [M+H] ⁺ 336.0.

1-(2-Chlorophenyl)-7-isopropyl-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-isopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.56 (s, 1H), 8.03 (d, J=7.0 Hz, 1H), 7.78-7.66 (m, 1H) , 7.60-7.51 (m, 2H), 7.48-7.41 (m, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.09 (s, 1H), 2.98 (s, 3H), 2.76 (p, J = 6.6 Hz, 1H), 1.05 (d, J = 6.7 Hz, 6H). m/z [M+H] ⁺ 328.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(pyridin-3-ylamino)quinazoline-2(1H)-one was prepared using 3-aminopyridine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.08 (s, 1H), 8.96 (s, 1H), 8.43-8.19 (m, 3H), 7.80-7, 71 (m, 1H), 7.64-7.40 (m, 4H), 6.94 (d, J = 8.4 Hz, 1H), 6.11 (s, 1H), 1.91-1.81 (m, 1H), 0.99 (d, J = 8.3 Hz, 2H), 0.69-0.58 (m, 2H). m/z [M+H] ⁺ 389.05.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(pyridin-4-ylamino)quinazoline-2(1H)-one was prepared using 4-aminopyridine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.09 (s, 1H), 8.53 (s, 2H), 8.39 (d, J = 8.5 Hz, 1H), 8.03 (b.s, 2H), 7.83-7.73 (m, 1H), 7.64-7.49 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 1.92-1.83 (m, 1H), 1.00 (d, J = 8 .3 Hz, 2H), 0.69-0.60 (m, 2H). m/z [M+H] ⁺ 389.05.

4-((1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)picolinonitrile was prepared using 4-aminopicolinonitrile and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.64 (d, J = 5.7 Hz, 1H), 8.44 (s, 1H), 8.31 (d, J = 8.5 Hz , 1H), 8.07 (s, 1H), 7.81-7.74 (m, 1H), 7.66-7.50 (m, 3H), 6.95 (d, J = 8.5 Hz, 1H), 6.12 (s, 1H), 1.92-1.83 (m, 1H) , 0.99 (d, J = 8.4 Hz, 2H), 0.69-0.58 (m, 2H). m/z [M+H] ⁺ 414.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-methoxypyridin-4-yl)amino)quinazoline-2(1H)-one was prepared using 2-methoxypyridin-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 8.36 (bps, 1H), 8.16-8.01 (m, 1H), 7.84- 7.73 (m, 1H), 7.67-7.49 (m, 5H), 6.95 (d, J= 8.3 Hz, 1H), 6.12 (s, 1H), 3.86, 4H), 1.93-1.82 (m, 1H), 0.99 (d, J = 8.5 Hz, 2H), 0.70-0.52 (m, 2H). m/z [M+H] ⁺ 419.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-morpholinopyridin-4-yl)amino)quinazoline-2(1H)-one was prepared using 2-morpholinopyridin-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.86 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 5.6 Hz , 1H), 7.82-7.69 (m, 1H), 7.62-7.41 (m, 5H), 6.94 (d, J = 8.5 Hz, 1H), 6.12 (s, 1H), 3.73 (s, 5H), 1.93-1.80 (m, 1H), 0.99 (d, J = 8.4 Hz, 2H), 0.68-0.56 (m, 2H). m/z [M+H] ⁺ 474.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-fluoropyridin-4-yl)amino)quinazoline-2(1H)-one was prepared using 2-fluoropyridin-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (b, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 5, 1 Hz, 1H), 7.83-7.73 (m, 2H), 7.82 (bs, 1H), 7.66-7.49 (m, 3H), 6.96 (d, J = 8.5 Hz, 1H), 6.13 (s, 1H), 1.92-1.82 (m, 1H) , 1.00 (d, J = 8.3 Hz, 2H), 0.70-0.58 (m, 2H). m/z [M+H] ⁺ 407.0.

1-(2-Chlorophenyl)-4-((2-chloropyridin-4-yl)amino)-7-cyclopropylquinazoline-2(1H)-one was prepared using 2-chloropyridin-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (b.s, 1H), 8.33 (d, J = 6.1 Hz, 2H), 8.16 (b.s, 1H) , 7.91 (b.s, 1H), 7.81-7.70 (m, 1H), 7.66-7.41 (m, 3H), 6.95 (d, J = 8.5 Hz, 1H), 6.12 (s, 1H), 1.93-1.80 (m, 1H) , 0.99 (d, J = 8.3 Hz, 2H), 0.72-0.54 (m, 2H). m/z [M+H] ⁺ 423.0.

1-(2-Chlorophenyl)-5-methoxy-4-(methylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 384.1

1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using cyclopropylmethanamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.01 (s, 1H), 8.49 (d, J = 8.5 Hz, 1H), 7.81-7.70 (m, 1H) , 7.67-7.54 (m, 4H), 6.44 (s, 1H), 3.50-3.25 (m, 1H), 1.28-1.15 (m, 1H), 0.52 (d, J = 7.8 Hz, 2H), 0.38-0.29 (m, 2H). m/z [M+H] ⁺ 394.1.

(R)-1-(2-Chlorophenyl)-7-(trifluoromethyl)-4-((1,1,1-trifluoropropan-2-yl)amino)quinazoline-2(1H)-one was prepared using (R)-1,1,1-trifluoropropan-2-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.03-8.92 (m, 1H), 8.66 (t, J = 7.3 Hz, 1H), 7.83-7.74 ( m, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.67-7.53 (m, 3H), 6.49 (s, 1H), 5.43 (hept, J = 7.6 Hz, 1H), 1.53-1.47 (m, 3H), 1.34-1.15 (m , 1H). m/z [M+H] ⁺ 436.0.

(trans)-3-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)cyclobutane-1-carbonitrile was prepared using trans-3-aminocyclobutane-1-carbonitrile and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (d, J = 6.3 Hz, 1H), 8.50 (d, J = 8.5 Hz, 1H), 7.81-7.74 (m, 1H), 7.70-7.53 (m, 4H), 6.44 (s, 1H), 4.93 (p, J = 7.6 Hz, 1H), 3.40-3.25 (m, 1H), 2.76-2.58 (m, 4H). m/z [M+H] ⁺ 419.05.

4-(isopropylamino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using isopropylamine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (d, J = 5.8 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 7.68-7.49 (m, 4H), 7.35 (d, J = 7.6 Hz, 2H), 6.54 (s, 1H), 4.55-4.45 (m, 1H), 1.29 (d, J = 6.2 Hz, 6H). m/z [M+H] ⁺ 348.1.

1-(2-Chlorophenyl)-4-(isopropylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using isopropylamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (d, J = 8.2 Hz, 2H), 7.81-7.73 (m, 1H), 7.66-7.53 (m, 4H), 6.43 (s, 1H), 4.52 (hept, J = 7.0 Hz, 1H), 1.35-1.25 (m, 6H). m/z [M+H] ⁺ 382.0.

1-(2-Chlorophenyl)-4-(cyclopropylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using cyclopropylamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.78 (s, 1H), 8.44 (d, J=8.5 Hz, 1H), 7.81-7.74 (m, 1H) , 7.65-7.51 (m, 3H), 6.68 (b.s, 1H), 6.43 (s, 1H), 3.18-3.08 (m, 1H), 0.85 (d, J = 7.4 Hz, 2H), 0.80-0.70 (m, 2H). m/z [M+H] ⁺ 380.0.

1-(2-Chlorophenyl)-4-(isoxazol-4-ylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using isoxazol-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 406.75.

1-(2-Chlorophenyl)-4-((1,3-difluoropropan-2-yl)amino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1,3-difluoropropan-2-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (d, J = 7.5 Hz, 1H), 8.62 (d, J = 8.5 Hz, 1H), 7.81-7.76 (m, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.65-7.56 (m, 3H), 6.47 (s, 1H), 5.06-4.89 (m, 1H), 4.89-4.62 (m, 4H). m/z [M+H] ⁺ 418.1.

1-(2-Chlorophenyl)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1R,2S)-2-fluorocyclopropan-1-amine HCl and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 7.84-7.75 (m, 1H), 7.69-7.53 (m, 4H), 6.46 (s, 1H), 4.90 (d, J = 65.0 Hz, 1H), 3.15-3.05 (m, 1H), 1.48-1.17 (m, 2H). m/z [M+H] ⁺ 398.05.

1-(2-Chlorophenyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1S,2R)-2-fluorocyclopropan-1-amine HCl and 1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 7.84-7.75 (m, 1H), 7.69-7.53 (m, 4H), 6.46 (s, 1H), 4.90 (d, J = 65.0 Hz, 1H), 3.15-3.05 (m, 1H), 1.48-1.17 (m, 2H). m/z [M+H] ⁺ 398.1.

4-((Cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using cyclopropylmethanamine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.91 (s, 1H), 8.44 (d, J = 8.9 Hz, 1H), 7.66-7.49 (m, 3H) , 7.35 (d, J = 7.6 Hz, 2H), 6.90 (bps, 1H), 6.55 (s, 1H), 3.38-3.26 (m, 2H), 1.31-1.16 (m, 1H), 0.51 (d, J = 7.7 Hz, 2H), 0. 36-0.26 (m, 2H). m/z [M+H] ⁺ 360.1.

7-isopropyl-4-(methylamino)-1-phenylquinazoline-2(1H)-one was prepared using 7-isopropyl-1-phenylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.46 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.58 (t, J = 7.0 Hz , 2H), 7.51 (d, J = 6.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 2H), 7.11 (d, J = 8.4 Hz, 1H), 6.20 (s, 1H), 2.97 (s, 3H), 2.73 (p, J = 7.1 Hz, 1H), 1.04 (d, J = 6.6 Hz, 6H). m/z [M+H] ⁺ 294.2.

4-((2,2-difluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 2,2-difluorocyclopropan-1-amine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.41 (s, 1H), 7.65-7.59 (m, 3H), 7.56 (t, J=7.7 Hz, 2H) , 7.35 (t, J = 7.6 Hz, 2H), 6.57 (d, J = 8.9 Hz, 1H), 6.18-5.87 (m, 1H), 3.78-3.65 (m, 1H), 2.15-2.06 (m, 1H), 1.94-1.82 ( m, 1H). m/z [M+H] ⁺ 382.05.

4-((1,3-difluoropropan-2-yl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1,3-difluoropropan-2-amine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J = 7.4 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 6.8 Hz, 3H), 7.56 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 7.6 Hz, 2H), 6.58 (s, 1H), 5.03-4.87 (m, 1H), 4.86-4.75 (m, 2H), 4.76-4.62 (m, 2H). m/z [M+H] ⁺ 384.1.

(R)-4-((1-Cyclopropylethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (R)-1-cyclopropylethan-1-amine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.43 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.45-7 .28 (m, 4H), 7.16 (s, 2H), 6.35 (s, 1H), 3.67 (kv, J = 7.6 Hz, 1H), 2.34-2.27 (m, 1H), 1.13 (d, J = 6.4 Hz, 3H), 0.99-0.87 ( m, 2H), 0.40-0.22 (m, 2H). m/z [M+H] ⁺ 374.1.

4-(((1-Fluorocyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1-fluorocyclopropyl)methanamine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.06 (d, J = 6.2 Hz, 1H), 8.53 (d, J = 8.5 Hz, 1H), 7.66-7 .49 (m, 4H), 7.36 (d, J = 7.6 Hz, 2H), 6.57 (s, 1H), 4.02 (dd, J = 21.5, 5.4 Hz, 2H), 1.07 (d, J = 19.0 Hz, 2H), 0.95 (d, J = 8.0 Hz, 2H). m/z [M+H] ⁺ 378.1.

4-((((trans)-2-(hydroxymethyl)cyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (trans-2-(aminomethyl)cyclopropyl)methanol and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.85 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 7.66-7.48 (m, 4H) , 7.35 (d, J = 7.6 Hz, 2H), 6.55 (s, 1H), 4.53 (s, 1H), 3.55-3.41 (m, 2H), 3.36-3.19 (m, 2H), 1.16-1.06 (m, 1H), 1.02-0.92 ( m, 1H), 0.52-0.35 (m, 2H). m/z [M+H] ⁺ 390.1.

1-(Imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.12 (s, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 9.1 Hz , 1H), 7.71-7.65 (m, 2H), 7.60 (s, 1H), 7.46 (t, J = 8.1 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H), 6.50 (s, 1H), 3.09-3.02 (m, 3H). m/z [M+H] ⁺ 360.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(methylamino)pyrido[2,3-d]pyrimidine-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 5.4 Hz, 1H), 7.48-7.40 (m, 2H), 7.34 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 2.99 (d, J = 4.3 Hz, 3H), 2.05-1.96 (m, 1H), 0.87-0.79 (m, 2H), 0.54-0.47 (m, 2H). m/z [M+H] ⁺ 327.1.

7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 7-cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.65 (d, J = 4.9 Hz, 1H), 8.59 (d, J = 7.4 Hz, 1H), 8.31 (d , J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 7.3 Hz, 1H), 2.99 (s, 3H), 2.06-1.97 (m, 1H), 0.89-0.82 (m, 2H), 0.64-0.56 (m, 2H). m/z [M+H] ⁺ 333.1.

7-Methoxy-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 7-methoxy-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.46 (d, J = 4.9 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 7.48 (t , J = 7.7 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.24 (d, J = 7.6 Hz, 2H), 6.64 (d, J = 8.6 Hz, 1H), 3.48 (s, 3H), 2.97 (d, J = 2.7 Hz , 3H). m/z [M+H] ⁺ 283.1.

1-(3-Chloropyridin-2-yl)-4-(methylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(3-chloropyridin-2-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.04 (s, 1H), 8.68 (d, J = 4.5 Hz, 1H), 8.40 (d, J = 8.4 Hz , 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.72-7.62 (m, 2H), 6.47 (s, 1H), 3.03 (d, J = 4.3 Hz, 3H). m/z [M+H] ⁺ 355.0.

4-(Methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2(1H)-one was prepared using 7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.04 (s, 1H), 8.93 (d, J = 4.7 Hz, 1H), 8.37 (d, J = 8.3 Hz , 1H), 8.18 (d, J = 8.1 Hz, 1H), 8.01 (t, J = 6.3 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 6.52 (s, 1H), 3.02 (s, 3H). m/z [M+H] ⁺ 389.1.

4-(Methylamino)-1-(pyrimidin-5-yl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(pyrimidin-5-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.34 (s, 1H), 9.01 (s, 1H), 8.94 (s, 2H), 8.36 (d, J = 8, 4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 6.80 (s, 1H), 3.03 (s, 3H). m/z [M+H] ⁺ 322.1.

(S)-1-Phenyl-7-(trifluoromethyl)-4-((1,1,1-trifluoropropan-2-yl)amino)quinazoline-2(1H)-one was prepared using (S)-1,1,1-trifluoropropan-2-amine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.88 (d, J = 8.2 Hz, 1H), 8.59 (d, J = 8.1 Hz, 1H), 7.68-7 .52 (m, 4H), 7.44-7.33 (m, 2H), 6.59 (s, 1H), 5.42 (s, 1H), 1.48 (d, J = 7.1 Hz, 3H). m/z [M+H] ⁺ 402.1.

4-((Oxetan-2-ylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using oxetan-2-ylmethanamine and 1-phenyl-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.96 (s, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.67-7.50 (m, 4H) , 7.35 (d, J = 7.5 Hz, 2H), 6.56 (s, 1H), 5.01 (p, J = 6.5 Hz, 1H), 4.61-4.44 (m, 2H), 3.92-3.71 (m, 2H), 2.69 (kV, J = 8.4, 6. 8 Hz, 1H), 2.52-2.42 (m, 1H). m/z [M+H] ⁺ 376.1.

4-(((1R,2S)-2-fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1R,2S)-2-fluorocyclopropan-1-amine HCl and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.79 (s, 1H), 8.47 (d, J=8.5 Hz, 1H), 7.67-7.49 (m, 4H) , 7.37 (s, 2H), 6.57 (s, 1H), 4.89 (d, J = 65.1 Hz, 1H), 3.13-3.02 (m, 1H), 1.45-1.18 (m, 2H). m/z [M+H] ⁺ 364.1.

4-(((trans)-2-fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using (trans)-2-fluorocyclopropan-1-amine HCl and 1-phenyl-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.66 (s, 1H), 8.31 (d, J=8.0 Hz, 1H), 7.69-7.51 (m, 4H) , 7.35 (d, J = 7.5 Hz, 2H), 6.56 (s, 1H), 4.88 (d, J = 63.1 Hz, 1H), 3.35-3.23 (m, 1H), 1.61-1.45 (m, 1H), 1.30-1.17 (m, 1H). m/z [M+H] ⁺ 364.1.

4-(((2,2-difluorocyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (2,2-difluorocyclopropyl)methanamine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.03 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.66-7.50 (m, 4H) , 7.35 (d, J = 7.6 Hz, 2H), 6.56 (s, 1H), 3.69-3.54 (m, 2H), 2.28-2.14 (m, 1H), 1.73-1.58 (m, 1H), 1.48-1.36 (m, 1H ). m/z [M+H] ⁺ 396.1.

(R)-4-((1-Hydroxypropan-2-yl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using (R)-2-aminopropan-1-ol and 1-phenyl-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.50 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 7.7 Hz, 1H), 7.64-7 .52 (m, 4H), 7.34 (d, J = 7.6 Hz, 2H), 6.55 (s, 1H), 4.90 (s, 1H), 4.45 (p, J = 6.8 Hz, 1H), 3.55 (d, J = 40 Hz, 1H), 1.24 (d, J = 6.6 Hz, 3H). m/z [M+H] ⁺ 364.1.

4-(oxetan-3-ylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using oxetan-3-amine and 1-phenyl-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.24 (s, 1H), 8.50 (d, J = 8.5 Hz, 1H), 7.61 (t, J = 7.5 Hz , 4H), 7.33 (d, J = 7.7 Hz, 2H), 6.56 (s, 1H), 5.16 (p, J = 6.5 Hz, 1H), 4.88 (t, J = 7.3 Hz, 2H), 4.70 (t, J = 6.4 Hz, 2H). m/z [M+H] ⁺ 362.1.

4-(((trans)-3-methoxycyclobutyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (trans)-3-methoxycyclobutan-1-amine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.80 (d, J = 6.3 Hz, 1H), 8.49 (d, J = 8.5 Hz, 1H), 7.64-7 .53 (m, 4H), 7.34 (d, J = 7.6 Hz, 2H), 6.54 (s, 1H), 4.77-4.62 (m, 1H), 4.12-4.00 (m, 1H), 3.20 (s, 3H), 2.44-2.31 (m, 4H) . m/z [M+H] ⁺ 390.1.

4-((3-Methoxypropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 3-methoxypropan-1-amine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.76 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.64-7.51 (m, 4H) , 7.35 (d, J = 7.6 Hz, 2H), 6.55 (s, 1H), 3.57 (kv, J = 6.8 Hz, 2H), 3.45 (t, J = 6.2 Hz, 2H), 3.28 (s, 3H), 1.91 (p, J = 7.1 Hz , 2H). m/z [M+H] ⁺ 378.1.

4-((2-Methoxyethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 2-methoxyethane-1-amine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J = 8.5 Hz, 1H), 7.64-7.51 (m, 4H), 7.35 (d, J = 7.6 Hz, 2H), 6.55 (s, 1H), 3.75-3.66 (m, 2H), 3.61 (t, J = 5.9 Hz, 2H), 3.32 (s, 3H). m/z [M+H] ⁺ 364.1.

4-((2-(Difluoromethoxy)ethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 2-(difluoromethoxy)ethan-1-amine and 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.41 (d, J=8.5 Hz, 1H), 7.67-7.51 (m, 4H), 7.36 (d, J= 7.6 Hz, 2H), 6.84 (d, J = 75.8 Hz, 1H), 6.56 (s, 1H), 4.17-4.07 (m, 2H), 3.82-3.73 (m, 2H). m/z [M+H] ⁺ 400.1.

7-Cyclopropyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 7-cyclopropyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.56 (d, J = 5.2 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.49-7 .35 (m, 3H), 7.16 (d, J = 7.6 Hz, 3H), 2.97 (d, J = 4.3 Hz, 3H), 1.98 (p, J = 6.6 Hz, 1H), 0.82 (d, J = 7.7 Hz, 2H), 0.54-0.46 (m, 2H). m/z [M+H] ⁺ 293.1.

(R)-4-(3-Hydroxypyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using (R)-pyrrolidin-3-ol and 1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.79 (bps, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.49 (m, 2H), 7 .41 (m, 2H), 7.24 (d, J = 7.6 Hz, 2H), 4.45 (s, 1H), 3.74 (m, 4H), 2.03 (t, J = 11.5 Hz, 2H).

1-(2-Bromophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(2-bromophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 9.13 (bbs, 1H), 8.81 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7.4 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.48-7.33 (m, 2H), 3.04 (s, 3H). m/z [M+H] ⁺ 401.0, 399.0.

1-(2-Fluorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(2-fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.79 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H) , 7.49 (m, 1H), 7.46-7.27 (m, 3H), 3.03 (s, 3H). m/z [M+H] ⁺ 339.1.

1-(2-chlorophenyl)-4-(pyridin-3-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using pyridin-3-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.19 (d, J = 8.2 Hz, 1H), 9.03 (s, 1H), 8.45 (d, J = 4.6 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.73-7.62 (m, 1H), 7.52 (d, J = 7.9 Hz, 4H). m/z [M+H] ⁺ 418.0.

1-(2-Chlorophenyl)-4-((1-methyl-1H-pyrazol-5-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-methyl-1H-pyrazol-5-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 9.05 (d, J = 8.2 Hz, 1H), 8.33 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.66 (m, 1H), 7.50 (m, 3H), 3.90 (s, 3H). m/z [M+H] ⁺ 421.0.

1-(2-chlorophenyl)-4-((1-methyl-1H-imidazol-4-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-methyl-1H-imidazol-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.82 (d, J = 7.7 Hz, 1H), 8.01 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H) , 7.68 (d, J = 6.4 Hz, 1H), 7.63-7.57 (m, 1H), 7.53 (dd, J = 5.9, 3.2 Hz, 3H), 7.44 (s, 1H), 3.76 (s, 3H). m/z [M+H] ⁺ 421.0.

1-(2-chlorophenyl)-4-((1-methyl-1H-pyrazol-3-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-methyl-1H-pyrazol-3-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 8.96 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.50 ( d, J = 27.4 Hz, 4H), 6.32 (s, 1H), 3.77 (s, 3H). m/z [M+H] ⁺ 421.0.

1-(2-chlorophenyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-methyl-1H-pyrazol-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 8.83 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.72-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.57-7.47 (m, 3H), 6.36 (s, 1H), 3.94 (s, 3H). m/z [M+H] ⁺ 421.0.

1-(2-chlorophenyl)-4-(isoxazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using isoxazol-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 11.09 (b.s, 1H), 9.50 (s, 1H), 9.02 (d, J = 8.2 Hz, 1H), 8.94 ( s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 6.1 Hz, 1H), 7.58-7.44 (m, 3H). m/z [M+H] ⁺ 408.0.

1-(2-Chlorophenyl)-4-((5-methylisoxazol-3-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using isoxazol-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.98 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.68-7.58 (m, 1H), 7.53 (s, 4H), 6.25 (s, 1H), 2.48 (s, 3H). m/z [M+H] ⁺ 422.05.

1-(2-Chlorophenyl)-4-((2-methylpyridin-4-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 2-methylpyridin-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.73 (d, J = 8.3 Hz, 1H), 7.91 (bs, 1H), 7.72 (d, J = 8.1, 1H ), 7.66 (d, J = 7.3 Hz, 1H), 7.60-7.38 (m, 3H), 6.70 (br.s, 1H), 6.65 (s, 1H), 2.47 (s, 3H).

1-(2-Chlorophenyl)-4-((2-methoxypyridin-4-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 2-methoxypyridin-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 448.1.

1-(2-Chlorophenyl)-7-(trifluoromethyl)-4-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 2-(trifluoromethyl)pyridin-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 9.07 (bs, 1H), 8.72 (bs, 1H), 8.49 (bs, 1H), 7.82 (bs , 1H), 7.65 (b.s, 1H), 7.59-7.42 (m, 4H). m/z [M+H] ⁺ 486.05.

1-(2-chlorophenyl)-4-(isothiazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using isothiazol-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 9.63 (s, 1H), 9.00 (d, J = 8.4 Hz, 1H), 8.93 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.72-7.61 (m, 1H), 7.59-7.38 (m, 3H). m/z [M+H] ⁺ 424.0.

7-ethyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 7-ethyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO) δ 8.61 (br, 1H), 8.37 (d, J = 8.2, 1H), 7.52-7.42 (m, 2H), 7.41-7.33 (m, 1H), 7.20 (d, J = 7.7 Hz, 2H), 7.13 (d, J = 8.0, 1H), 2.98 (d, J = 4.5, 3H), 2.56 (q, J = 7.6 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H). m/z [M+H] ⁺ 281.2.

7-Ethyl-4-(methylamino)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 7-ethyl-1-(o-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.63 (bps, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.30 (m, 3H), 7.11 ( m, 2H), 3.04-2.94 (s, 3H), 2.55 (kV, J = 7.7 Hz, 2H), 1.90 (s, 3H), 0.98 (t, J = 7.6, 3H). m/z [M+H] ⁺ 295.15.

1-(2-Chlorophenyl)-7-ethyl-4-(methylamino)pyrido[2,3-d]pyrimidine-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO) δ 8.72 (b.s, 1H), 8.40 (d, J = 8.2 Hz, 1H), 7.61 (b.s, 1H), 7, 50-7.41 (m, 2H), 7.37 (b.s, 1H), 7.16 (d, J = 8.2 Hz, 1H), 2.99 (s, 3H), 2.58 (kv, J = 7.6 Hz, 2H), 0.99 (t, J = 7.6 Hz, 3H). m/z [M+H] ⁺ 315.1.

7-ethyl-1-(2-fluorophenyl)-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(2-fluorophenyl)-7-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.28 (d, J = 8.0, 1H), 7.50 (m, 1H), 7.32 (m, 8.3 Hz, 2H), 7. 17 (d, J = 8.3, 1H), 3.14 (s, 3H), 2.79-2.59 (sq, J = 7.6 Hz, 2H), 1.33 (d, J = 6.6 Hz, 1H), 1.10 (t, J = 7.6 Hz, 3H). m/z [M+H] ⁺ 299.1.

7-Ethyl-4-(methylamino)-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one was obtained using 7-ethyl-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.60 (bps, 1H), 8.51 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.85 ( d, J = 8.3 Hz, 1H), 7.64 (m, 1H), 7.19 (d, J = 8.2 Hz, 1H), 3.15 (s, 3H), 2.70 (kv, J = 7.3 Hz, 2H), 1.33 (d, J = 6.6 Hz, 1H), 1.10 ( dd, J = 8.5, 6.7 Hz, 3H). m/z [M+H] ⁺ 282.15.

1-(2-chlorophenyl)-4-(cyclopropylamino)-7-(trifluoromethoxy)quinazolin-2(1H)-one were obtained using cyclopropylamine and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.21 (d, J = 8.7 Hz, 1H), 7.75 (m, 1H), 7.61 (m, 2H), 7.55-7.36 (m, 1H), 7.17 (d, J = 9.0 Hz, 1H), 6.24 (s, 1H), 3.17 (m, 1H), 0.95 (d, J = 7.2 Hz, 2H), 0.80 (m, 2H). m/z [M+H] ⁺ 396.0.

1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using cyclopropylmethanamine and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.28 (d, J = 8.8 Hz, 1H), 7.74 (m, 1H), 7.60 (m, 2H), 7.48 (m, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.25 (s, 1H), 3.53 (m, 2H), 1.40-1.19 (m, 1H), 0.60 (d, J = 7.7 Hz, 2H), 0.39 (m, 2H). m/z [M+H] ⁺ 410.0.

1-(2-chlorophenyl)-4-((2-methoxyethyl)amino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using 2-methoxyethane-1-amine and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.25 (d, J = 9.1 Hz, 1H), 7.74 (m, 1H), 7.67-7.57 (m, 2H), 7.49 (s, 1H), 7.20 (d, J = 9.2 Hz, 1H), 6.25 (s, 1H), 3.85 (m, 2H), 3.72 (m, 2H), 3.43 (s, 2H). m/z [M+H] ⁺ 414.0.

1-(2-Chlorophenyl)-4-(((trans)-3-hydroxycyclobutyl)amino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using trans-3-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.35 (d, J = 8.8 Hz, 1H), 7.81-7.66 (m, 1H), 7.65-7.53 (m, 2H ), 7.47 (m, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.24 (s, 1H), 4.53 (m, 1H), 2.63-2.40 (m, 4H). m/z [M+H] ⁺ 426.1.

1-(2-Chlorophenyl)-4-((2-hydroxyethyl)amino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using 2-aminoethan-1-ol and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.30 (d, J = 9.0, Hz, 1H), 7.75 (m, 1H), 7.69-7.58 (m, 2H), 7 .51 (m, 1H), 7.25 (d, J = 9.0 Hz, 1H), 6.28 (s, 1H), 3.92-3.86 (m, 2H), 3.86-3.76 (m, 2H). m/z [M+H] ⁺ 400.1.

1-(2-Chlorophenyl)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using (1R,2S)-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.38 (d, J = 9.0 Hz, 1H), 7.75 (m, 1H), 7.69-7, 49 (m, 3H), 7.25 (d, J = 8.8 Hz, 1H), 6.11 (s, 1H), 4.86 (d, J = 64.6 Hz, 1H), 3.06 (bsp, 1H), 1.38-1.24 (m, 1H), 1.19 (d, J = 6, 4 Hz, 1H). m/z [M+H] ⁺ 414.05.

1-(2-Chlorophenyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using (1S,2R)-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.38 (d, J = 9.0 Hz, 1H), 7.75 (m, 1H), 7.69-7, 49 (m, 3H), 7.25 (d, J = 8.8 Hz, 1H), 6.11 (s, 1H), 4.86 (d, J = 64.6 Hz, 1H), 3.06 (bsp, 1H), 1.38-1.24 (m, 1H), 1.19 (d, J = 6, 4 Hz, 1H). m/z [M+H] ⁺ 414.05.

1-(2-Chlorophenyl)-4-(isoxazol-4-ylamino)-7-(trifluoromethoxy)quinazolin-2(1H)-one was prepared using isoxazol-4-amine and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 8.90 (s, 1H), 8.50 (d, J = 8.5 Hz, 1H), 7.78 (m, 1H), 7.61 (m, 3H), 7.39 (d, J = 8.9 Hz, 1H), 6.18 (s, 1H). m/z [M+H] ⁺ 423.0.

1-(2-Chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using trans-2-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.31 (d, J = 9.0, 2.1 Hz, 1H), 7.74 (m, 1H), 7.67-7.54 (m, 2H), 7.48 (m, 1H), 7.21 (d, J = 9.0 Hz, 1H), 6.25 (s, 1H), 4.23 (m, 1H), 2.24 (m, 2H), 1.68 (m, 2H). m/z [M+H] ⁺ 426.1.

4-Amino-1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using ammonia in THF (2M) and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione

m/z [M+H] ⁺ 356.0.

1-(2-Chlorophenyl)-4-(cyclopropylamino)-7-(1,1-difluoroethyl)quinazoline-2(1H)-one was prepared using cyclopropanamine and 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.19 (d, J = 8.5 Hz, 1H), 7.74 (m, 1H), 7.60 (m, 1H), 7.49 (m, 1H), 7.41 (d, J = 8.5 Hz, 1H), 6.56 (s, 1H), 3.17 (b.s, 1H), 1.82 (t, J = 18.4 Hz, 2H), 1.31 (d, J = 6.4 Hz, 1H), 0.95 (d, J = 7, 2 Hz, 1H), 0.81 (m, 1H). m/z [M+H] ⁺ 376.1.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-((2-hydroxyethyl)amino)quinazoline-2(1H)-one was prepared using 2-aminoethan-1-ol and 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.22 (d, J = 8.5 Hz, 1H), 7.73 (m, 1H), 7.60 (m, 2H), 7.46 (m, 2H), 6.56 (s, 1H), 3.97-3.72 (m, 4H), 1.83 (t, J = 18.1, 3H). m/z [M+H] ⁺ 380.05.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-((2-methoxyethyl)amino)quinazoline-2(1H)-one was prepared using 2-methoxyethane-1-amine and 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.22 (d, J = 8.4 Hz, 1H), 7.84-7.69 (m, 1H), 7.60 (m, 2H), 7.46 (m, 2H), 6.56 (s, 1H), 3.94-3.80 (m, 2H), 3.73 (m, 2H), 3.43 (s, 3H), 1.83 (t, J = 18.4, 3H). m/z [M+H] ⁺ 394.05.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-3-hydroxycyclobutyl)amino)quinazoline-2(1H)-one was prepared using trans-3-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.32 (d, J = 8.5 Hz, 1H), 7.73 (m, 1H), 7.60 (m, 2H), 7.46 (m, 2H), 6.56 (s, 1H), 4.59-4.45 (m, 1H), 2.63-2.44 (m, 4H), 1.83 (t, J = 18.4, 3H). m/z [M+H] ⁺ 406.1.

7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.20 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.70-7.56 ( m, 3H), 7.50 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 7.1 Hz, 1H), 6.58 (s, 1H), 3.20 (s, 3H), 1.78 (t, J = 18.5, 3H). m/z [M+H] ⁺ 356.1.

4-(Cyclopropylamino)-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2(1H)-one was prepared using cyclopropylamine and 7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.29 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 9.3 Hz, 1H), 7.88 (m, 3H) , 7.50 (t, J = 8.5 Hz, 2H), 6.71 (s, 1H), 3.23 (m, 1H), 1.80 (t, J = 18.5, 3H), 0.98 (d, J = 7.4 Hz, 2H), 0.86 (m, 2H). m/z [M+H] ⁺ 382.2.

4-((Cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.35 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.92-7.79 (m , 3H), 7.54 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 3.68-3.48 (m, 2H), 1.81 (t, J = 18.5, 3H), 1.33 (m, 1H), 0 .62 (d, J = 7.7 Hz, 2H), 0.42 (m, 2H). m/z [M+H]⁺396.2.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(cyclopropylamino)quinazoline-2(1H)-one was prepared using cyclopropylamine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 7.95 (d, J = 8.5 Hz, 1H), 7.72 (m, 1H), 7.58 (m, 2H), 7.44 (m, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 3.12 (m, 1H), 1.83 (m, 1H), 1.01 (d, J = 8.2 Hz, 2H), 0.93 (d, J = 7.0 Hz, 2H), 0.78 (m, 2H), 0.61 (m, 2H). m/z [M+H] ⁺ 352.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 7.80 (d, J = 8.2 Hz, 1H), 7.50 (m, 1H), 7.37 (m, 2H), 7.22 (m, 1H), 6.74 (d, J = 8.5 Hz, 1H), 5.94 (s, 1H), 3.30 (m, 2H), 2.61 (m, 2H), 1.63 (m, 1H), 1.16-0.98 (m, 2H), 0.80 (d, J = 8.2 Hz, 2H), 0.43-0.32 (m, 2H), 0.17 (d, J = 4.5 Hz, 2H). m/z [M+H] ⁺ 366.1.

1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxyethyl)amino)quinazoline-2(1H)-one was prepared using 2-aminoethan-1-ol and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 7.97 (d, J = 8.5 Hz, 1H), 7.71 (m, 1H), 7.58 (m, 2H), 7.51-7.36 (m, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.15 (s, 1H), 3.84 (m, 2H), 3.78 (m, 2H), 1.83 (br s, 1H), 1.01 (d, J = 8.2 Hz, 2H), 0.62 (br s, 2H). m/z [M+H] ⁺ 356.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-methoxyethyl)amino)quinazoline-2(1H)-one was prepared using 2-methoxyethane-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 7.97 (d, J = 8.7 Hz, 1H), 7.72 (m, 1H), 7.58 (m, 2H), 7.44 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.15 (s, 1H), 3.93-3.76 (m, 2H), 3.71 (m, 2H), 3.42 (s, 3H), 1.84 (m, 1H), 1.01 (d, J = 7.9 Hz, 2H), 0.62 (br s, 2H). m/z [M+H] ⁺ 370.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((trans)-2-hydroxycyclobutyl)amino)quinazoline-2(1H)-one was prepared using trans-2-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.04 (d, J = 8.5 Hz, 1H), 7.81-7.66 (m, 1H), 7.58 (m, 2H), 7. 43 (m, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.15 (s, 1H), 4.21 (s, 1H), 2.23 (m, 2H), 1.84 (m, 1H), 1.68 (m, 2H), 1.02 (d, J = 8.3 Hz, 2H ), 0.62 (d, J = 4.8 Hz, 2H). m/z [M+H] ⁺ 382.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((1-methylcyclobutyl)amino)quinazoline-2(1H)-one was prepared using 1-methylcyclobutan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 7.99 (d, J = 9.1 Hz, 1H), 7.71 (m, 1H), 7.57 (m, 2H), 7.48-7, 26 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.12 (s, 1H), 2.46 (m, 2H), 2.31 (m, 2H), 1.94 (m, 2H), 1.83 (m, 1H), 1.72 (s, 3H), 1.00 (d , J = 8.1 Hz, 2H), 0.67-0.45 (m, 2H). m/z [M+H] ⁺ 380.15.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((R)-1-hydroxypropan-2-yl)amino)quinazoline-2(1H)-one was prepared using (R)-2-aminopropan-1-ol and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.05 (d, J = 8.4, 1H), 7.72 (m, 1H), 7.57 (m, 2H), 7.43 (m, 1H ), 6.94 (d, J = 8.5 Hz, 1H), 6.14 (s, 1H), 4.77-4.53 (m, 1H), 3.71 (m, 2H), 1.82 (m, 1H), 1.35 (d, J = 6.3 Hz, 3H), 1.01 (d, J = 8.1 Hz, 2H), 0.62 (s, 2H). m/z [M+H] ⁺ 370.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((S)-1-hydroxypropan-2-yl)amino)quinazoline-2(1H)-one was prepared using (S)-2-aminopropan-1-ol and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.05 (d, J = 8.4, 1H), 7.72 (m, 1H), 7.57 (m, 2H), 7.43 (m, 1H ), 6.94 (d, J = 8.5 Hz, 1H), 6.14 (s, 1H), 4.77-4.53 (m, 1H), 3.71 (m, 2H), 1.82 (m, 1H), 1.35 (d, J = 6.3 Hz, 3H), 1.01 (d, J = 8.1 Hz, 2H), 0.62 (s, 2H). m/z [M+H] ⁺ 370.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3-hydroxypropyl)amino)quinazoline-2(1H)-one was prepared using 3-aminopropan-1-ol and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 7.95 (d, J = 5.9, 1H), 7.71 (m, 1H), 7.58 (m, 2H), 7.44 (m, 1H ), 6.95 (d, J = 8.5 Hz, 1H), 6.15 (s, 1H), 3.72 (m, 4H), 1.96 (t, J = 6.7 Hz, 2H), 1.83 (s, 1H), 1.01 (d, J = 8.2 Hz, 2H), 0.71-0, 49 (m, 2H). m/z [M+H] ⁺ 370.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3-methoxypropyl)amino)quinazoline-2(1H)-one was prepared using 3-methoxypropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 7.91 (d, J = 8.5, 1H), 7.71 (bs, 1H), 7.58 (bs, 2H), 7.43 (b.s, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.15 (s, 1H), 3.72 (t, J = 7.2 Hz, 2H), 3.55 (t, J = 6.1, 2H), 3.38 (s, 3H), 2.02 (quint, J = 5, 9 Hz, 2H), 1.84 (d, J = 7.8 Hz, 1H), 1.01 (brs, 2H), 0.61 (d.kv, J = 4.8, 2.5 Hz, 2H). m/z [M+H] ⁺ 384.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)(methyl)amino)quinazoline-2(1H)-one was prepared using 1-cyclopropyl-N-methylmethanamine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 9.24 (s, 1H), 8.17 (d, J = 6.1 Hz, 1H), 7.74 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.24 (s, 1H), 2.44 (s, 2H), 1.88 (m, 1H), 1.05 (d, J = 8.4 Hz, 1H), 0.67 (m, 1H). m/z [M+H] ⁺ 380.15.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((5-methylisoxazol-4-yl)amino)quinazoline-2(1H)-one was prepared using 5-methylisoxazol-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 9.24 (s, 1H), 8.29-8.09 (m, 1H), 7.74 (d, J = 5.0 Hz, 1H), 7. 70-7.57 (m, 2H), 7.47 (d, J = 6.3 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.24 (s, 1H), 2.44 (s, 3H), 1.88 (brs, 1H), 1.05 (d, J = 8.4 Hz , 2H), 0.67 (b.s, 2H). m/z [M+H] ⁺ 393.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3-methylisoxazol-4-yl)amino)quinazoline-2(1H)-one was prepared using 3-methylisoxazol-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.7 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H) , 7.59 (d, J = 6.5 Hz, 3H), 7.46 (b.s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.22 (s, 1H), 2.50 (s, 3H), 1.87 (bps, 1H), 1.05 (d, J = 8.8 Hz, 2H), 0.65 (lat.s, 2H). m/z [M+H] ⁺ 393.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3,5-dimethylisoxazol-4-yl)amino)quinazoline-2(1H)-one was prepared using 3,5-dimethylisoxazol-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.12 (d, J = 8.7 Hz, 1H), 7.72 (bs, 1H), 7.59 (m, 2H), 7.46 ( br.s, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.23 (s, 1H), 2.41 (s, 3H), 2.26 (s, 3H), 1.88 (s, 1H), 1.05 (m, 2H), 0.75-0.50 (m, 2H). m/z [M+H] ⁺ 407.1.

4-(Methylamino)-1-(pyrazin-2-yl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(pyrazin-2-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.86 (s, 1H), 8.81 (d, J = 7.2 Hz, 2H), 8.25 (d, J = 8.5 Hz, 1H) , 7.60 (d, J = 8.5 Hz, 1H), 6.84 (s, 1H), 3.18 (d, J = 1.9 Hz, 3H). m/z [M+H] ⁺ 322.1.

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2(1H)-one was prepared using cyclopropylmethanamine and 7-cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.11 (m, 3H), 8.03 (s, 2H), 7.65 (d, J = 5.6 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.47 (s, 1H), 3.55 (m, 2H), 1.86 (s, 1H), 1.44-1.26 (m, 1H), 1.00 (d, J = 8.1 Hz, 2H), 0.70 (d, J = 5.9 Hz, 2H) , 0.61 (d, J = 7.9 Hz, 2H), 0.39 (m, 2H). m/z [M+H] ⁺ 372.15.

4-(Methylamino)-1-(pyridazin-3-yl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(pyridazin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 9.05 (bps, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.02 ( t, J = 6.6 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 3.04 (s, 3H). m/z [M+H] ⁺ 322.1.

7-Cyclopropyl-4-(isoxazol-4-ylamino)-1-(o-tolyl)quinazoline-2(1H)-one was prepared using isoxazol-4-amine and 7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 10.42 (bps, 1H), 9.47 (s, 1H), 8.88 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.54-7.36 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.09 (s, 1H), 1.96 (s, 3H), 1.82 (brs, 1H), 0, 97 (d, J = 8.4 Hz, 2H), 0.61 (br s, 2H). m/z [M+H] ⁺ 359.1.

7-Cyclopropyl-4-(isothiazol-4-ylamino)-1-(o-tolyl)quinazoline-2(1H)-one was prepared using thioisoxazol-4-amine and 7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.37 (s, 1H), 8.95 (s, 1H), 8.29 (s, 1H), 7.57- 7.32 (m, 3H), 7.22 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.10 (s, 1H), 1.96 (s, 3H), 1.83 (brs, 1H), 0.97 (d, J = 8.3 Hz , 2H), 0.62 (b.s, 2H). m/z [M+H] ⁺ 375.1.

1-(Imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using 1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.99 (bbs, 1H), 8.32 (d, J = 9.5 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.53 (t, J = 8.2 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 6.31 (s, 1H), 3.04 ( m, 3H). m/z [M+H] ⁺ 376.1.

4-((Cyclopropylmethyl)amino)-1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)-quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 9.03 (bbs, 1H), 8.43 (d, J = 9.0 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 7.1 Hz, 1H), 6.23 (s, 1H), 1.24 ( fifth, J = 6.7 Hz, 1H), 0.53 (d, J = 7.9 Hz, 2H), 0.34 (b.s, 2H). m/z [M+H] ⁺ 416.1.

7-Cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.57 (b.s, 1H), 8.41 (s, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.83 ( s, 1H), 7.50 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.16 (s, 1H), 2.98 (s, 3H), 1.87 (m, 1H), 0.95 (d, J = 8.7 Hz, 2H), 0.63 (m, 2H ). m/z [M+H] ⁺ 359.1.

7-Cyclopropyl-4-(methylamino)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.60 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.99 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 6.06 (s, 1H), 3.04-2.93 (m, 3H), 1.87 (m, 1H), 0.94 (d, J = 8.2 Hz, 2H), 0.61 (m, 2H). m/z [M+H] ⁺ 361.1.

4-Amino-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2(1H)-one was prepared using ammonia in THF (2M) and 7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 8.10-7.88 (m, 3H), 6.96 (d, J = 8.5 Hz, 1H), 6, 11 (s, 1H), 1.96-1.72 (m, 1H), 1.03 (dd, J = 3.4 Hz, 2H), 0.65 (d, J = 3.9 Hz, 2H). m/z [M+H] ⁺ 347.0.

7-Bromo-6-chloro-1-(2-chlorophenyl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO) δ 8.82 (b.s, 1H), 8.47 (s, 1H), 7.75 (m, 1H), 7.58 (m, 2H), 7. 52 (d, J = 4.6 Hz, 1H), 6.53 (s, 1H), 3.06-2.90 (s, 3H).m/z [M+H] ⁺ 399.9.

7-Bromo-6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 7-bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.73-7.56 (m, 3H), 6, 61 (s, 1H), 2.67 (br s, 1H), 1.26 (m, 4H). m/z [M+H] ⁺ 439.9.

6-Bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-4-ylamino)quinazolin-2(1H)-one was prepared using isoxazol-4-amine and 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 9.67 (s, 1H), 8.79 (s, 1H), 8.58 (s, 1H), 7.76 (m, 1H), 7.62 ( m, 2H), 7.49 (m, 1H), 6.04 (s, 1H), 2.22 (br.s, 1H), 1.06 (d, J = 8.1 Hz, 2H), 0.39 (bps, 2H).m/z [M+H] ⁺ 458.0.

6-Bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.74 (bps, 1H), 8.56 (s, 1H), 7.81-7.67 (m, 1H), 7.66-7.54 (m, 2H), 7.53-7.34 (m, 1H), 5.75 (s, 1H), 2.08 (s, 1H), 1.19 (s, 1H), 0.98 (d, J = 8.3 Hz, 2H), 0.51 (d, J = 7.7 Hz, 2H), 0.35 -0.22 (m, 4H).m/z [M+H] ⁺ 445.0.

4-Amino-6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2(1H)-one was prepared using ammonia in THF (2M) and 6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.21 (s, 1H), 7.72 (m, 1H), 7.65-7.53 (m, 2H), 7.44 (m, 1H), 5.97 (s, 1H), 2.23 (m, 1H), 1.13-0.96 (m, 2H), 0.39 (m, 2H). m/z [M+H] ⁺ 347.0.

(R)-6-Chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxypropyl)amino)quinazoline-2(1H)-one was prepared using (R)-2-aminopropan-1-ol and 6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 405.05.

(S)-6-Chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxypropyl)amino)quinazoline-2(1H)-one was prepared using (S)-2-aminopropan-1-ol and 6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 405.1.

5-fluoro-4-(((trans)-2-fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using trans-2-fluorocyclopropan-1-amine and 5-fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 7.86 (d, J = 12.2 Hz, 1H), 7.70-7.53 (m, 3H), 7.38 (bs, 2H), 6.39 (s, 1H), 4.92 (d, J = 64.9 Hz, 1H), 3.08 (br.s, 1H), 1.40 (br.d, J = 25.4 Hz, 1H), 1.27 (m, 1H). m/z [M+H] ⁺ 382.1.

4-((Cyclopropylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.70 (m, 1H), 7.56 (dt, J = 30.6, 7.5 Hz, 3H), 7.31 (d, J = 7.6 Hz, 2H), 7.09 (s, 1H), 6.81 (s, 1H), 6.14 (s, 1H), 4.13 (s, 3H), 1.26 (s, 1H), 0.50 (d, J = 7.8 Hz, 2H), 0.35 (d, J = 4.9 Hz, 2H). m/z [M+H] ⁺ 390.1.

4-((2-Hydroxyethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using 2-aminoethan-1-ol and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.56 (m, 2H), 7.31 (d, J = 7.5 Hz, 1H), 7.10 (s, 1H), 6.14 (s, 1H), 4.11 (d, J = 2.2 Hz, 3H), 3.71 (t, J = 6.2 Hz, 1H), 3.60 (t, J = 6.1 Hz, 1H). m/z [M+H] ⁺ 380.1.

5-Methoxy-4-((2-methoxyethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 2-methoxyethane-1-amine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 394.1.

(S)-4-((2-Hydroxypropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (S)-2-aminopropan-1-ol and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO) δ 8.72 (m, 1H), 7.68-7.45 (m, 3H), 7.31 (d, J = 7.5 Hz, 2H), 7. 11 (s, 1H), 6.15 (s, 1H), 5.12 (b.s, 1H), 4.11 (s, 3H), 4.03-3.90 (brs, 1H), 3.64 (dd, J = 12.6, 6.0 Hz, 1H), 1.16 (d, J = 6 ,3, 3H). m/z [M+H] ⁺ 394.1.

4-(((trans)-2-Hydroxycyclobutyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 406.1.

4-(((trans)-2-Fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 7.76-7.51 (m, 3H), 7.33 (d, J = 7.5 Hz, 2H), 7. 10 (s, 1H), 6.37 (s, 1H), 4.62 (m, 1H), 4.14 (s, 3H), 3.53 (m, 1H), 1.55 (m, 1H), 1.22 (m, 1H). m/z [M+H] ⁺ 394.05.

4-Amino-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using ammonia in THF (2M) and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 7.61 (m, 4H), 7.33 (d, J = 7.6 Hz, 2H), 7.11 (s, 1H), 6.36 (s, 1H), 4.62 (br s, 1H), 4.16 (s, 3H). m/z [M+H] ⁺ 336.0.

4-(((1S,2R)-2-Fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1S,2R)-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 7.71-7.54 (m, 3H), 7.35 (d, J = 7.4 Hz, 2H), 7.13 (s, 1H), 6, 39 (s, 1H), 4.28-4.18 (m, 1H), 4.15 (s, 3H), 4.06 (br.s, 1H), 3.90 (psv, J = 6.5 Hz, 1H), 1.34 (m, 1H), 1.14 (br.d, J = 26.1 Hz, 1H ). m/z [M+H] ⁺ 394.05.

4-(((1R,2S)-2-Fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (1R,2S)-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 7.71-7.54 (m, 3H), 7.35 (d, J = 7.4 Hz, 2H), 7.13 (s, 1H), 6, 39 (s, 1H), 4.28-4.18 (m, 1H), 4.15 (s, 3H), 4.06 (br.s, 1H), 3.90 (psv, J = 6.5 Hz, 1H), 1.34 (m, 1H), 1.14 (br.d, J = 26.1 Hz, 1H ). m/z [M+H] ⁺ 394.05.

4-(Isobutylamino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using sec-butylamine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 7.72-7.53 (m, 3H), 7.32 (d, J = 7.6 Hz, 2H), 7.12 (s, 1H), 6.36 (s, 1H), 4.18 (s, 3H), 3.53 (d, J = 7.1, 2H), 2.13 (pseudo q, J = 7.2 Hz, 1H), 1.06 (d, J = 6.9, 8H). m/z [M+H] ⁺ 392.15.

5-Methoxy-4-((oxazol-2-ylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using oxazol-2-ylmethanamine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.71-7.52 (m, 3H), 7.38-7.24 (d, J = 7.8 Hz, 2H ), 7.16 (d, J = 8.6 Hz, 2H), 6.38 (s, 1H), 5.03 (s, 2H), 4.20 (s, 3H). m/z [M+H] ⁺ 417.1.

4-((Isoxazol-4-ylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using isoxazol-4-ylmethanamine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 8.62 (s, 1H), 7.76-7.52 (m, 3H), 7.34 (d, J=7 .6 Hz, 2H), 7.11 (s, 1H), 6.36 (s, 1H), 4.74 (s, 2H), 4.17 (s, 3H). m/z [M+H] ⁺ 417.1.

5-Methoxy-4-((oxazol-4-ylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using oxazol-4-ylmethanamine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 8.05 (s, 1H), 7.71-7.54 (m, 3H), 7.33 (d, J=7 .6 Hz, 2H), 7.12 (s, 1H), 6.36 (s, 1H), 4.80 (s, 2H), 4.17 (1, 3H). m/z [M+H] ⁺ 417.1.

5-Methoxy-4-(((3-methoxyisoxazol-5-yl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (3-methoxyisoxazol-5-yl)methanamine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 7.74-7.51 (m, 3H), 7.33 (d, J = 7.6 Hz, 2H), 7.13 (s, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.93 (s, 3H), 4.19 (s, 3H), 3.93 (s, 3H). m/z [M+H] ⁺ 447.1.

4-((isoxazol-3-ylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using isoxazol-3-ylmethanamine and 1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.73-7.53 (m, 3H), 7.34 (d, J = 7.6 Hz, 2H), 7. 14 (s, 1H), 6.64 (s, 1H), 6.38 (s, 1H), 5.00 (s, 2H), 4.19 (d, J = 2.5 Hz, 3H). m/z [M+H] ⁺ 417.1.

7-cyclopropyl-4-((cyclopropylmethyl)amino)-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazolin-2(1H)-one was prepared using cyclopropylmethylamine and 7-cyclopropyl-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.78 (s, 1H), 7.83 (d, J = 8.5, 1H), 6.75 (d, J = 8.5 Hz, 1H), 5.97 (s, 1H), 3.31 (m, 2H), 1.68 (m, 1H), 1.08 (m, 1H), 0.82 (d, J = 8.5 Hz, 3H), 0.48 (m, 2H), 0.38 (d, J = 7.7 Hz, 2H), 0.18 (d, J = 5.0 Hz, 2H). m/z [M+H] ⁺ 402.1.

7-cyclopropyl-4-(methylamino)-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.81 (s, 1H), 7.73 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 5.98 (s, 1H), 2.95 (s, 3H), 1.69 (br.s, 1H), 0.83 (d, J = 8.5 Hz, 3H), 0.49 (b.s, 2H). m/z [M+H] ⁺ 362.1.

6-Bromo-4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 6-bromo-1-phenyl-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 7.62 (m, 3H), 7.35 (d, J = 7.6 Hz, 2H), 6.49 (s, 1H), 3.51 (d, J = 6.9, 2H), 1.30 (m, 1H), 0.60 (d, J = 7.7 Hz, 2H), 0.38 (m, 2H). m/z [M+H] ⁺ 456.1, 454.1.

6-Bromo-4-((cyclopropylmethyl)amino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 6-bromo-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.56-7.35 (m, 3H), 7.24 (d, J = 7.6 Hz, 1H), 6, 38 (s, 1H), 3.60-3.46 (m, 2H), 2.06 (d, J = 2.1 Hz, 3H), 1.30 (d, J = 6.7 Hz, 1H), 0.61 (d, J = 7.7 Hz, 2H), 0.38 (d, J = 5.0 Hz, 2H) . m/z [M+H] ⁺ 468.0, 470.0.

6-Bromo-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using 6-bromo-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.51 (s, 1H), 7.54-7.44 (m, 3H), 7.33 (d, J = 7.6 Hz, 1H), 6, 39 (s, 1H), 6.24 (s, 1H), 3.16 (s, 3H), 2.07 (s 3H). m/z [M+H] ⁺ 430.0, 428.0.

4-(((3-Methoxyisoxazol-5-yl)methyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (3-methoxyisoxazol-5-yl)methanamine and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.30 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.54-7.43 ( m, 2H), 7.26 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 6.18 (s, 1H), 3.94 (d, J = 2.6 Hz, 3H), 2.05 (d, J = 2.6 Hz, 3H). m/z [M+H] ⁺ 431.1.

(R)-4-(2-(Hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using (R)-pyrrolidin-2-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.43 (t, J = 10.3 Hz, 1H), 7.62-7.40 (m, 5H), 7.23 (dd, J = 19.6 , 7.7 Hz, 1H), 6.69 (d, J = 14.6 Hz, 1H), 4.15 (s, 2H), 4.04 (s, 1H), 3.85 (s, 1H), 2.27-1.97 (m, 6H). m/z [M+H] ⁺ 404.1.

(S)-4-(3-(Hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using (S)-pyrrolidin-3-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.48 (d, J = 8.7 Hz, 1H), 7.51 (q, J = 8.9, 7.9 Hz, 4H), 7.23 ( s, 1H), 6.69 (d, J = 5.8 Hz, 1H), 4.15 (s, 2H), 3.77-3.58 (m, 2H), 2.61 (s, 1H), 2.22 (s, 1H), 2.05 (dd, J = 12.3, 2.5 Hz, 3H) .m/z [M+H] ⁺ 404.1.

(R)-4-(3-(Hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using (R)-pyrrolidin-3-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.48 (d, J = 8.5 Hz, 1H), 7.66-7.38 (m, 4H), 7.23 (s, 1H), 6, 68 (d, J = 5.8 Hz, 1H), 4.15 (s, 2H), 3.69 (d, J = 12.9 Hz, 2H), 2.60 (s, 1H), 2.22 (s, 1H), 2.15-1.99 (m, 3H), 1.93 (s, 1H). m/z [M+H] ⁺ 404.1.

(R)-4-(2-(methoxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using (R)-2-(methoxymethyl)pyrrolidine and 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.49-8.22 (m, 1H), 7.50 (dt, J = 23.2, 7.9 Hz, 4H), 7.31-7.10 (m, 1H), 6.69 (d, J = 14.9 Hz, 1H), 4.93 (s, 1H), 4.20-4.03 (m, 2H), 3.88 (d, J = 8.8 Hz, 1H), 3.74 (d, J = 10.1 Hz, 1H), 3.40 (s , 3H), 2.18 (d, J = 7.1 Hz, 3H), 2.06 (dd, J = 30.0, 2.3 Hz, 4H). m/z [M+H] ⁺ 418.1.

4-(3-(2-Hydroxyethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using 2-(pyrrolidin-3-yl)ethan-1-ol and 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.48 (s, 1H), 7.61-7.37 (m, 4H), 7.23 (t, J = 8.2 Hz, 1H), 6.68 (d, J = 11.2 Hz, 1H), 3.71 (m, 2H), 2.49 (m, 1H), 2.30 (m, 1H), 2.05 (pseudo d, J = 23.1 Hz, 3H), 1.79 (m, 3H). m/z [M+H] ⁺ 418.1.

4-(Pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using pyrrolidine and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, MeOD) δ 8.96-8.75 (m, 1H), 7.63 (dd, J = 8.2, 2.5 Hz, 1H), 7.48-7.26 (m, 3H), 7.14 (d, J = 7.5 Hz, 1H), 4.04 (m, J = 61.3 Hz, 4H), 2.13 (m, 4H), 2.02 (d, J = 2.5 Hz, 3H). m/z [M+H] ⁺ 375.2.

(R)-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using (R)-pyrrolidin-2-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.83 (t, J = 10.0 Hz, 1H), 8.18 (s, 1H), 7.63 (dd, J = 8.4, 2.4 Hz, 1H), 7.47-7.28 (m, 3H), 7.14 (dd, J = 23.5, 7.7 Hz, 1H), 4.78 (s, 1H), 4.21-3.99 (m, 3H), 3.83 (ddt, J = 11.4, 5.9, 2.8 Hz , 1H), 2.19 (dd, J = 19.4, 10.9 Hz, 3H), 2.13-2.04 (m, 2H), 1.97 (d, J = 2.5 Hz, 2H). m/z [M+H] ⁺ 405.00.

(R)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using (R)-pyrrolidin-3-ylmethanol and 1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, MeOD) δ 8.86 (d, J = 8.3 Hz, 1H), 8.40 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H) , 7.46-7.25 (m, 3H), 7.14 (t, J = 7.1 Hz, 1H), 4.07 (m, 4H), 3.70 (m, 2H), 2.62 (m, 1H), 2.21 (m, 1H), 2.08-1.86 (m, 4H). m/z [M+H] ⁺ 405.00.

4-Amino-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2(1H)-one was prepared using ammonia (7 M solution in MeOH) and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.15-7.84 (m, 3H), 7.73 (dt, J = 6.1, 2.8 Hz, 1H), 7.62- 7.39 (m, 3H), 6.80 (d, J = 8.4 Hz, 1H), 6.02 (s, 1H), 1.91-1.73 (m, 1H), 0.94 (d, J = 8.4 Hz, 2H), 0.61 (d, J = 6.5 Hz, 2H). m/z [M+H] ⁺ 312.00.

1-(2-chlorophenyl)-7-cyclopropyl-4-(isopropylamino)quinazoline-2(1H)-one was prepared using isopropylamine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.12 (t, J = 9.1 Hz, 2H), 7.72 (q, J = 3.6, 2.2 Hz, 1H), 7 .63-7.39 (m, 3H), 6.82 (d, J = 8.4 Hz, 1H), 6.00 (s, 1H), 4.49 (kv, J = 6.8 Hz, 1H), 1.81 (s, 1H), 1.34-1.17 (m, 5H), 0.94 (d, J = 8.3 Hz, 2H), 0.59 (s, 2H). m/z [M+H] ⁺ 354.20.

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazoline-2(1H)-one was prepared using (1S,2R)-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.49 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.74 (hept, J = 4.0, 3.2 Hz, 1H), 7.63-7.40 (m, 3H), 6.84 (d, J = 8.4 Hz, 1H), 6.04 (s, 1H), 4.85 (d, J = 65.2 Hz, 1H), 3.63 (dt, J = 20.5, 6.8 Hz, 1H), 3.05 (d, J = 6.8 Hz, 1H), 1.90-1.73 (m, 1H), 1.45-1.14 (m, 3H), 0.95 (d, J = 8.3 Hz, 2H), 0.60 (d, J = 6.5 Hz, 2H). m/z [M+H] ⁺ 370.00.

1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-4-ylamino)quinazolin-2(1H)-one was prepared using isoxazol-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.48 (s, 1H), 9.43 (s, 1H), 8.89 (d, J = 1.9 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.85-7.42 (m, 4H), 6.95 (d, J = 8.4 Hz, 1H), 6.68 (s, 1H), 6.12 (s, 1H), 1.86 (kv, J = 7.6, 7.1 Hz, 1H) , 0.98 (d, J = 8.3 Hz, 2H), 0.66 (kv, J = 8.0, 6.6 Hz, 2H). m/z [M+H] ⁺ 379.00.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(isothiazol-4-ylamino)quinazolin-2(1H)-one was prepared using thioisoxazol-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.65 (s, 1H), 9.36 (s, 1H), 8.96 (s, 1H), 8.34 (d, J = 8, 5 Hz, 1H), 7.87-7.69 (m, 1H), 7.57 (ddt, J= 23.9, 5.8, 2.4 Hz, 3H), 6.96 (d, J = 8.3 Hz, 1H), 6.12 (s, 1H), 1.99-1.77 (m , 1H), 0.99 (d, J = 8.3 Hz, 2H), 0.66 (d, J = 6.8 Hz, 2H). m/z [M+H] ⁺ 395.00.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-(trifluoromethyl)pyridin-4-yl)amino)quinazoline-2(1H)-one was prepared using 2-(trifluoromethyl)pyridin-4-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 10.33 (s, 1H), 8.73 (d, J = 5.3 Hz, 1H), 8.56 (s, 1H), 8.41 (d, J=13.3 Hz, 2H), 7.79 (s, 1H), 7.59 (d, J= 17.1 Hz, 3H), 7.00 (d, J = 8.5 Hz, 1H), 6.17 (s, 1H), 1.91 (s, 1H), 1.01 (d, J = 8.4 Hz, 2H), 0.68 (s, 2H). m/z [M+H] ⁺ 457.00.

7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazolin-2(1H)-one was prepared using 7-cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, Methanol- _d4 ) δ 8.42 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.5, 2.1 Hz, 1H), 7 .70 (d, J = 9.2 Hz, 1H), 7.57-7.29 (m, 3H), 7.11-6.99 (m, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.10 (s, 1H), 3.05 (d, J = 2.1 Hz , 3H), 1.69 (t, J = 6.8 Hz, 1H), 0.86 (d, J = 8.7 Hz, 2H), 0.47 (d, J = 15.0 Hz, 2H). m/z [M+H] ⁺ 332.00.

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-1-(pyrazin-2-yl)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 7-cyclopropyl-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.79 (d, J = 2.8 Hz, 2H), 8.69 (d, J = 6.7 Hz, 1H), 8.09 (d , J = 8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.21 (s, 1H), 3.39 (d, J = 6.4 Hz, 3H), 1.87 (s, 1H), 1.20 (s, 2H), 0.95 (d, J = 7, 9 Hz, 2H), 0.65 (d, J = 5.1 Hz, 2H), 0.49 (d, J = 7.9 Hz, 2H), 0.31 (d, J = 4.9 Hz, 2H). m/z [M+H] ⁺ 334.20.

7-Cyclopropyl-4-(methylamino)-1-(3-methylpyrazin-2-yl)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(3-methylpyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO-d6) d 8.78-8.53 (m, 3H), 8.02 (dd, J = 8.4, 2.1 Hz, 1H), 6.84 (d , J = 8.5 Hz, 1H), 6.09 (s, 1H), 3.06-2.92 (m, 3H), 2.29 (d, J = 2.1 Hz, 3H), 1.87 (kv, J = 7.4 Hz, 1H), 0.94 (d, J = 6.8 Hz, 2H), 0. 65 (s, 2H). m/z [M+H] ⁺ 308.20.

7-cyclopropyl-4-((cyclopropylmethyl)amino)-1-(3-methylpyrazin-2-yl)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 7-cyclopropyl-1-(3-methylpyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.79-8.53 (m, 3H), 8.20-8.04 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.09 (s, 1H), 3.61 (dt, J = 38.2, 6.6 Hz, 2H), 3.44 (d, J = 7.8 Hz, 2H), 2.29 (d, J = 2.2 Hz, 3H), 1.86 (d, J = 7.3 Hz, 1H) , 1.82-1.68 (m, 1H), 1.64-1.51 (m, 1H), 1.22 (d, J = 8.0 Hz, 2H), 0.95 (t, J = 6.1 Hz, 2H), 0.66 (s, 2H), 0.50 (d, J = 7.9 Hz, 2H), 0.31 (d, J = 4.8 Hz, 2H). m/z [M+H] ⁺ 348.20.

7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.00 (d, J = 7.1 Hz, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 8.13-7.95 (m, 1H), 7.96-7.81 (m, 1H), 7.36 (d, J = 6.9 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.56 (s, 1H), 5.72 (kv, J = 12 ,2, 11.5 Hz, 1H), 4.44-4.22 (m, 1H), 3.92 (t, J = 6.8 Hz, 2H), 3.13-3.05 (m, 2H), 3.04-2.96 (m, 2H), 2.55 (d, J = 2.0 Hz, 1H), 2.36 (d, J = 12.5 Hz, 1H), 1, 87 (s, 1H), 1.24 (t, J = 7.0 Hz, 5H), 0.94 (d, J = 8.0 Hz, 2H), 0.70 (d, J = 5.1 Hz, 2H). m/z [M+H] ⁺ 332.00.

4-((Cyclopropylmethyl)amino)-5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2(1H)-one was prepared using cyclopropylmethylamine and 5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.94 (d, J=4.7 Hz, 1H), 8.45-8.28 (m, 1H), 8.20 (d, J= 8.4 Hz, 1H), 8.02 (t, J = 6.2 Hz, 1H), 7.66 (d, J = 11.8 Hz, 1H), 6.41 (s, 1H), 3.59-3.37 (m, 2H), 1.27 (s, 1H), 0.59-0.25 (m, 4H ). m/z [M+H] ⁺ 447.00.

5-fluoro-4-(methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2(1H)-one was prepared using 5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile was prepared by using (1S,2R)-2-fluorocyclopropan-1-amine instead of methylamine and using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile.

¹ H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 7.53 (d, J = 5.7 Hz, 1H), 7.46-7.35 (m, 2H), 7.29 (d, J = 6.2 Hz, 1H), 4.77 (d, J = 63.1 Hz, 1H), 2.37 (d, J = 4.4 Hz, 2H), 1.41-1.22 (m, 2H), 1.12-0.96 (m, 3H), 0.75 (d, J = 23.4 Hz, 2H). m/z [M+H] ⁺ 396.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile was prepared by using cyclopropylmethanamine instead of methylamine and using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile.

^1H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.50 (dd, J = 5.1, 1.8 Hz, 1H), 7.41-7.33 (m , 2H), 6.89 (s, 1H), 3.56-3.39 (m, 2H), 2.42-2.32 (m, 1H), 1.18-1.09 (m, 1H), 1.09-0.95 (m, 2H), 0.75 (d, J = 23.2 Hz, 2H), 0.56 (d, J = 7.0 Hz, 2H), 0.32-0.23 (m, 2H). m/z [M+H] ⁺ 392.1.

6-bromo-4-((cyclopropylmethyl)(methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared by using 1-cyclopropyl-N-methylmethanamine instead of methylamine and using 6-bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.56 (t, J = 7.3 Hz, 2H), 7.53-7.46 (m, 1H), 7.24 (s, 2H), 6.87 (s, 1H), 3.65 (d, J = 6.4 Hz, 2H), 3.45 (s, 3H), 1.26-1.14 (m, 1H), 0.68 (d, J = 7.4 Hz, 2H), 0.35 (d, J = 4 ,3 Hz, 2H). m/z [M+H] ⁺ 452.0, 454.0.

6-bromo-4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared by using cyclopropylmethanamine instead of methylamine and using 6-bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 7.55 (t, J = 7.3 Hz, 2H), 7.51-7.45 (m, 1H), 7.25-7.22 (m, 3H), 6.85 (s, 1H), 3.51 (d, J = 7.0 Hz, 2H), 1.22-1.11 (m, 1H), 0.57 (d, J = 7.1 Hz, 2H), 0.31 (d, J = 4.0 Hz, 2H). m/z [M+H] ⁺ 438.0, 440.0.

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1-(o-tolyl)-1,2-dihydroquinazoline-6-carbonitrile was prepared by using cyclopropylmethanamine instead of methylamine and using 7-cyclopropyl-2,4-dioxo-1-(o-tolyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.43-7.34 (m, 3H), 7.10 (d, J = 7.3 Hz, 1H), 5.90 (s, 1H), 3.56 (t, J = 7.9 Hz, 2H), 2.24-2.16 (m, 1H), 2.04 (s, 3H), 1.24-1.15 (m, 1H), 1.09 (d, J = 8.2 Hz, 2H), 0.65 (d, J = 7.5 Hz, 2H), 0.49 (d, J = 4.5 Hz, 2H), 0.35 (d, J = 4.5 Hz, 2H). m/z [M+H] ⁺ 371.2.

7-cyclopropyl-4-(methylamino)-2-oxo-1-(o-tolyl)-1,2-dihydroquinazoline-6-carbonitrile was prepared using 7-cyclopropyl-2,4-dioxo-1-(o-tolyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.43-7.31 (m, 3H), 7.12 (d, J = 6.9 Hz, 1H), 5.90 (s, 1H), 3.19 (s, 3H), 2.23-2.14 (m, 1H), 2.05 (s, 3H), 1.09 (d, J = 7.8 Hz, 2H), 0.52-0.45 (m, 2H). m/z [M+H] ⁺ 331.2.

1-(2-Chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared by using cyclopropylmethanamine instead of methylamine and using 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.08 (s, 1H), 9.01 (s, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.59 (dd, J = 8.6, 4.9 Hz, 3H), 6.45 (s, 1H), 3.49-3.40 (m, 2H), 1.96 (t, J = 19.1 Hz, 3H), 1.24-1.16 (m, 1H), 0.53 (d, J = 7.1 Hz, 2H), 0.36-0.30 (m, 2H). m/z [M+H] ⁺ 415.0.

1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.08 (s, 1H), 8.86 (s, 1H), 7.76 (d, J = 3.1 Hz, 1H), 7.63 -7.57 (m, 2H), 7.57-7.50 (m, 1H), 6.45 (s, 1H), 3.01 (s, 3H), 1.95 (t, J = 19.4 Hz, 3H). m/z [M+H] ⁺ 375.0.

6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazoline-2(1H)-one was prepared by using (1S,2R)-2-fluorocyclopropan-1-amine instead of methylamine and using 6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.88 (s, 1H), 8.76 (s, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.58 (s, 2H), 7.08 (s, 1H), 6.47 (s, 1H), 4.89 (d, J= 62.4 Hz, 1H), 3.10 (s, 1H), 1.96 (t, J = 19.2 Hz, 3H), 1.42-1.21 (m, 2H). m/z [M+H] ⁺ 472.0, 474.0.

6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.93 (s, 1H), 8.61 (s, 1H), 7.75 (dd, J = 5.4, 2.3 Hz, 1H) , 7.60-7.54 (m, 2H), 7.54-7.49 (m, 1H), 6.96 (s, 1H), 6.45 (s, 1H), 2.99 (s, 3H), 1.96 (t, J = 19.0 Hz, 3H). m/z [M+H] ⁺ 428.0, 430.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((2,2-difluoroethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using 2,2-difluoroethane-1-amine instead of methylamine and using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.10 (s, 1H), 8.75 (s, 1H), 7.75 (d, J = 6.5 Hz, 1H), 7.65 -7.54 (m, 2H), 7.50 (d, J = 6.6 Hz, 1H), 6.27 (t, J = 56.7 Hz, 1H), 5.76 (s, 1H), 3.95 (d.kv, J = 31.0, 15.5, 14.6 Hz, 2H), 2.16 (p , J = 7.0, 6.5 Hz, 1H), 1.09 (d, J = 7.3 Hz, 2H), 0.41 (s, 2H). m/z [M+H] ⁺ 401.1.

1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinazoline-6-carbonitrile was prepared by using cyclopropylmethanamine instead of methylamine and using 1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.18 (s, 1H), 9.12 (s, 1H), 7.78 (d, J = 4.2 Hz, 1H), 7.61 (d, J=8.6 Hz, 3H), 6.57 (s, 1H), 3.44 (d, J= 14.3 Hz, 2H), 1.26-1.14 (m, 1H), 0.54 (d, J = 7.3 Hz, 2H), 0.40-0.29 (m, 2H). m/z [M+H] ⁺ 419.0.

1-(2-chlorophenyl)-4-(methylamino)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinazoline-6-carbonitrile was prepared using 1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 8.97 (s, 1H), 7.78 (d, J = 4.7 Hz, 1H), 7.65-7.54 (m, 3H), 6.57 (s, 1H), 3.03 (s, 3H). m/z [M+H] ⁺ 379.0.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((1-(hydroxymethyl)cyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using (1-aminocyclopropyl)methanol instead of methylamine and using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.90 (s, 1H), 8.49 (s, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.57 (dd, J = 6.3, 2.4 Hz, 2H), 7.46 (d, J = 6.7 Hz, 1H), 5.71 (s, 1H), 4.98 (t, J = 4.5 Hz, 1H), 3.90-3.76 (m, 2H), 2.31 (dd, J = 20 ,7, 10.0 Hz, 4H), 2.19-2.09 (m, 1H), 1.90-1.74 (m, 2H), 1.08 (d, J = 7.0 Hz, 2H), 0.39 (s, 2H).

4-Amino-1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using ammonia instead of methylamine and using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹ H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.55 (dt, J = 15.5, 7.4 Hz, 2H), 7.37 (d, J = 7.3 Hz, 1H), 5.88 (s, 1H), 2.32-2.23 (m, 1H), 1.15 (d, J = 8.3 Hz, 2H), 0.59-0.49 (m, 2H). m/z [M+H] ⁺ 337.0.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((trans)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using (trans)-2-fluorocyclopropan-1-amine instead of methylamine and using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J = 12.0 Hz, 1H), 7.63 (d, J = 3.9 Hz, 1H), 7.50 (s, 2H), 7.43-7.31 (m, 1H), 5.85 (s, 1H), 5.01-4.75 (m, 1H), 3.45 (d, J = 16.0 Hz, 1H), 2.20 (s, 1H), 1.52 (d, J = 25.1 Hz , 2H), 1.27 (s, 1H), 1.11 (d, J = 7.2 Hz, 2H), 0.52 (s, 2H). m/z [M+H] ⁺ 395.0.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using (1S,2R)-2-fluorocyclopropan-1-amine instead of methylamine and using 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.75 (d, J = 11.5 Hz, 2H), 7.75 (d, J = 6.5 Hz, 1H), 7.58 (d , J = 8.3 Hz, 2H), 7.56-7.45 (m, 1H), 5.76 (s, 1H), 4.88 (d, J = 66.7 Hz, 1H), 3.09 (d, J = 7.3 Hz, 1H), 2.20-2.09 (m, 1H), 1, 40-1.20 (m, 2H), 1.09 (d, J = 8.0 Hz, 2H), 0.41 (s, 2H). m/z [M+H] ⁺ 395.0.

6-Bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazoline-2(1H)-one was prepared by using (1S,2R)-2-fluorocyclopropan-1-amine instead of methylamine and using 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.64-7.58 (m, 1H), 7.50-7.42 (m, 2H), 7.34 (d, J = 3.3 Hz, 1H), 6.16 (s, 1H), 5.93 (s, 1H), 4.85 (d, J = 63.8 Hz, 1H), 3.35 (s, 1H), 2.11 (p, J = 7.0 Hz, 1H), 1.33 (dd, J = 16 ,0, 7.5 Hz, 1H), 1.20-1.04 (m, 1H), 0.98 (d, J = 8.0 Hz, 2H), 0.46-0.36 (m, 2H). m/z [M+H] ⁺ 448.0/450.0.

7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.73 (d, J = 7.4 Hz, 2H), 8.23 (d, J = 8.6 Hz, 1H), 8.08 (s , 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.41 (d, J= 7.9 Hz, 1H), 6.85 (d, J = 7.1 Hz, 1H), 6.73 (s, 1H), 3.03-2.95 (m, 3H), 1.87 ( t, J = 19.0 Hz, 3H). m/z [M+H] ⁺ 356.0.

4-Amino-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2(1H)-one was prepared by using ammonia instead of methylamine and using 7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.72 (d, J = 7.4 Hz, 1H), 8.26 (d, J = 8.6 Hz, 2H), 8.15 (s , 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.72 (s, 1H), 1.87 (t, J = 19 ,1 Hz, 3H). m/z [M+H] ⁺ 342.1.

1-(3-Chloropyridin-2-yl)-7-(1,1-difluoroethyl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.93-8.84 (m, 1H), 8.67 (d, J=4.4 Hz, 1H), 8.28 (d, J= 8.6 Hz, 2H), 7.70-7.63 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 6.32 (s, 1H), 3.02 (d, J = 3.3 Hz, 3H), 1.88 (t, J = 19.0 Hz, 3H). m/z [M+H] ⁺ 351.0.

4-Amino-1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazoline-2(1H)-one was prepared by using ammonia instead of methylamine and using 1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.67 (d, J = 4.4 Hz, 1H), 8.41 (s, 1H), 8.30 (t, J = 8.9 Hz , 3H), 7.70-7.64 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.32 (s, 1H), 1.88 (t, J = 19.0 Hz, 3H). m/z [M+H] ⁺ 337.0.

1-(3-Chloropyridin-2-yl)-7-ethyl-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(3-chloropyridin-2-yl)-7-ethylquinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.61 (t, J = 5.8 Hz, 2H), 8.22 (d, J = 8.1 Hz, 1H), 8.02 (d , J = 8.6 Hz, 1H), 7.65-7.57 (m, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.02 (s, 1H), 2.96 (d, J = 3.9 Hz, 3H), 2.51 (s, 2H), 1.01 (t, J = 7.4 Hz, 3H). m/z [M+H] ⁺ 315.0.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.80-8.74 (m, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.76-7.70 ( m, 1H), 7.59-7.53 (m, 2H), 7.49 (d, J = 3.1 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 6.35 (s, 1H), 2.99 (d, J = 3.5 Hz, 3H), 1.85 (t, J = 18.9 Hz, 3H). m/z [M+H] ⁺ 350.1.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(isoxazol-4-ylamino)quinazolin-2(1H)-one was prepared by using isoxazol-4-amine instead of methylamine and using 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.44 (s, 1H), 8.88 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.79 -7.74 (m, 1H), 7.62-7.50 (m, 4H), 6.41 (s, 1H), 1.87 (t, J = 18.8 Hz, 3H). m/z [M+H] ⁺ 403.0.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(amino)quinazoline-2(1H)-one was prepared using ammonia instead of methylamine and using 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.34-8.24 (m, 2H), 8.18 (s, 1H), 7.76-7.70 (m, 1H), 7. 59-7.53 (m, 2H), 7.53-7.47 (m, 1H), 7.39 (d, J= 8.4 Hz, 1H), 6.34 (s, 1H), 1.85 (t, J = 18.9 Hz, 3H). m/z [M+H] ⁺ 336.1.

1-(2-Chlorophenyl)-4-(methylamino)-7-(trifluoromethoxy)quinazoline-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.78 (d, J = 3.5 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.76-7 .70 (m, 1H), 7.60-7.52 (m, 2H), 7.52-7.46 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.07 (s, 1H), 2.98 (d, J = 3.3 Hz, 3H). m/z [M+H] ⁺ 370.1.

7-Chloro-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-chloro-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.90 (s, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.76 (d, J = 8.3 Hz , 1H), 7.63 (s, 1H), 7.57 (s, 1H), 7.45-7.39 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 6.9 Hz, 1H), 6.33 (s, 1H), 3.01 (d, J = 3.5 Hz, 3H). m/z [M+H] ⁺ 326.0.

7-chloro-4-((2,2-difluoroethyl)amino)-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2(1H)-one was prepared by using 2,2-difluoroethane-1-amine instead of methylamine and using 7-chloro-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.97 (t, J = 6.2 Hz, 1H), 8.71 (d, J = 7.6 Hz, 1H), 8.21 (d , J = 8.9 Hz, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.64 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 7.0 Hz, 1H), 6.70 (s, 1H), 6.43-6.09 (m, 1H), 3.92 (t, J = 14.6 Hz, 2H). m/z [M+H] ⁺ 376.0.

7-chloro-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-chloro-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.70 (dd, J = 11.0, 5.5 Hz, 2H), 8.13 (s, 1H), 8.07 (s, 1H) , 7.68 (s, 1H), 7.62 (s, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H), 6.66 (s, 1H), 2.98 (d, J = 3.7 Hz, 3H). m/z [M+H] ⁺ 326.0.

7-bromo-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)quinazoline-2(1H)-one was prepared using 7-bromo-1-(2-chlorophenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 381.9/384.0.

(R)-1-(2-Bromophenyl)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)quinazoline-2(1H)-one was prepared using (R)-pyrrolidin-3-ol and 1-(2-bromophenyl)-7-chloroquinazoline-2,4(1H,3H)-dione.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (br s, 1H), 7.90-7.88 (m, 1H), 7.63-7.59 (m, 1H), 7.51-7.46 (m, 2H), 7.26-7.23 (m, 1H), 6.21 (dd, J = 4.4, 2.0 Hz, 1H), 5.13 (dd, J = 11.6, 3.2 Hz, 1H), 4.42 (s, 1H), 4.02-3.90 (m, 3H), 3.71-3.68 (m, 1H), 3.05-2.98 (m, 2H). m/z [M+H] ⁺ 420.0.

1-(2-Chlorophenyl)-4-(((trans)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one, a single enantiomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. Purification was performed by supercritical fluid chromatography (SFC) (20% MeOH, R,R WHELK-01, peak 1).

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.93 (d, J = 10.8 Hz, 1H), 8.77 (d, J = 8.0 Hz, 1H), 7.79 (d , J = 8.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.50-7.44 (m, 3H), 4.96-4.79 (m, 1H), 3.50-3.47 (m, 1H), 1.61-1.51 (m, 1H), 1.27-1 .24 (m, 1H). m/z [M+H] ⁺ 399.4.

1-(2-Chlorophenyl)-4-(((trans)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one, a single enantiomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. Purification was performed by supercritical fluid chromatography (SFC) (20% MeOH, R,R WHELK-01, peak 2).

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.93 (d, J = 10.8 Hz, 1H), 8.77 (d, J = 8.0 Hz, 1H), 7.79 (d , J = 8.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.50-7.44 (m, 3H), 4.96-4.79 (m, 1H), 3.50-3.47 (m, 1H), 1.61-1.51 (m, 1H), 1.27-1 .24 (m, 1H). m/z [M+H] ⁺ 399.4.

1-(2-Chloropyridin-3-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-(2-chloropyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.19 (s, 1H), 8.81 (s, J = 8.0 Hz, 1H), 8.50 (dd, J = 4.5 Hz , J = 1.5 Hz, 1H), 7.99 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.62 (m, 1H), 3.04 (s, 3H). m/z [M+H] ⁺ 356.3.

4-(Methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.20 (d, J = 4.5 Hz, 1H), 8.85-8.81 (m, 2H), 8.08 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 8.0, 4.5 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 3.04 (d, J = 4.5 Hz, 3H). m/z [M+H] ⁺ 390.4.

7-Cyclopropyl-1-(2-methylpyridin-3-yl)-4-((3-morpholinopropyl)amino)quinazoline-2(1H)-one was prepared using 3-morpholinopropan-1-amine and 7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.57 (dd, J = 5.0, 1.5 Hz, 1H), 8.46 (t, J = 5.5 Hz, 1H), 8 .03 (d, J = 8.5 Hz 1H), 7.66 (dd, J = 8.0, 1.5 Hz, 1H), 7.45-7.42 (m, 1H), 6.82 (dd, J = 8.5, 1.5 Hz, 1H), 6.03 (s, 1H), 3.58-3 .49 (m, 6H), 2.39-2.36 (m, 6H), 2.13 (s, 3H), 1.84-1.80 (m, 3H), 0.94-0.92 (m, 2H), 0.62-0.57 (m, 2H). m/z [M+H] ⁺ 420.31.

3-((7-Cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylpropanamide was prepared using 3-amino-N-methylpropanamide and 7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.74 (bps, 1H), 8.75 (dd, 4.8, 1.2 Hz 1H), 8.00 (d, J = 8 .8 Hz, 1H), 7.66 (dd, J = 8, 1.6 Hz, 1H), 7.47 (dd, 8,0,5,2 Hz, 1H), 6.83 (dd, J = 8.4, 1.2 Hz, 1H), 6.76 (brs, 1H), 6.13 ( s, 1H), 4.01 (t, J = 5.6 Hz, 2H), 2.83 (d, J = 4.8 Hz, 3H), 2.79 (t, J = 5.6 Hz, 2H), 2.40 (s, 3H), 1.79-1.75 (m, 1H), 1.07-1.02 (m, 2H), 0.69-0.65 (m, 2H). m/z [M+H] ⁺ 378.47.

2-((7-Cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N,N-dimethylethane-1-sulfonamide was prepared using 2 -amino-N,N-dimethylethane-1-sulfonamide and 7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.67 (t, J = 5.5 Hz, 1H), 8.60-8.58 (dd, J = 5.1.5 Hz, 1H) , 7.97 (d, J = 8.58.5 Hz, 1H), 7.69-7.67 (dd, J = 8.1.5 Hz, 1H), 7.49-7.47 (m, 1H), 6.87-6.85 (dd, J = 8.5,1.5 Hz, 1H), 3.90 -3.84 (m, 2H), 3.46-3.42 (m, 2H), 2.81 (s, 6H), 2.15 (s, 3H), 1.85-1.82 (m, 1H), 0.98-0.95 (m, 2H), 0.63-0.58 (m, 2H). m/z [M+H] ⁺ 428.49.

7-Cyclopropyl-4-((2-(dimethylamino)ethyl)amino)-1-(2-methylpyridin-3-yl)quinazoline-2(1H)-one was prepared using N1,N1-dimethylethane-1,2-diamine and 7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.57 (dd, J = 4.5, 1.5 Hz, 1H), 8.38 (t, J = 5 Hz, 1H), 8.03 (d, J = 8.5 Hz 1H), 7.66 (dd, J = 8.0, 1.5 Hz, 1H), 7.44 (dd, J = 8.0, 5 Hz, 1H), 6.83 (dd, J = 8.5, 1.5 Hz, 1H), 6.03 (s, 1H), 3.66-3.53 (m, 2H), 2.54-2.50 (m, 2 H), 2.23 (s, 6 H), 2.10 (s, 3H), 1.85-1.81 (m, 1H), 0.94-0.92 (m, 2H), 0.62-0.58 (m, 2H). m/z [MH] ⁺ 362.52.

3-((1-(2-Chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)-N-methylpropanamide was prepared using 3-amino-N-methylpropanamide and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.13 (s, 1H), 8.85 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 4.0 Hz , 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.65-7.63 (m, 1H), 7.49-7.43 (m, 3H), 3.72-3.72 (m, 2H), 2.60 (d, J = 4.5 Hz, 3H), 2.54-2 .52 (m, 2H). m/z [M+H] ⁺ 426.4.

2-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylethanesulfonamide was prepared using 2-amino-N,N-dimethylethane-1-sulfonamide and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ): δ 8.98 (bps, 1H), 8.85 (d, J = 10 Hz, 1H), 7.80 (d, J = 10 Hz, 1H), 7.64-7.61 (m, 1H), 7.49-7.43 (m, 3H), 3.69-3.65 (m, 2H), 3.58 (t, J = 5.5 Hz, 4H), 2.62 (d, J = 8.5 Hz, 2H), 2.5 (m , 4H).

4-(((trans)-2-fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one, a single enantiomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (40% MeOH, Chiralpak IC, peak 1).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.27 (s, 1H), 7.62-7.59 (m, 2H), 7.55-7.51 (m, 1H), 7. 33-7.31 (m, 2H), 7.07 (d, J = 1.0 Hz, 1H), 6.14 (d, J = 1.0 Hz, 1H), 5.01-4.86 (m, 1H), 4.08 (s, 3H), 3.43-3.41 (m, 1H), 1, 54-1.47 (m, 1H), 1.30-1.23 (m, 1H). m/z [M+H] ⁺ 394.4.

4-(((trans)-2-fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one, a single enantiomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (40% MeOH, Chiralpak IC, peak 2).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.27 (s, 1H), 7.62-7.59 (m, 2H), 7.55-7.51 (m, 1H), 7. 33-7.31 (m, 2H), 7.07 (d, J = 1.0 Hz, 1H), 6.14 (d, J = 1.0 Hz, 1H), 5.01-4.86 (m, 1H), 4.08 (s, 3H), 3.43-3.41 (m, 1H), 1, 54-1.47 (m, 1H), 1.30-1.23 (m, 1H). m/z [M+H] ⁺ 394.4.

7-Cyclopropyl-4-(methylamino)-2-oxo-1-(2-(trifluoromethyl)phenyl)-1,2-dihydroquinazoline-6-carbonitrile was prepared using 7-cyclopropyl-2,4-dioxo-1-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.79 (d, J = 4 Hz, 1H), 8.59 (s, 1H), 7.98 (d, J = 7.5 Hz, 1H ), 7.91 (t, J = 7.5 Hz, 1H), 7.78 (t, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 5.65 (s, 1H), 2.99 (s, 3H), 2.14-2.11 (m, 1H), 1, 08-1.03 (m, 2H),0.40-0.37 (dd, J = 10.5, 2 Hz, 2H). m/z [M+H] ⁺ 385.44.

7-Cyclopropyl-1-(2-cyclopropylphenyl)-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using 7-cyclopropyl-1-(2-cyclopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.69 (d, J = 4.0 Hz, 1H), 8.58 (s, 1H), 7.44-7.41 (m, 1H) , 7.36-7.33 (m, 1H), 7.16-7.11 (m, 2H), 5.76 (s, 1H), 2.98 (d, J = 4.0 Hz, 3H), 2.13-2.11 (m, 1H), 1.40-1.39 (m, 1H), 1, 09-1.04 (m, 2H), 0.79-0.71 (m, 2H), 0.59-0.57 (m, 1H), 0.36-0.31 (m, 3 H). m/z [M+H] ⁺ 357.40.

1-(2-Bromophenyl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile, a single atropisomer of unknown stereochemistry, was prepared using 1-(2-bromophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile. Purification by supercritical fluid chromatography (SFC) (30% MeOH, (R,R) WHELK-01, peak 1).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.79 (s, 1H), 8.60 (s, 1H), 7.88 (dd, 8.0, 1.0 Hz 1H), 7, 62-7.59 (m, 1H), 7.51-7.45 (m, 2 H), 5.71 (s, 1H), 2.98 (s, 3H), 2.16-2.11 (m, 1H), 1.09-1.05 (m, 2H), 0.42-0.39 (m, 2H ). m/z [M+H] ⁺ 395.41.

1-(2-Bromophenyl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile, a single atropisomer of unknown stereochemistry, was prepared using 1-(2-bromophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile. Purification by supercritical fluid chromatography (SFC) (30% MeOH, (R,R) WHELK-01, peak 2).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.79 (s, 1H), 8.60 (s, 1H), 7.88 (dd, 8.0, 1.0 Hz 1H), 7, 62-7.59 (m, 1H), 7.51-7.45 (m, 2 H), 5.71 (s, 1H), 2.98 (s, 3H), 2.16-2.11 (m, 1H), 1.09-1.05 (m, 2H), 0.42-0.39 (m, 2H ). m/z [M+H] ⁺ 395.41.

6-Bromo-7-cyclopropyl-4-(methylamino)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2(1H)-one was prepared using 6-bromo-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.92-8.91 (m, 1H), 8.75 (d, J = 4.0 Hz, 1H), 8.45 (s, 1H) , 8.10-8.08 (m, 1H), 7.98 (dd, J = 8.0, 5.0 Hz, 1H), 5.70 (s, 1H), 2.97 (d, J = 4.5 Hz, 3H), 2.10-2.05 (m, 1H), 0.99-0.95 (m , 2H), 0.35-0.28 (m, 2H). m/z [M+H] ⁺ 439.4.

6-Bromo-1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)quinazoline-2(1H)-one was prepared using 6-bromo-1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.75 (d, J = 4.5 Hz, 1H), 8.58 (dd, J = 5.0, 2.0 Hz, 1H), 8 .46 (s, 1H), 8.02 (dd, J = 8.0, 2.0 Hz, 1H), 7.67 (dd, J = 8.0, 5.0 Hz, 1H), 5.78 (s, 1H), 2.97 (d, J = 4.5 Hz, 3H), 2.11-2 .06 (m, 1H), 1.00-0.96 (m, 2H), 0.37-0.34 (m, 2H). m/z [M+H] ⁺ 405.2.

1-(2-Chlorophenyl)-6-(difluoromethyl)-4-(methylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(2-Chlorophenyl)-6-(difluoromethyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.19 (d, J = 4.5 Hz, 1H), 8.74 (s, 1H), 7.79-7.77 (m, 1H ), 7.62-7.56 (m, 3H), 7.27 (t, J = 53.5 Hz, 1H), 6.54 (s, 1H), 3.02 (d, J = 4.4 Hz, 3H). m/z [M+H] ⁺ 404.4.

1-(2-Chlorophenyl)-7-cyclopropyl-6-(difluoromethyl)-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(2-Chlorophenyl)-7-cyclopropyl-6-(difluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.81 (d, J = 4.4 Hz, 1H), 8.36 (s, 1H), 7.75-7.73 (m, 1H) , 7.58-7.54 (m, 2H), 7.49-7.21 (m, 2H), 5.82 (s, 1H), 2.98 (d, J = 4.4 Hz, 3H), 2.09-2.07 (m, 1H), 0.95-0.92 (m, 2H), 0. 32-0.31 (m, 2H). m/z [M+H] ⁺ 376.4.

1-(2-Chlorophenyl)-6-methyl-4-(methylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 1-(2-Chlorophenyl)-6-methyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.83 (d, J = 4.5 Hz, 1H), 8.23 (s, 1H), 7.76-7.74 (m, 1H) , 7.59-7.56 (m, 2H), 7.53-7.51 (m, 1H), 6.44 (s, 1H), 3.01 (d, J = 4.5 Hz, 3H), 2.45 (s, 3H). m/z [M+H] ⁺ 368.4.

1-(2-Chlorophenyl)-7-cyclopropyl-6-methyl-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(2-Chlorophenyl)-7-cyclopropyl-6-methylquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.45 (d, J = 4 Hz, 1H), 7.89 (s, 1H), 7.72-7.70 (m, 1H), 7 .56-7.52 (m, 2H), 7.41-7.39 (m, 1H), 5.76 (s, 1H), 2.97 (d, J = 4 Hz, 3H), 2.39 (s, 3H), 1.92-1.88 (m, 1H), 0.88-0.85 (m, 2H ), 0.23-0.20 (m, 2H). m/z [M+H] ⁺ 340.34.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using (1-methyl-1H-pyrazol-3-yl)methanamine and 1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (500 MHz, DMSO- _d6 ): δ 9.12 (s, 1H), 8.76 (s, 1H), 7.75-7.72 (m, 1H), 7.61 (d , J = 2 Hz, 1H), 7.60-7.54 (m, 2H), 7.49-7.47 (m, 1H), 6.23 (s, 1H), 5.74 (s, 1H), 4.66 (dd, J = 26, 15 Hz, 2H), 3.81 (s, 3H), 2.16- 2.11 (m, 1H), 1.08-1.06 (m, 2H), 0.42-0.38 (m, 2H), m/z [M+H] ⁺ 431.38.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((isoxazol-3-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using isoxazol-3-ylmethanamine and 1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.29 (s, 1H), 8.88 (d, J = 1.5 Hz, 1H), 8.71 (s, 1H), 7.76 -7.74 (m, 1H), 7.60-7.56 (m, 2H), 7.50-7.48 (m, 1H), 6.63 (d, J = 1.5 Hz, 1H), 5.77 (s, 1H), 4.83 (dd, J = 40.0, 15.5 Hz, 2H) , 2.15-2.14 (m, 1H), 1.10-1.08 (m, 2H), 0.43-0.42 (m, 2H). m/z [M+H] ⁺ 418.3.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((isoxazol-5-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using isoxazol-5-ylmethanamine and 1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (500 MHz, DMSO- _d6 ): δ 9.34 (t, J = 5.5 Hz, 1 H), 8.72 (s, 1H), 8.54 (d, J = 1, 5 Hz, 1H), 7.76-7.74 (m, 1H), 7.60-7.55 (m, 2H), 7.51-7.49 (m, 1H), 6.49 (s, 1H), 4.95 (dd, J = 16.5, 5.5 Hz, 2H), 4.87 (dd, J = 16, 5.5 Hz, 1H), 2.17-2.13 (m, 1H), 1.23 (d, J = 3.5 Hz, 1H), 1.11-1.07 (m, 2H), 0.42-0.41 (m, 2H). m/z [M+H] ⁺ 418.35.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((1-methyl-1H-pyrazol-5-yl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using 1-methyl-1H-pyrazol-5-amine and 1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (500 MHz, DMSO- _d6 ) δ 10.30 (s, 1H), 8.87 (bps, 1H), 7.78 (d, J = 7 Hz, 1H), 7.60 -7.55 (m, 3H), 7.44 (lat.s, 1H), 6.27 (lat.s, 1H), 5.77 (t, J = 15.5 Hz, 1H), 3.74 (bs, 3H), 2.21-2.16 (m, 1H), 1.13-1.09 (m, 2H), 0.5-0.4 (m, 2H). m/z [M+H] ⁺ 417.36.

1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-4-(thiazol-5-ylamino)-1,2-dihydroquinazoline-6-carbonitrile was prepared using thiazol-5-amine and 1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

^1H NMR (500 MHz, DMSO- _d6 ): δ 11.9 (bps, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 7.84 (s, 1H ), 7.76-7.73 (m, 1H), 7.60-7.55 (m, 2H), 7.50-7.47 (m, 1H), 5.74 (s, 1H), 2.17-2.12 (m, 1H), 1.08-1.07 (m, 2H), 0. 45-0.41 (m, 2H). m/z [M+H] ⁺ 420.1.

1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-4-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,2-dihydroquinazoline-6-carbonitrile was prepared using 2-(trifluoromethyl)pyridin-4-amine and 1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.54 (br s, 1H), 8.92-8.17 (m, 4H), 7.79-7.77 (m, 1H), 7.64-7.54 (m, 3H), 5.79 (d, J = 13.5 Hz, 1H), 2.22-2.16 (m, 1H), 1.13-1.11 (m, 2H), 0.45-0.45 (m, 2H). m/z [M+H] ⁺ 482.5.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-hydroxycyclobutyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile as a single enantiomer/atropisomer of unknown stereochemistry was prepared using trans-2-aminocyclobutan-1-ol and 1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile. Purification by supercritical fluid chromatography (SFC) (20% MeOH, Chiralpak IC, peak 3).

^1H NMR (500 MHz, DMSO- _d6 ): δ 8.86 (s, 1H), 8.73 (s, 1H), 7.74-7.72 (m, 1H), 7.59-7 .54 (m, 2H), 7.47-7.46 (m, 1H), 5.71 (d, J = 10 Hz, 1H), 4.44 (s, 1H), 4.11 (s, 1H), 2.14-2.12 (m, 1H), 2.08-2.02 (m, 2H), 1.56 -1.48 (m, 1H), 1.43-1.37 (m, 1H), 1.23 (s, 1H), 1.06 (dd, J = 8.2 Hz, 2 H), 0.40 (d, J = 4.5 Hz, 2H), m/z [M+H] ⁺ 407.47.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared using 1-(2-chloropyridin-3-yl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.88 (d, J = 4.0 Hz, 1H), 8.63 (s, 1H), 8.59 (dd, J = 5.0, 1.5 Hz, 1H), 8.04 (dd, J = 8.0, 1.5 Hz, 1H), 7.68 (dd, J = 7.5, 5.0 Hz, 1H), 5.82 (s, 1H), 2.99 (d, J = 4.5 Hz, 3H), 2.18-2.13 (m, 1H), 1.09 (dd, J = 8.0, 2.0 Hz, 2H), 1.54-1.53 (m, 2H). m/z [M+H] ⁺ 352.4.

1-(2-Chlorophenyl)-4-((trans-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one, a single enantiomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (20% MeOH, R,R Whelk-01, peak 1).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.59 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.77-7.75 (m, 1H) , 7.60-7.52 (m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 4.92-4.78 (m, 1H), 3.49-3.43 (m, 1H), 1.57-1.48 (m, 1H), 1. 35-1.26 (m, 1H). m/z [M+H] ⁺ 414.3.

1-(2-Chlorophenyl)-4-((trans-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one, a single enantiomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (20% MeOH, R,R Whelk-01, peak 2).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.59 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 7.77-7.75 (m, 1H) , 7.60-7.52 (m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 4.92-4.78 (m, 1H), 3.49-3.43 (m, 1H), 1.57-1.48 (m, 1H), 1. 35-1.26 (m, 1H). m/z [M+H] ⁺ 414.3.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-2-hydroxycyclobutyl)amino)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (15% MeOH, Chiralpak IC, peak 1).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.82 (d, J = 7 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 7.76-7.73 (m, 1H), 7.59-7.55 (m, 2H), 7.52-7.45 (m, 1H), 7.43 (dd, J = 8.5, 1.5 Hz, 1H), 6.36 (s, 1H), 5.43 (d, J = 7 Hz, 1H), 4.55-4.49 (m, 1H), 4.20-4.14 (m, 1H), 2.09-2.02 (m, 2H), 1.83 (t, J = 19 Hz, 3H), 1.57-1.49 (m, 1H), 1.46-1.39 (m, 1H). m/z [M+H] ⁺ 406.37.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-2-hydroxycyclobutyl)amino)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (15% MeOH, Chiralpak IC, peak 1).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.82 (d, J = 7 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 7.76-7.73 (m, 1H), 7.59-7.55 (m, 2H), 7.52-7.45 (m, 1H), 7.43 (dd, J = 8.5, 1.5 Hz, 1H), 6.36 (s, 1H), 5.43 (d, J = 7 Hz, 1H), 4.55-4.49 (m, 1H), 4.20-4.14 (m, 1H), 2.09-2.02 (m, 2H), 1.83 (t, J = 19 Hz, 3H), 1.57-1.49 (m, 1H), 1.46-1.39 (m, 1H). m/z [M+H] ⁺ 406.37.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-2-hydroxycyclobutyl)amino)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (15% MeOH, Chiralpak IC, peak 1).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.82 (d, J = 7 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 7.76-7.73 (m, 1H), 7.59-7.55 (m, 2H), 7.52-7.45 (m, 1H), 7.43 (dd, J = 8.5, 1.5 Hz, 1H), 6.36 (s, 1H), 5.43 (d, J = 7 Hz, 1H), 4.55-4.49 (m, 1H), 4.20-4.14 (m, 1H), 2.09-2.02 (m, 2H), 1.83 (t, J = 19 Hz, 3H), 1.57-1.49 (m, 1H), 1.46-1.39 (m, 1H). m/z [M+H] ⁺ 406.37.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazoline-2(1H)-one was prepared using (1S,2R)-2-fluorocyclopropan-1-amine and 1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.58-8.53 (m, 2H), 8.14 (d, J = 8.5 Hz, 1H), 8.08-8.07 ( m, 1H), 7.69-7.66 (m, 1H), 6.84 (dd, J = 8.5, 1.5 Hz, 1H), 6.15 (d, J = 1.5 Hz, 1H), 4.91-4.77 (m, 1H), 3.06-3.05 (m, 1H), 1.91-1.88 (m, 1H), 1.38-1.32 (m, 1H), 1.25-1.21 (m, 1H), 0.97-0.95 (m, 2H), 0.68-0.62 (m, 2H). m/z [M+H] ⁺ 371.3.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazoline-2(1H)-one was prepared using cyclopropylmethanamine and 1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.63 (t, J=5.0 Hz, 1H), 8.57-8.56 (m, 1H), 8.10 (d, J= 8.5 Hz, 1H), 8.03 (dd, J = 7.5, 2.0 Hz, 1H), 7.68-7.65 (m, 1H), 6.83 (dd, J = 8.5, 1.5 Hz, 1H), 6.11 (d, J = 1.5 Hz, 1H), 3 .41-3.39 (m, 1H), 3.31-3.31 (m, 1H), 1.90-1.87 (m, 1H), 1.20-1.85 (m, 1H), 0.96-0.94 (m, 2H), 0.66-0.62 (m, 2H), 0.51-0.47 (m, 2H), 0.32-0.29 (m, 2H ). m/z [M+H] ⁺ 367.4.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (30% MeOH, R,R Whelk-01, peak 1).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.32 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.74-7.71 (m, 1H) , 7.58-7.55 (m, 2H), 7.45 (dd, J = 6, 3.5 Hz, 1H), 6.81 (dd, J = 8.5, 1.5 Hz, 1H), 6.02 (d, J = 1 Hz, 1H), 4.90-4.70 (m, 1H), 3.45-3.41 (m, 1H), 1.83-1.79 (m, 1H), 1.50-1.45 (m, 1H), 1.22-1.18 (m, 1H), 0.94-0.92 (m, 2H), 0.60-0.56 (m, 2H). m/z [M+H] ⁺ 370.34.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (30% MeOH, R,R Whelk-01, peak 2).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.32 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.74-7.71 (m, 1H) , 7.58-7.55 (m, 2H), 7.45 (dd, J = 6, 3.5 Hz, 1H), 6.81 (dd, J = 8.5, 1.5 Hz, 1H), 6.02 (d, J = 1 Hz, 1H), 4.90-4.70 (m, 1H), 3.45-3.41 (m, 1H), 1.83-1.79 (m, 1H), 1.50-1.45 (m, 1H), 1.22-1.18 (m, 1H), 0.94-0.92 (m, 2H), 0.60-0.56 (m, 2H). m/z [M+H] ⁺ 370.34.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (30% MeOH, R,R Whelk-01, peak 3).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.32 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.74-7.71 (m, 1H) , 7.58-7.55 (m, 2H), 7.45 (dd, J = 6, 3.5 Hz, 1H), 6.81 (dd, J = 8.5, 1.5 Hz, 1H), 6.02 (d, J = 1 Hz, 1H), 4.90-4.70 (m, 1H), 3.45-3.41 (m, 1H), 1.83-1.79 (m, 1H), 1.50-1.45 (m, 1H), 1.22-1.18 (m, 1H), 0.94-0.92 (m, 2H), 0.60-0.56 (m, 2H). m/z [M+H] ⁺ 370.34.

1-(2-Chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (30% MeOH, R,R Whelk-01, peak 1).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.74 (s, 1H), 8.36 (d, J=8.5 Hz, 1H), 7.79-7.76 (m, 1H) , 7.64-7.55 (m, 4H), 6.45 (s, 1H), 4.95-4.80 (m, 1H), 3.52-3.45 (m, 1H), 1.58-1.49 (m, 1H), 1.29-1.22 (m, 1H). m/z [M+H] ⁺ 398.3.

1-(2-Chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (30% MeOH, R,R Whelk-01, peak 2).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.74 (s, 1H), 8.36 (d, J=8.5 Hz, 1H), 7.79-7.76 (m, 1H) , 7.64-7.55 (m, 4H), 6.45 (s, 1H), 4.95-4.80 (m, 1H), 3.52-3.45 (m, 1H), 1.58-1.49 (m, 1H), 1.29-1.22 (m, 1H). m/z [M+H] ⁺ 398.3.

1-(2-Chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (30% MeOH, R,R Whelk-01, peak 3).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.74 (s, 1H), 8.36 (d, J=8.5 Hz, 1H), 7.79-7.76 (m, 1H) , 7.64-7.55 (m, 4H), 6.45 (s, 1H), 4.95-4.80 (m, 1H), 3.52-3.45 (m, 1H), 1.58-1.49 (m, 1H), 1.29-1.22 (m, 1H). m/z [M+H] ⁺ 398.3.

1-(2-Chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one, a single enantiomer/atropisomer of unknown stereochemistry, was prepared using trans-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropylquinazolin-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (30% MeOH, R,R Whelk-01, peak 4).

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.74 (s, 1H), 8.36 (d, J=8.5 Hz, 1H), 7.79-7.76 (m, 1H) , 7.64-7.55 (m, 4H), 6.45 (s, 1H), 4.95-4.80 (m, 1H), 3.52-3.45 (m, 1H), 1.58-1.49 (m, 1H), 1.29-1.22 (m, 1H). m/z [M+H] ⁺ 398.3.

5-Chloro-4-(methyl amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2(1H)-one was prepared using 5-chloro-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 368.36.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-5-methoxy-4-(methylamino)quinazoline-2(1H)-one was prepared using trans-2-1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.56-8.51 (m, 2H), 7.98 (dd, J = 1.5, 2 Hz, 1H), 7.67-7, 64 (m, 1H), 6.39 (d, J = 1.5 Hz, 1H), 3.99 (s, 3H), 2.99 (d, J = 5 Hz, 3H), 1.84 (m, 1H), 0.94--0.92 (m, 2H), 0.67-0.64 (m, 2H). m/z [M+H] ⁺ 357.37.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-methoxyquinazoline-2(1H)-one was prepared using methanol and 1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.63 (dd, J = 5.0, 2.0 Hz, 1H), 8.13 (dd, J = 7.5, 1.5 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.73-7.71 (m, 1H), 6.90 (dd, J = 8.5, 1.5 Hz, 1H), 6.30 (d, J = 1.5 Hz, 1H), 4.09 (s, 3H), 1.99-1.94 (m, 1H), 1.01-0.97 (m, 2H), 0.73-0.71 (m, 2H). m/z [M+H] ⁺ 328.3.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)quinazoline-2(1H)-one was prepared using 1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.57 (dd, J = 5.0, 2.0 Hz, 2H), 8.03-7.99 (m, 2H), 7.68- 7.66 (m, 1H), 6.82 (dd, J = 8.5, 1.5 Hz, 1H), 6.12 (d, J = 1.5 Hz, 1H), 2.97 (d, J = 4.5 Hz, 3H), 1.89-1.85 (m, 1H), 0.96-0 .94 (m, 2H), 0.68-0.66 (m, 2H). m/z [M+H] ⁺ 327.3.

4-(Methylamino)-7-(trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazoline-2(1H)-one was prepared using 17-(trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazoline-2,4(1H,3H)-dione.

m/z [M+H] ⁺ 468.3.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((2,2-difluorocyclopropyl)methyl)amino)-5-methoxyquinazoline-2(1H)-one was prepared using (2,2-difluorocyclopropyl)methanamine and 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.59 (t, J = 5.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.56-7.52 ( m, 2H), 7.45-7.42 (m, 1H), 6.42 (d, J = 1.0 Hz, 1H), 5.59 (d, J = 1.0 Hz, 1H), 4.01 (s, 3H), 3.73-3.66 (m, 2H), 2.26-2.23 (m , 1H), 1.80-1.77 (m, 1H), 1.65-1.61 (m, 1H), 1.49-1.45 (m, 1H), 0.94-0.91 (m, 2H), 0.62-0.58 (m, 2H). m/z [M+H] ⁺ 432.4.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-5-methoxyquinazoline-2(1H)-one was prepared using cyclopropylmethanamine and 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.48 (s, 1H), 7.71-7.69 (m, 1H), 7.54-7.52 (m, 2H), 7. 43-7.41 (m, 1H), 6.42 (d, J = 1.5 Hz, 1H), 5.58 (d, J = 1.5 Hz, 1H), 4.01 (s, 3H), 3.31-3.31 (m, 2H), 1.79-1.76 (m, 1H), 1, 23-1.20 (m, 1H), 0.92 (dd, J = 8.0, 2.0 Hz, 2H), 0.61-0.59 (m, 2H), 0.51-0.47 (m, 2H), 0.33-0.32 (m, 2H). m/z [M+H] ⁺ 396.4.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-5-methoxyquinazoline-2(1H)-one was prepared using (1S,2R)-2-fluorocyclopropan-1-amine and 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.32-8.29 (m, 1H), 7.74-7.70 (m, 1H), 7.57-7.53 (m, 2H ), 7.47-7.43 (m, 1H), 6.43 (d, J = 1.5 Hz, 1H), 5.62 (d, J = 1 Hz, 1H), 4.88-4.86 (m, 1H), 3.99 (s, 3H), 3.15-3.12 (m, 1H), 1 .81-1.78 (m, 1H), 1.27-1.16 (m, 2H), 0.94-0.93 (m, 2H), 0.63-0.60 (m, 2H). m/z [M+H] ⁺ 400.33.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(cyclopropylamino)-5-methoxyquinazoline-2(1H)-one was prepared using cyclopropylamine and 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.17 (d, J = 4.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.56-7.52 ( m, 2H), 7.44-7.41 (m, 1H), 6.39 (d, J = 1 Hz, 1H), 5.58 (d, J = 1.5 Hz, 1H), 3.98 (s, 3H), 3.06-3.05 (m, 1H), 1.77 (m, 1H), 0.92 (dd, J = 2.2 Hz, 2H), 0.82 (dd, J = 1.5, 1 Hz, 2H), 0.70-0.69 (m, 2H), 0.68-0.59 (m, 2H). m/z [M+H] ⁺ 382.35.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(isopropylamino)-5-methoxyquinazoline-2(1H)-one was prepared using isopropylamine and 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.08 (d, J = 7.5 Hz, 1H), 7.71-7.69 (m, 1H), 7.54-7.52 ( m, 2H), 7.43-7.41 (m, 1H), 6.41 (s, 1H), 5.58 (s, 1H), 4.40-4.36 (m, 1H), 4.01 (s, 3H), 1.79-1.76 (m, 1H), 1.28-1.25 (m , 7H), 0.93-0.91 (m, 2H), 0.61-0.58 (m, 2H). m/z [M+H] ⁺ 384.4.

1-(2-Bromophenyl)-7-cyclopropyl-4-(methylamino)quinazoline-2(1H)-one was prepared as a pure atropisomer using isopropylamine and 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (30% MeOH, Chiralpak IG-3, peak 2).

¹H NMR (500 MHz, DMSO-d6) δ 8.48-8.49 (brm, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.87 (dd, J = 8.0, 1.0 Hz, 1 H), 7.59 (td, J = 7.5, 1.0 Hz, 1 H), 7.42-7.48 (m, 2 H), 6.81 (dd, J = 8.5, 1.5 Hz, 1 H), 5.99 (d, J = 1.5 Hz, 1 H), 2.97 (d, J = 4.5 Hz, 3 H), 1.77-1.99 (m, 1 H), 0.90-0.96 (m, 2 H), 0.58-0.63 (m, 2 H). m/z [M+H] 370.3.

4-((trans-2-Hydroxycyclobutyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using trans-2-aminocyclobutan-1-ol and 1-phenyl-7-(trifluoromethyl)quinazolin-2,4(1H,3H)-dione.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.89-8.88 (m, 1H), 8.46 (d, J = 8.5 Hz, 1H), 7.62-7.52 (m, 4H), 7.35-7.33 (m, 2H), 7.44-7.41 (m, 1H), 6.55 (s, 1H), 5.44 (d, J = 7 Hz, 1H), 4.5-4.47 (m, 1H), 4.2-4.13 (m, 1H), 2.09-2.02 (m, 2H), 1.58-1.50 (m, 1H), 1.47-1.39 (m, 1H). m/z [M+H] ⁺ 376.36.

4-Amino-7-cyclopropyl-1-(pyrimidin-5-yl)quinazoline-2(1H)-one was prepared using ammonia (7.4 M solution in THF) and 7-cyclopropyl-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.30 (s, 1H), 8.87 (s, 2H), 8.13 (s, 1H), 8.02 (d, J = 8, 5 Hz, 2H), 6.83 (dd, J = 8.5, 1.5 Hz, 1H), 6.30 (s, 1H), 1.92-1.88 (m, 1H), 0.97-0.93(m, 2H), 0.68-0.65 (m, 2H). m/z [M+H] ⁺ 280.26.

4-Amino-7-cyclopropyl-1-(pyrazin-2-yl)quinazoline-2(1H)-one was prepared using ammonia (0.4 M solution in THF) and 7-cyclopropyl-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.78 (s, 3H), 8.15 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 6.82 (dd, J = 8.5, 1.5 Hz, 1H), 6.21 (d, J = 1.5 Hz, 1H), 1.89-1.84 (m, 1H), 0.96-0.92 (m, 2H), 0.66-0.65 (m, 2H). m/z [M+H] ⁺ 280.4.

4-Amino-1-(3-chloropyridin-2-yl)-7-cyclopropylquinazoline-2(1H)-one was prepared using ammonia (0.4 M solution in THF) and 1-(3-chloropyridin-2-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.65 (dd, J = 4.5, 1.2 Hz, 1H), 8.25 (dd, J = 8.5, 2.0 Hz, 1H), 8.13 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.65-7.63 (m, 1H), 6.81 (dd, J=8.5, 1.5 Hz, 1H), 6.00 (d, J= 1.5 Hz, 1H), 1.87-1.82 (m, 1H), 0.96-0.93 (m, 2H), 0.66-0.62 (m, 2H). m/z [M+H] ⁺ 313.3.

7-Cyclopropyl-4-(methylamino)-1-(pyrimidin-5-yl)quinazoline-2(1H)-one was prepared using 7-cyclopropyl-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.30 (s, 1H), 8.86 (s, 1H), 8.57 (d, J = 4.5, 1H), 7.98 ( d, J = 10, 1H), 6.83 (dd, J = 8.5, 1.5 Hz, 1H), 6.30 (s, 1H), 2.97 (d, J = 4.5, 3H), 1.92-1.87 (m, 1H), 0.96-0.92 (m, 2H), 0.68-0.65 (m, 2H). m/z [M+H] ⁺ 294.33.

7-Cyclopropyl-4-(methylamino)-1-(pyrazin-2-yl)quinazolin-2(1H)-one was prepared using 4-chloro-7-cyclopropyl-1-(pyrazin-2-yl)quinazolin-2(1H)-one.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.79-8.78 (m, 3H), 8.60 (d, J = 4.5 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 8.5, 1.5 Hz, 1H), 6.21 (d, J = 1.5 Hz, 1H), 2.98 (d, J = 4.5 Hz, 3H), 1.89-1.83 (m, 1H), 0.95-0.92 (m, 2H), 0.66-0.63 (m, 2H). m/z [M+H] ⁺ 294.4.

1-(2-Chlorophenyl)-4-(((1-methyl-1H-imidazol-4-yl)methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using (1-methyl-1H-imidazol-4-yl)methanamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.36 (t, J = 5 Hz, 1H), 8.93 (d, J = 8 Hz, 1H), 7.76 (d, J = 8 .5 Hz, 1H), 7.64-7.62 (m, 1H), 7.54 (s, 1H), 7.48-7.43 (m, 3H), 7.1 (s, 1H), 4.60 (t, J = 5 Hz, 2H), 3.62 (s, 1H). m/z [M+H] ⁺ 435.27.

1-(2-Chlorophenyl)-4-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using (1-methyl-1H-pyrazol-5-yl)methanamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ): δ 9.43 (t, J = 5 Hz, 1H), 8.91 (d, J = 8 Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 7.63 (m, 1H), 7.50-7.44 (m, 3H), 7.36 (d, J = 1.5 Hz, 1H), 6.29 (d, J = 2 Hz, 1H), 4.87-4.74 (m, 2H), 3.90 (s, 3H ). m/z [M+H] ⁺ : 435.27.

1-(2-Chlorophenyl)-4-((isoxazol-5-ylmethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using isoxazol-5-ylmethanamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.66 (t, J = 5.5 Hz, 1H), 8.89 (d, J = 3.0 Hz, 1H), 8.55 (d , J = 1.5 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.50-7.46 (m, 3H), 6.52 (d, J = 2.0 Hz, 1H), 5.01-4.89 ( m, 2H). m/z [M+H] ⁺ 422.2.

1-(2-Chlorophenyl)-4-((isoxazol-3-ylmethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using isoxazol-3-ylmethanamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.62 (t, J=5.5 Hz, 1H), 8.91-8.88 (m, 2H), 7.83 (d, J= 8.5 Hz, 1H), 7.66-7.63 (m, 1H), 7.50-7.45 (m, 3H), 6.66 (d, J = 2.0 Hz, 1H), 4.93-4.81 (m, 2H). m/z [M+H] ⁺ 422.3.

1-(2-Chlorophenyl)-4-((isoxazol-4-ylmethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using isoxazol-4-ylmethanamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.41 (s, 1H), 8.98 (s, 1H), 8.86 (d, J = 8.0 Hz, 1H), 8.68 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.65-7.63 (m, 1H), 7.50-7.44 (m, 3H), 4.65 (dd, J = 40.0, 15.0 Hz, 2H). m/z [M+H] ⁺ 422.3.

1-(2-Chlorophenyl)-4-(thiazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using isoxazol-3-ylmethanamine and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 11.8 (s, 1H), 9.12 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.62-7.60 (m, 1H), 7.51-7.46 (m, 3H). m/z [M+H] ⁺ 424.2.

7-Cyclopropyl-4-(pyridin-4-ylamino)-1-(o-tolyl)quinazoline-2(1H)-one was prepared using pyridin-4-amine and 7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 9.97 (s, 1H), 8.52 (d, J = 6.5 Hz, 2H), 8.38 (d, 8.5 Hz, 1H ), 8.04 (dd, 4.5 Hz, 1.5 Hz, 2H), 7.49-7.41 (m, 3H), 7.23 (dd, 7.5, 1.5 Hz, 1H), 6.95 (dd, 8.5, 1.5 Hz, 1H), 6.10 (s, 1H) , 1.96 (s, 3H), 1.86-1.82 (m, 1H), 0.98-0.96 (m, 2H), 0.64-0.63 (m, 2 H). m/z [M+H] ⁺ 369.39.

4-(Methylamino)-7-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one was prepared using 4-chloro-7-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one.

m/z [M+H] ⁺ 454.38.

7-Cyclopropyl-4-(methylamino)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one was prepared using 7-cyclopropyl-4-hydroxy-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one.

4-Amino-7-cyclopropyl-5-methoxy-1-(pyridin-3-yl)quinazolin-2(1H)-one was prepared using ammonia (2 M solution in THF) and 4-chloro-1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxyquinazolin-2(1H)-one.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.66 (d, J = 4 Hz, 1H), 8.46-8.45 (m, 1H), 8.03 (s, 1H), 7 .88 (s, 1H), 7.77-7.75 (m, 1H), 7.62-7.59 (m, 1H), 6.38 (s, 1H), 5.67 (s, 1H), 3.97 (s, 3H), 1.83-1.78 (m, 1H), 0.95-0.90 (m, 2H), 0.64 (m, 2H). m/z [M+H] ⁺ 309.36.

7-Cyclopropyl-5-methoxy-4-(methylamino)-1-(pyridin-3-yl)quinazolin-2(1H)-one was prepared using 4-chloro-1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxyquinazolin-2(1H)-one.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.68-8.67 (m, 1H), 8.47-8.45 (m, 2H), 7.77-7.75 (m, 1H ), 7.62-7.59 (m, 1H), 6.40 (d, J = 1.5 Hz, 1H), 5.67 (d, J = 1 Hz, 1H), 3.98 (s, 3H), 2.98 (d, J = 4.5 Hz, 3H), 1.81-1.78 (m, 1H ), 0.93-0.90 (m, 2H), 0.62-0.61 (m, 2H). m/z [M+H] ⁺ 323.36.

4-Amino-7-cyclopropyl-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one was prepared using ammonia (2 M solution in THF) and 4-chloro-7-cyclopropyl-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.54 (s, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.43-7.34 (m, 3H), 7.12-7.10 (m, 1H), 6.36 (s, 1H), 5.56 (s, 1H), 3.96 (s, 3H), 1.92 (s, 3H), 1.76-1.71 (m, 1H), 0.91-0.89 (m, 2H), 0.57 -0.56 (m, 2H). m/z [M+H] ⁺ 322.36.

7-Cyclopropyl-5-methoxy-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one was prepared using 4-chloro-7-cyclopropyl-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.39 (d, J = 4.4 Hz, 1H), 7.44-7.34 (m, 3H), 7.11-7.09 ( m, 2H), 6.38 (s, 1H), 5.56 (d, J = 0.8 Hz, 1H), 3.98 (s, 3H), 2.98 (d, J = 4.8 Hz, 3H), 1.91 (s, 3H), 1.76-1.69 (m, 1H), 0.91 -0.88 (m, 2H), 0.57-0.54 (m, 2H). m/z [M+H] ⁺ 336.44.

4-Amino-1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazolin-2(1H)-one was prepared using ammonia (2 M solution in THF) and 1-(2-chlorophenyl)-7-cyclopropyl-4-hydroxy-5-methoxyquinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.0 (s, 1H), 7.86 (s, 1H), 7.71-7.68 (m, 1H), 7.55-7, 51 (m, 2H), 7.43-7.40 (m, 1H), 6.37 (d, J = 1.5 Hz, 1H), 5.57 (s, 1H), 3.97 (s, 3H), 1.80-1.75 (m, 1H), 0.93-0.90 (m, 2H), 0.64 -0.63 (m, 1H). m/z [M+H] ⁺ 342.31.

1-(2-Chlorophenyl)-7-cyclopropyl-5-methoxy-4-(methylamino)quinazolin-2(1H)-one was prepared using 1-(2-chlorophenyl)-7-cyclopropyl-4-hydroxy-5-methoxyquinazolin-2(1H)-one.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.45 (d, 1H), 7.71-7.69 (m, 1H), 7.54-7.52 (m, 2H), 7. 41-7.39 (m, 1H), 6.39 (s, 1H), 5.57 (d, J = 1 Hz, 1H), 3.98 (s, 3H), 2.98 (d, J = 4.5 Hz, 3H), 1.78-1.74 (m, 1H), 0.92-0.90 (m , 2H), 0.59 (m, 2H). m/z [M+H] ⁺ 356.35.

4-Amino-1-(2-Bromophenyl)-7-cyclopropylquinazolin-2(1H)-one was prepared using ammonia (2 M solution in THF) and 1-(2-Bromophenyl)-7-cyclopropyl-4-hydroxyquinazolin-2(1H)-one.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.01-7.99 (m, 2H), 7.89-7.85 (m, 2H), 7.60-7.58 (m, 1H ), 7.47-7.42 (m, 2H), 6.79 (dd, J = 8.5, 1.5 Hz, 1H), 5.98 (d, J = 1.5 Hz, 1H), 1.82-1.78 (m, 1H), 0.94-0.90 (m, 2H), 0.62-0 .57 (m, 2H). m/z [M+H] ⁺ 356.1.

1-(2-Chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one single enantiomer/atropisomer of unknown stereochemistry was prepared using trans-2-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (20% MeOH, Chiralpak IC, peak 1).

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.15 (s, 1H), 8.83 (s, 1H), 7.72-7.71 (m, 1H), 7.67-7, 60 (m, 1H), 7.46-7.41 (m, 3H), 5.67 (s, 1H), 4.37 (d, J = 5.0 Hz, 1H), 4.07 (s, 1H), 2.06 (dd, J = 17.0, 8.5 Hz, 2H), 1.56-1 .42 (m, 2H). m/z [M+H] ⁺ 411.3.

1-(2-Chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one single enantiomer/atropisomer of unknown stereochemistry was prepared using trans-2-aminocyclobutan-1-ol and 1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (20% MeOH, Chiralpak IC, peak 2).

^1H NMR (400 MHz, DMSO- _d6 ) δ 9.15 (s, 1H), 8.83 (s, 1H), 7.72-7.71 (m, 1H), 7.67-7, 60 (m, 1H), 7.46-7.41 (m, 3H), 5.67 (s, 1H), 4.37 (d, J = 5.0 Hz, 1H), 4.07 (s, 1H), 2.06 (dd, J = 17.0, 8.5 Hz, 2H), 1.56-1 .42 (m, 2H). m/z [M+H] ⁺ 411.3.

7-Chloro-1-(2-chlorophenyl)-5-fluoro-4-(methylamino)quinazolin-2(1H)-one was prepared using 4,7-dichloro-1-(2-chlorophenyl)-5-fluoroquinazolin-2(1H)-one.

m/z [M+H] ⁺ 338.2.

7-Chloro-5-fluoro-4-(((trans)-3-methoxycyclobutyl)amino)-1-(o-tolyl)quinazolin-2(1H)-one was prepared using (trans)-3-methoxycyclobutan-1-amine and 7-chloro-5-fluoro-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one.

m/z [M+H]+ 388.29.

7-Chloro-4-((2,2-difluoroethyl)amino)-5-fluoro-1-(o-tolyl)quinazolin-2(1H)-one was prepared using 2,2-difluoroethane-1-amine and 7-chloro-5-fluoro-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one.

m/z [M+H] ⁺ 368.29.

4-Amino-7-chloro-5-fluoro-1-(o-tolyl)quinazolin-2(1H)-one was prepared using ammonia (0.4 M solution in THF) and 7-chloro-5-fluoro-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one.

m/z [M+H] ⁺ 304.29.

1-Benzyl-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 1-benzyl-4-hydroxy-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.89 (d, J = 4.5 Hz, 1H), 8.71 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.35-7.33 (m, 2H), 7.28-7.25 (m, 1H), 7.22-7.19 (m, 1H), 5.35 (s, 2H), 2.97 (d, J = 4.5 Hz, 3H). m/z [M+H] ⁺ 335.3.

1-(2-Chlorophenyl)-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one single enantiomer of unknown stereochemistry was prepared using 3-methylpyrrolidin-3-ol and 1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione. Purification by supercritical fluid chromatography (SFC) (25% MeOH, Chiralpak IC, peak 1).

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.88-8.76 (m, 1H), 7.64-7.63 (m, 2H), 7.48-7.45 (m, 2H ), 7.42-7.39 (m, 1H), 5.03 (s, 1H), 4.30-3.64 (m, 4H), 2.07-1.94 (m, 2H), 1.40 (s, 3H). m/z [M+H] ⁺ 425.1.

7-Cyclopropyl-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one was prepared using 7-Cyclopropyl-4-hydroxy-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.58-8.57 (dd, J = 4.5, 1.5 Hz, 1H), 8.51 (d, J = 4 Hz, 1H), 8.0 (d, J = 8.5 Hz, 1H), 7.66-7.65 (dd, J = 8, 1.5 Hz, 1H), 7.45-7.43 (dd, J = 7.5, 4.7 Hz, 1H), 6.83-6.81 (dd, J = 8.5, 1.5 Hz, 1H), 6.03 (s, 1H), 2.97 (d, J =4.5 Hz, 3H), 2.13 (s, 3H), 1.85-1.80 (m, 1H), 0.94-0.90 (m, 2H), 0.64-0.59 (m, 2H). m/z [M+H] ⁺ 307.22.

1-(2-Chloro-6-fluorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 4-chloro-1-(2-chloro-6-fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.26 (d, J = 4.5 Hz, 1H), 8.84 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.59-7.52 (m, 2H), 7.46-7.43 (m, 1H), 3.04 (d, J = 4.5 Hz, 3H). m/z [M+H] ⁺ 373.2.

5-Methoxy-4-(methylamino)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared using 5-methoxy-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.56 (d, J = 5.0 Hz, 1H), 7.62-7.59 (m, 2H), 7.55-7.52 ( m, 1H), 7.35-7.33 (m, 2H), 6.22 (s, 1H), 4.11 (s, 3H), 3.03 (d, J = 5.0 Hz, 3H). m/z [M+H] ⁺ 351.3.

Example 3

Synthesis of 7-methyl-4-(methylamino)-1-phenylquinazolin-2(1H)-one

To a vial were placed 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one (1 equiv), methylboronic acid (3 equiv), and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) (0.1 equiv). A 1:1 mixture of toluene:tert-butanol (0.1 M) was added, followed by aqueous potassium carbonate solution (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 evaporated under reduced pressure. The residue was purified by preparative HPLC (20-40% MeCN/water, 0.1% formic acid) to give the title compound. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J = 8.3 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.24 (s, 3H), 6.95 (d, J = 8.2 Hz, 1H), 6.30 (s, 1H), 3.18 (s, 3H), 2.23 (s, 3H). m/z [M+H] ⁺ 266.1

The following compounds were obtained using the method described above:

7-Cyclopropyl-4-(methylamino)-1-phenylquinazolin-2(1H)-one was prepared using cyclopropylboronic acid instead of methylboronic acid

^1H NMR (400 MHz, CDCl ₃ ) δ 7.92 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.48-7.40 (m, 1H), 7.24 (s, 2H), 6.71 (d, J = 8.3 Hz, 1H), 6.23 (s, 1H), 3.15 (s, 3H), 1.77-1.66 (m, 1H), 0.94 (d, J = 7.8 Hz, 2H), 0.58 (d, J = 4.9 Hz, 2H). m/z [M+H] ⁺ 292.2.

4-(Dimethylamino)-7-(oxetan-3-yl)-1-phenylquinazolin-2(1H)-one was prepared by using potassium trifluoro(oxetan-3-yl)borate instead of methyl boronic acid and 7-bromo-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one instead of 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one.

¹ H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J = 8.5 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H), 7.51-7.44 (m, 1H), 7.28 (d, J = 7.7 Hz, 3H), 7.17 (d, J = 8.5 Hz, 1H), 6.46 (d, J = 11.3 Hz, 2H), 6.30 (dt, J = 15.4, 4.8 Hz, 1H), 4.28 (d, J = 4.8 Hz, 2H), 3.41 (s, 6H). m/z [M+H] ⁺ 322.0.

4-(Dimethylamino)-1-phenyl-7-(tetrahydrofuran-3-yl)quinazolin-2(1H)-one was prepared by using potassium tetrahydrofuran-3-trifluoroborate instead of methyl boronic acid and 7-bromo-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one instead of 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one.

^1H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J = 8.6 Hz, 1H), 7.56 (t, J = 7.4 Hz, 2H), 7.49 (sq, J = 7.1, 6.2 Hz, 1H), 7.29 (d, J = 7.9 Hz, 3H), 7.18 (d, J = 8.4 Hz, 1H), 6.43 (s, 1H), 6.33 (d, J = 17.6 Hz, 1H), 6.22 (dt, J = 15 ,6, 6.9 Hz, 1H), 3.73 (t, J = 6.0 Hz, 2H), 3.43 (s, 6H), 2.44 (kv, J = 6.6, 6.1 Hz, 2H). m/z [M+H] ⁺ 336.0.

7-Ethyl-4-(methylamino)-1-phenylquinazolin-2(1H)-one was prepared using ethylboronic acid instead of methylboronic acid.

^1H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.3 Hz, 1H), 6.35 (s, 1H), 3.24 (s, 3H), 2.54 (kv, J = 7.7 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H). m/z [M+H] ⁺ 280.1.

6-Chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one was prepared by using cyclopropylboronic acid instead of methylboronic acid and 7-bromo-6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one instead of 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.72 (s, 1H), 8.41 (s, 1H), 7.73 (d, J = 6.6 Hz, 1H), 7.65 -7.53 (m, 2H), 7.53-7.41 (m, 1H), 5.75 (d, J= 2.0 Hz, 1H), 2.12 (bps, 1H), 1.19 (s, 1H), 0.99 (d, J = 8.3 Hz, 2H), 0.51 (d, J = 7.8 Hz, 2H), 0.40-0.21 (m, 4H). m/z [M+H] ⁺ 400.1

6-Chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one was prepared using cyclopropylboronic acid and 7-bromo-6-chloro-1-(2-chlorophenyl)-4-(methylamino)quinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO) δ 8.67 (bps, 1H), 8.28 (s, 1H), 7.75 (m, 1H), 7.65-7.55 (m, 2H ), 7.46 (m, 1H), 5.76 (s, 1H), 2.98 (s, 3H), 2.12 (s, 1H), 0.98 (d, J = 8.2 Hz, 2H), 0.28 (s, 2H).m/z [M+H] ⁺ 360.0.

4-((Cyclopropylmethyl)amino)-6-methyl-1-phenyl-7-(trifluoromethoxy)quinazolin-2(1H)-one was prepared using 6-bromo-4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethoxy)quinazolin-2(1H)-one.

¹ H NMR (400 MHz, MeOD) δ 8.15 (s, 1H), 7.61 (m, 3H), 7.33 (d, J = 7.8 Hz, 2H), 6.38 (s, 1H), 3.52 (d, J = 8.3 Hz, 2H), 2.37 (s, 3H), 1.30 (m, 2H), 0.59 (d, J = 7.8 Hz, 2H), 0.39 (br s, 2H). m/z [M+H] ⁺ 390.1.

6-Methyl-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one was prepared using 6-bromo-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one.

¹ H NMR (400 MHz, MeOD) δ 8.04 (s, 1H), 7.58-7.37 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 6.27 (s, 1H), 3.15 (s, 3H), 2.37 (s, 3H), 2.05 (s, 3H). m/z [M+H] ⁺ 364.1.

4-((Cyclopropylmethyl)amino)-6-methyl-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one was prepared using 6-bromo-4-((cyclopropylmethyl)amino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one.

^1H NMR (400 MHz, MeOD) δ 8.18 (s, 1H), 7.59-7.39 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 6, 27 (s, 1H), 3.52 (pesvedo t, J = 6.9 Hz, 2H), 2.38 (s, 3H), 2.05 (s, 3H), 1.31 (s, 1H), 0.60 (d, J = 7.8 Hz, 2H), 0.39 (br s, 2H). m/z [M+H] ⁺ 404.1

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-fluoroquinazolin-2(1H)-one was prepared using cyclopropylboronic acid and 7-bromo-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-6-fluoroquinazolin-2(1H)-one.

m/z [M+H] ⁺ 384.0.

1-(2-chlorophenyl)-7-cyclopropyl-6-fluoro-4-(methylamino)quinazolin-2(1H)-one was prepared using cyclopropylboronic acid and 7-bromo-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)quinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.56 (s, 1H), 7.97 (d, J=11.0 Hz, 1H), 7.76-7.69 (m, 1H) , 7.55 (d, J = 6.7 Hz, 2H), 7.44 (d, J = 3.0 Hz, 1H), 5.75 (d, J = 5.4 Hz, 1H), 2.97 (s, 3H), 2.05-1.93 (m, 1H), 0.95 (d, J = 8 .4 Hz, 2H), 0.40 (t, J = 5.2 Hz, 2H). m/z [M+H] ⁺ 344.0.

Example 4

Synthesis of 7-chloro-1-(3-hydroxyphenyl)-4-(methylamino)-3,4-dihydroquinazolin-2(1H)-one

Step 1. 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenyl acetate

A vial was charged with 7-chloro-1-(3-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione (1.0 equiv) and pyridine (0.6 M). Acetic anhydride (1.2 equiv) was added to the reaction vessel and the mixture was stirred at reflux for 60 min. The reaction mixture was evaporated in vacuo and the residue was purified by reverse phase chromatography (0-20% MeOH/DCM) to give the title compound. m/z [M+H] ⁺ 331.1.

3-(7-Chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenyl acetate was converted to 3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl acetate according to the procedures described in Examples 1 and 2.

Step 2. 7-chloro-1-(3-hydroxyphenyl)-4-(methylamino)-3,4-dihydroquinazolin-2(1H)-one

Crude 3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenylacetate (1.0 equiv) was added to a vial. THF:MeOH (3:2 ratio, 0.6 M) was added followed by 2N aqueous LiOH (10 equiv). The reaction mixture was stirred at room temperature for 30 min. The mixture was evaporated in vacuo and the residue was purified by reverse phase chromatography (20-55% MeCN/water, 0.1% formic acid) to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.2 (br s, 1H), 8.63 (d, J = 5.1 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 6.64 (s, 1H), 6.38 (s, 1H), 2.97 (d, J = 4.2 Hz, 4H). m/z [M+H] ⁺ 302.1.

According to the method described above, the compounds listed below were obtained, replacing 7-chloro-1-(3-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione and methylamine as needed:

7-Chloro-1-[3-(2-hydroxyethyl)phenyl]-4-(methylamino)hydroquinazolin-2-one was prepared using 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenethyl acetate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J = 5.0 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 7.9 Hz, 2H), 6.34 (d, J = 2.0 Hz, 1H), 4.69 (t, J = 5.3 Hz, 1H), 3.66 (d, J = 6.7 Hz, 2H), 2.98 (d, J = 4.3 Hz, 3H), 2.81 (t, J = 6.9 Hz, 2H). m/z [M+H] ⁺ 330.1.

7-Chloro-1-[3-(3-hydroxypropyl)phenyl]-4-(methylamino)hydroquinazolin-2-one was prepared using 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenpropyl acetate.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.61 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.50 (t , J = 7.7 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.12 (s, 2H), 6.31 (s, 1H), 4.49 (t, J = 5.2 Hz, 1H), 3.45 (d, J = 6.1 Hz, 3H), 2.98 (d, J = 4.3 Hz, 3H), 2.70 (t, J = 7.8 Hz, 2H), 1.76 (p, J = 6.9 Hz, 3H), 11.81 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.31 (dd, J = 8.4, 1.8 Hz, 1H), 7.29-7.22 (m, 2H), 2.40 (s, 3H). m/z [M+H] ⁺ 344.1.

4-(dimethylamino)-7-chloro-1-(3-hydroxyphenyl)hydroquinazolin-2-one was prepared using 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenyl acetate and dimethylamine.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 8.03 (dd, J = 8.7, 1.4 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.23-7.14 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 3.32-3.27 (m, 7H). m/z [M+H] ⁺ 316.1.

4-(dimethylamino)-7-chloro-1-[3-(hydroxymethyl)phenyl]hydroquinazolin-2-one was prepared using 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenmethyl acetate and dimethylamine.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.05 (d, J = 8.8 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.46 (d , J = 7.9 Hz, 1H), 7.22 (s, 1H), 7.20-7.14 (m, 2H), 6.35 (s, 1H), 5.35 (s, 1H), 4.59 (s, 2H), 3.31 (s, 11H). m/z [M+H] ⁺ 330.0.

Example 5

Synthesis of 7-methoxy-4-(methylamino)-1-phenylquinazolin-2(1H)-one

In a vial were placed 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one (1 equiv) and copper iodide (2 equiv). DMF (0.1 M) and sodium methoxide (10 equiv) were added. The reaction mixture was heated at 100 °C for 2 h and then cooled. The mixture was diluted with ethyl acetate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-30% MeCN/water, 0.1% formic acid) to give the title compound. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 9.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.51-7.43 (m, 1H), 7.28 (d, J = 7.7 Hz, 2H), 6.74 (d, J = 9.0 Hz, 1H), 5.95 (s, 1H), 3.66 (s, 3H), 3.20 (s, 3H). m/z [M+H] ⁺ 282.1.

According to the above-described method, 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-methoxyquinazolin-2(1H)-one was obtained using 6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.59 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.53 (d, J=3, 7 Hz, 2H), 7.41 (d, J = 6.7 Hz, 1H), 5.64 (s, 1H), 3.90 (s, 3H), 3.42 (dd, J = 12.8, 6.9 Hz, 2H), 2.12-2.05 (m, 1H), 1.26-1.19 ( m, 1H), 0.88 (d, J = 8.4 Hz, 2H), 0.51 (d, J = 9.1 Hz, 2H), 0.32 (d, J = 4.0 Hz, 2H), 0.27-0.20 (m, 2H). m/z [M+H] ⁺ 396.2.

Example 6

Synthesis of 4-(methylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-7-carbonitrile

In a vial were placed 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one (1 equiv), tetrakis(triphenylphosphine)palladium (0.1 equiv), and zinc cyanide (0.5 equiv). DMF (0.1 M) was added and the reaction mixture was heated at 100 °C for 12 h. More zinc cyanide (0.5 equiv) was added and the reaction mixture was heated at 100 °C for another 24 h. The mixture was cooled, diluted with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-30% MeCN/water, 0.1% formic acid) to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, J = 8.4 Hz, 1H), 7.67 (t, J = 7.7 Hz, 2H), 7.61 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 7.7 Hz, 2H), 6.82 (s, 1H), 3.15 (s, 3H). m/z [M+H] ⁺ 277.0.

According to the above-described method, 4-((cyclopropylmethyl)amino)-2-oxo-1-(o-tolyl)-7-(trifluoromethoxy)-1,2-dihydroquinazoline-6-carbonitrile was obtained using 6-Bromo-4-((cyclopropylmethyl)amino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2(1H)-one.

^1H NMR (400 MHz, MeOD) δ 8.78 (s, 1H), 7.58-7.40 (m, 3H), 7.25 (d, J = 7.7 Hz, 1H), 6, 40 (s, 1H), 3.52 (m, 2H), 2.07 (s, 3H), 1.29 (br.s, 1H), 0.62 (d, J = 7.7 Hz, 2H), 0.40 (brs, 2H). m/z [M+H] ⁺ 415.1.

Example 7

Synthesis of 4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one

In a vial were placed 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one (1 equiv), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2 equiv). Copper iodide (2 equiv) and DMF (0.1 M) were added and the reaction mixture was heated at 100 °C for 12 h. More methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2 equiv) and copper iodide (2 equiv) were added and the reaction mixture was heated at 100 °C for another 24 h. The mixture was cooled, diluted with ethyl acetate, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC (10-30% MeCN/water, 0.1% formic acid) to give the title compound. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.76 (d, J = 8.7 Hz, 1H), 7.59 (t, J = 7.4 Hz, 2H), 7.52 (d, J = 7.0 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 7.6 Hz, 2H), 6.81 (s, 1H), 3.27 (s, 3H). m/z [M+H] ⁺ 320.0.

According to the method described above, the following compounds were obtained, replacing 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one as required:

6-chloro-1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using 7-bromo-6-chloro-1-(2-chlorophenyl)-4-(methylamino)quinazolin-2(1H)-one.

¹ H NMR (400 MHz, DMSO) δ 8.99 (bs, 1H), 8.58 (s, 1H), 7.77 (bs, 1H), 7.67-7.52 (m , 3H), 6.54 (s, 1H), 3.02 (s, 3H). m/z [M+H] ⁺ 388.0.

6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using 7-bromo-6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO) δ 9.03 (br, 1H), 8.71 (s, 1H), 7.76 (br, 1H), 7.59 (br, 3H), 6 .53 (s, 1H), 3.43 (d, J = 5.8 Hz, 2H), 1.21 (b.s, 1H), 0.54 (d, J = 7.8 Hz, 2H), 0.33 (b.s, 2H).m/z [M+H] ⁺ 428.0.

Example 8

Synthesis of 4-amino-7-chloro-1-cyclohexylquinazolin-2(1H)-one

Step 1. Synthesis of 4-chloro-2-(cyclohexylamino)benzonitrile

A microwave reaction vial was charged with 2-bromo-4-chlorobenzonitrile (1.0 equiv), Pd(OAc) ₂ (0.05 equiv), DPPF (0.1 equiv), cyclohexylamine (2.8 equiv), and toluene (0.4 M) under nitrogen atmosphere. The reaction vessel was sealed, purged with nitrogen for 10 min, and microwaved for 30 min at 120 °C. The reaction mixture was diluted by adding 15 mL EtOAc and 5 mL water. The layers were extracted twice with ethyl acetate (2 X 5 mL). The combined organic phases were dried, and the resulting mixture was purified by reverse phase chromatography (0-70% EtOAc/Hex). m/z [M+H] ⁺ 235.1.

Step 2. Synthesis of 2,2,2-trichloro-N-((5-chloro-2-cyanophenyl)(cyclohexyl)carbamoyl)acetamide.

4-Chloro-2-(cyclohexylamino)benzonitrile (1.0 equiv) and anhydrous DCM (0.2 M) were placed in a vial under nitrogen atmosphere. The reaction mixture was cooled to 0 °C and 2,2,2-trichloroacetyl isocyanate (1.0 equiv) was added. The mixture was stirred for 1 h at room temperature. The reaction mixture was cooled to 0 °C and 3 mL of water was added. The layers were extracted twice with dichloromethane (2 X 5 mL). The combined organic phases were dried and the resulting residue was used further without further purification. m/z [M+H] ⁺ 422.0.

Step 3. Synthesis of 4-amino-7-chloro-1-cyclohexylquinazolin-2(1H)-one

2,2,2-Trichloro-N-((5-chloro-2-cyanophenyl)(cyclohexyl)carbamoyl)acetamide (1.0 equiv.) was added to a vial cooled to -10°C under nitrogen atmosphere, followed by a 7N solution of NH ₃ in methanol (20.0 equiv.). The reaction mixture was stirred for 18 h at room temperature. The mixture was evaporated in vacuo, and the residue was purified by reverse-phase chromatography (20-45% MeCN/water, 0.1% formic acid). ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.74 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 4.35 (s, 1H), 2.63-2.44 (m, 2H), 1.88 (d, J = 13.7 Hz, 3H), 1.72 (d, J = 12.6 Hz, 3H), 1.51 (dt, J = 17.0, 11.5 Hz, 2H), 1.30 (q, J = 13.3, 12.7 Hz, 1H). m/z [M+H] ⁺ 278.1.

Example 9

Synthesis of N-(3-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)methanesulfonamide

A vial was charged with 1-(3-bromophenyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (1 equiv), tBuXPhosPd(allyl)OTf (Johnson Matthey C4277, 0.1 equiv), methanesulfonamide (1.6 equiv), potassium carbonate (2.2 equiv), and acetonitrile (0.075 M). The vial was purged with nitrogen and then heated at 80 °C for 18 h. The mixture was cooled to room temperature, diluted with DMSO, filtered, and purified by preparative reversed-phase HPLC (15-100% MeCN/water, 0.1% formic acid) to give the title compound. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.04 (d, J = 8.6 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 7.07 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.41 (s, 1H), 3.30 (s, 6H), 3.06 (s, 3H). m/z [M+H] ⁺ 393.0.

Example 10

Synthesis of 7-chloro-4-(dimethylamino)-1-(3-(2-phenoxyethyl)phenyl)quinazolin-2(1H)-one

A vial was charged with 1-(3-bromophenyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (75 mg, 0.178 mmol), precatalyst AmPhosPd(crotyl)Cl (Johnson Mathey, Pd-161, 0.1 equiv), potassium (2-phenyloxy)ethyl trifluoroborate (1.2 equiv), potassium carbonate (3 equiv), and toluene/water (5:1, 0.1 M). The vial was purged with nitrogen and then heated at 100 °C for 1.3 h. The reaction mixture was cooled to room temperature, filtered, and purified by preparative reversed-phase HPLC (20-80% MeCN/water, 0.1% formic acid) to give the title compound. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.03 (d, J = 8.7 Hz, 1H), 7.59-7.42 (m, 2H), 7.23 (p, J = 8.6, 8.2 Hz, 4H), 7.14 (d, J = 7.7 Hz, 1H), 6.96-6.80 (m, 3H), 6.35 (s, 1H), 4.23 (t, J = 6.6 Hz, 2H), 3.30 (s, 6H), 3.11 (t, J = 6.5 Hz, 2H). m/z [M+H] ⁺ 420.0.

Example 11

Synthesis of 2-(3-(7-Chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)acetic acid

To a stirred solution of iodine (0.1 equiv.) in acetonitrile (0.3 M) and water (0.15 M) was added 7-chloro-4-(methylamino)-1-(3-vinylphenyl)quinazolin-2(1H)-one (1 equiv.). After 5 min, Oxone® (2 equiv.) was added portionwise and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate, and the combined organic layer was washed with water, saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The dried organic phase was filtered and evaporated under reduced pressure to give a crude product which was purified by preparative HPLC (MeCN/ _H2O 60-100%, 0.1% formic acid) to give the title compound as an off-white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.62 (d, J = 4.5 1H), 8.10 (d, J = 8.5, 1H), 7.48 (t, J = 8.0, 1H), 7.38 (d, J = 7.5, 1H), 7.25 (dd, J = 11.0, 2.0 Hz, 1H), 7.15-7.11 (m, 2H), 6.33 (s, 1H), 3.51 (s, 2H), 2.98 (d, J = 4.5 3H). m/z [M+H] ⁺ 344.30.

Example 12

Synthesis of 5-methoxy-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one

To a 20 mL vial under nitrogen atmosphere were added 5-fluoro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one (1.0 equiv.), MeOH (0.6 M) and MeONa (5.4 g in MeOH, 10 equiv.). The reaction mixture was stirred for 60 min at 45°C. The reaction mixture was acidified by adding AcOH. The resulting solution was purified by reverse-phase chromatography (20-60% MeCN/water, with 0.1% formic acid). ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.65 (bps, 1H), 7.60 (t, J = 7.6 Hz, 2H), 7.53 (d, J = 6.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 2H), 7.07 (s, 1H), 6.13 (s, 1H), 4.10 (s, 3H), 3.02 (d, J = 3.9 Hz, 3H). m/z [M+H] ⁺ 350.1.

According to the method described above, the compounds listed below were obtained, replacing 5-fluoro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one as required:

5-methoxy-4-(methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-one was prepared using 4-chloro-5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.94 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 8.18 (d, J = 8.1 Hz , 1H), 8.02 (t, J = 6.5 Hz, 1H), 7.81-7.57 (m, 4H), 6.41 (s, 1H), 3.04 (s, 3H), 2.36 (d, J = 2.1 Hz, 3H).

5-Methoxy-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using 5-chloro-4-(methyl amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.67-8.66 (m, 1H), 7.47-7.38 (m, 3H), 7.14 (dd, J = 1.5, 1.5 Hz, 1H), 7.08 (s, 1H), 6.02 (d, J = 1 Hz, 1H), 4.1 (s, 3H), 3.02 (d, J = 4.5 Hz, 3H), 1.94 (s, 3H). m/z [M+H] ⁺ 364.19.

7-Chloro-1-(2-chlorophenyl)-5-methoxy-4-(methylamino)quinazolin-2(1H)-one was prepared using 7-chloro-1-(2-chlorophenyl)-5-fluoro-4-(methylamino)quinazolin-2(1H)-one.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.57 (d, J = 4.5 Hz, 1H), 7.73-7.72 (m, 1H), 7.57-7.54 ( m, 2H), 7.47-7.46 (m, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.78 (d, J = 2.0 Hz, 1H), 4.04 (s, 3H), 3.00 (d, J = 4.5 Hz, 3H). m/z [M+H] ⁺ 350.2.

7-Chloro-5-methoxy4-((trans-3-methoxycyclobutyl)amino)-1-(o-tolyl)quinazolin-2(1H)-one was prepared using 7-Chloro-5-fluoro-4-((trans-3-methoxycyclobutyl)amino)-1-(o-tolyl)quinazolin-2(1H)-one.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.36 (d, J=6.5 Hz, 1H), 7.45-7.36 (m, 3H), 7.17 (d, J= 7.0 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 5.78 (d, J = 2.0 Hz, H), 4.70-4.63 (m, 1H), 4.07 (s, 3H), 4.04-4.02 (m, 1H), 3.19 (m, 3H ), 2.37-2.33 (m,4H), 1.93 (s, 3H). m/z [M+H] ⁺ 400.33.

7-Chloro-4-((2,2-difluoroethyl)amino)-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one was prepared using 7-Chloro-4-((2,2-difluoroethyl)amino)-5-fluoro-1-(o-tolyl)quinazolin-2(1H)-one.

^1H NMR (500 MHz, DMSO- _d6 ) δ 8.65 (t, J=5.5 Hz, 1H), 7.46-7.37 (m, 3H), 7.19 (dd, J= 7.5,1.5 Hz, 1H), 6.97 (d, J = 1.5 Hz, 1H), 6.43-6.18 (m, 1H), 5.80 (d, J = 1.5 Hz, 1H), 4.05 (s, 3H), 4.03-3.91 (m, 2H) , 1.94 (s, 3H). m/z [M+H] ⁺ 380.35.

Example 13

Synthesis of (S)-4-(pyrrolidin-3-ylamino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one

Tert-butyl (S)-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)pyrrolidine-1-carboxylate (1.0 equiv), MeCN (0.6 M) and HCl (4N solution in dioxane, 25 equiv) were placed in a 20 mL vial. The reaction mixture was stirred for 30 min at 45 °C. The mixture was evaporated on a Genevac apparatus. The residue was purified by reverse-phase chromatography (10-40% ACN/water, with 0.1% formic acid). ^1H NMR (400 MHz, MeCN- _d3 ) δ 8.87 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.38 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.54-7.38 (m, 3H) 7.25 (d, J = 7.6 Hz, 1H), 6.44 (s, 1H), 4.85-4.72 (m, 1H), 3.80-2.94 (m, 4H), 2.24-2.11 (m, 1H), 2.03-1.88 (m, 1H), 1.95 (s, 3H). m/z [M+H] ⁺ 389.15.

According to the above-described procedure, (S)-4-(3-(methylamino)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using tert-butyl (S)-methyl(1-(2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)pyrrolidin-3-yl)carbamate.

^1H NMR (400 MHz, Methanol- _d4 ) δ 8.35 (d, J=8.6 Hz, 1H), 7.49-7.31 (m, 4H), 7.11 (d, J= 7.6 Hz, 1H), 6.60 (s, 1H), 4.20-4.00 (m, 3H), 3.97-3.89 (m, 1H), 3.64-3.56 (m, 1H), 2.54 (s, 3H), 2.40-2.26 (m, 1H), 2. 16-2.02 (m, 1H), 1.94 (s, 3H). m/z [M+H] ⁺ 403.1.

Example 14

Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)-6-(methylthio)quinazolin-2(1H)-one

To a solution of 6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one (1 eq.) in dimethyl sulfoxide (0.05 M) were added copper(I) iodide (2 eq.) and dimethylamine in THF (2 M, 4 eq.). The reaction mixture was heated at 90 °C for 18 h and then cooled. The crude mixture was filtered and purified by reversed-phase liquid chromatography (20-60% MeCN/water, 0.1% formic acid) to give the title compound. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.69-8.62 (m, 1H), 7.85 (s, 1H), 7.71 (d, J = 4.3 Hz, 1H), 7.58-7.51 (m, 2H), 7.46-7.39 (m, 1H), 5.77 (s, 1H), 3.02-2.97 (m, 3H), 2.55 (s, 3H), 1.99 (p, J = 6.5 Hz, 1H), 0.91 (d, J = 8.1 Hz, 2H), 0.24 (d, J = 4.9 Hz, 2H). m/z [M+H] ⁺ 372.0.

According to the above-described method, 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-(methylthio)quinazolin-2(1H)-one was obtained using 1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-(methylthio)quinazolin-2(1H)-one.

^1H NMR (400 MHz, DMSO- _d6 ) δ 8.80-8.73 (m, 1H), 7.96 (s, 1H), 7.75-7.69 (m, 1H), 7. 59-7.51 (m, 2H), 7.47-7.41 (m, 1H), 5.76 (s, 1H), 3.43 (dt, J = 12.0, 5.8 Hz, 2H), 2.57 (s, 3H), 2.08-2.00 (m, 1H), 1.23 (dt , J = 13.0, 7.1 Hz, 1H), 0.92 (d, J = 7.8 Hz, 2H), 0.50 (d, J = 7.4 Hz, 2H), 0.35-0.29 (m, 2H), 0.23 (d, J = 4.6 Hz, 2H). m/z [M+H] ⁺ 412.0.

Example 15

1-((1H-imidazol-4-yl)methyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one

A vial was charged with 4-(methylamino)-7-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one (1.0 equiv) and DCM (0.5 M). TFA (6 equiv) was added at 0 °C and the reaction mixture was stirred with gradual warming to room temperature for 16 h. Purification by preparative HPLC gave the title product as a mixture of enantiomers. Purification by supercritical fluid chromatography (SFC) (30% MeOH, Lux Cellulose-2, peak 1). ^1H NMR (500 MHz, DMSO- _d6 ) δ 11.96 (s, 1H), 8.59 (d, J = 4 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H), 7.54-7.46 (m, 2H), 6.94 (s, 1H), 5.20 (s, 2H), 2.97-2.94 (m, 3H). m/z [M+H] ⁺ 324.35.

The following compounds were obtained using the method described above:

(R)-1-(1-(1H-imidazol-4-yl)ethyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using 4-(methylamino)-7-(trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazolin-2(1H)-one. Purification by supercritical fluid chromatography (SFC) (30% MeOH, Lux Cellulose-2, peak 1).

¹ H NMR (500 MHz, DMSO-d6) δ 8.58-8.57 (m, 1 H), 8.17 (d, J = 8.5 Hz, 1 H), 7.66 (s, 1 H), 7.55 (s, 1 H), 7.45-7.40 (m, 1 H), 7.07 (s, 1 H), 6.50 (q, J = 7 Hz, 1 H), 2.95 (d, J = 8.5 Hz, 3 H), 1.72 (d, J = 7.0 Hz, 3 H). m/z [M+H] 338.3.

(S)-1-(1-(1H-imidazol-4-yl)ethyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared using 4-(methylamino)-7-(trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazolin-2(1H)-one. Purification by supercritical fluid chromatography (SFC) (30% MeOH, Lux Cellulose-2, peak 2).

¹ H NMR (500 MHz, DMSO-d6) δ 8.58-8.57 (m, 1 H), 8.17 (d, J = 8.5 Hz, 1 H), 7.66 (s, 1 H), 7.55 (s, 1 H), 7.45-7.40 (m, 1 H), 7.07 (s, 1 H), 6.50 (q, J = 7 Hz, 1 H), 2.95 (d, J = 8.5 Hz, 3 H), 1.72 (d, J = 7.0 Hz, 3 H). m/z [M+H] 338.3.

1-((1H-imidazol-4-yl)methyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one was prepared using 7-cyclopropyl-4-(methylamino)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.18-8.20 (m, 1 H), 7.84 (d, J = 8.5 Hz, 1 H), 7.53 (s, 1 H), 7.25 (d, J = 1 Hz, 1 H), 6.85-6.81 (m, 2 H), 5.14 (s, 1 H), 2.91 (d, J = 4.5 Hz, 3 H), 1.94-1.92 (m, 1 H), 1.04-1.00 (m, 2 H), 0.98-0.97 (m, 2 H). m/z [M+H] ⁺ 294.4.

Biological examples

Example 1

Biochemical tests

The ability of the compounds of the present invention to inhibit the MAT2A enzyme was determined using the following fluorescence assay using a malachite green or phosphate sensor.

A. Analysis using malachite green

Materials:

Enzyme: MAT2A

- hMAT2A: 50 nM, Cepter, 10 mg/ml (234 µM), amino acids 1-395

- substrates: 500 µM each

- Reaction time: 1 hour

L-methionine substrate: Alfa Aesar catalog number # J61904

ATP substrate: Alfa Aesar catalog number # J60336

Malachite green developing reagent: Millip°re Sigma catalog number # MAK307-1KT

Assay buffer<%=X=%>50 mM Tris, pH 7.5/50 mM KCl/10 mM MgCl ₂ /0.01% Brij-35/1 mM DTT/0.1% BGG

Temperature: 23℃

Total volume: 20 µl

Control:

Control with 0% inhibition: DMSO

Control with 100% inhibition: no enzyme

Methodology:

Five microliters of solutions with 3x the final concentration of test compounds in DMSO or DMSO without added compounds were placed in the desired wells of the microplate, and the plate was centrifuged at 1000 rpm for 1 minute. Five microliters of solutions with 3x the final concentration of MAT2A enzyme in assay buffer or buffer without enzyme were added to the desired wells, and the plate was centrifuged at 1000 rpm for 1 minute. The plate was incubated at room temperature for 15 minutes, and then 5 microliters of solutions with 3x the final concentration of substrate mixture (L-methionine and ATP) in assay buffer were added to all wells. The plate was centrifuged at 1000 rpm for 1 minute and then incubated at room temperature for 1 hour. 5 µl of malachite green detection reagent was added to all wells, the plate was centrifuged at 1000 rpm for 1 minute, and then incubated at room temperature for 30 minutes. The plate was read for absorbance at 620 nm on a plate reader (e.g., Infinite M1000). The control with DMSO only has high absorbance and corresponds to no inhibition of the enzymatic reaction, and the control without enzyme has low absorbance and corresponds to complete inhibition of the enzymatic reaction.

IC ₅₀ values for a representative number of compounds from Table 1 (see above) are given below in Table 3:

(+) IC ₅₀ = 10 µM - 1 µM; (++) IC ₅₀ = 1 µM - 500 nM; (+++) IC ₅₀ = 500 nM - 200 nM; (++++) IC ₅₀ < 200 nM; (++++++) < 10 nM.

Table 3 Compound
(table 1) IC ₅₀ Compound
(table 1) IC ₅₀ Compound
(table 1) IC ₅₀ 2 ++++ 36 ++++ 70 ++++ 3 ++++ 37 ++++ 73 ++++ 4 +++ 38 ++++ 74 ++++ 5 ++++ 39 ++++ 75 ++++ 6 ++++ 42 +++ 76 ++++ 7 ++++ 43 + 77 ++++ 8 + 44 ++++ 80 ++++ 10 +++ 45 ++++ 81 ++++ 11 ++++ 46 ++++ 82 ++++ 12 +++ 47 ++++ 14 ++++ 48 ++++ 15 ++++ 49 ++++ 17 ++++ 50 ++++ 18 ++++ 51 ++++ 21 +++ 52 ++++ 22 +++ 54 ++++ 23 +++ 55 ++++ 24 ++++ 56 ++++ 25 ++++ 57 ++++ 26 ++++ 59 ++++ 27 + 60 ++++ 28 +++ 61 ++++ 29 + 62 +++ 31 ++ 63 + 32 +++ 64 + 34 ++++ 66 ++++ 35 ++++ 67 ++++

B. Fluorescence assay using a phosphate sensor

The MAT2A enzyme was incubated in a microplate with the test compound in DMSO or with DMSO alone, and with its substrates (L-methionine and ATP). The enzymatic reaction was stopped by adding a working mixture with a phosphate sensor. The fluorescence of the plate was analyzed at 450 nm. The control with DMSO, the enzyme, and its substrate yields a high level of fluorescence, which corresponds to the absence of inhibition of the enzyme activity, and the control with DMSO, MAT2A enzyme substrates, but without the addition of the enzyme yields a low level of fluorescence, which corresponds to complete inhibition of the enzyme activity.

Materials:

Human MAT2A: Cepter, amino acids 1-395

Tris, pH 7.5: Invitrogen catalog # 15567-027

KCl: Ambion part number #AM9640G

MgCl ₂ : Ambion catalog number # AM9530G

Brij-35: Sigma catalog number B4184-10ML

DTT: Goldbio part number #DTT100

BGG: Sigma catalog number # G5009-25G

PNP: Novus Biologicals catalog number # NBP1-50872

7-MEG: Cayman Chemical Part Number #15988

L-methionine: Alfa Aesar catalog number # J61904

ATF: Alfa Aesar catalog number # J60336

Phosphate Sensor: Thermo Fisher Part Number #PV4407

EDTA: Life Tech catalog number # 15575-038

Assay Plate: 384-well black polypropylene plate: Thomas Scientific catalog # 1149Q35

Final conditions for conducting the analysis

Assay buffer: 50 mM Tris, pH 7.5/50 mM KCl/10 mM _MgCl2 /0.01% Brij-35/1 mM DTT/0.1% BGG/40 nM PNP/6 μM 7-MEG

MAT2A: 10 nM Cepter clone ID 329, lot 00023-123, before adding working mixture with phosphate sensor

5 nM Cepter clone ID 334, lot 00023-148, before adding working mixture with phosphate sensor

L-methionine: 500 µM before adding the working mixture with the phosphate sensor

ATP: 500 µM before adding the working mixture with the phosphate sensor

Methodology:

The assay was prepared with 1 mM L-methionine/1 mM ATP (2X final concentration before addition of stop solution) in assay buffer; MAT2A (2X final concentration before addition of stop solution) in assay buffer; and phosphate sensor working mix (1.5 μM phosphate sensor/30 mM EDTA in assay buffer, representing 3X final concentration). Test compounds or DMSO were added to the desired wells using a D300e digital dispenser. 5 μL/well of assay buffer was added to the negative control wells and 5 μL/well of MAT2A was added to all wells except the negative control wells. After incubating the plate at room temperature for 15 min, 5 μl/well of 1 mM L-methionine/1 mM ATP was added to all wells. The plate was centrifuged at 1000 rpm for 1 min and then incubated at room temperature for 1 h. 5 μl of phosphate sensor working mixture was added to all wells and the plate was centrifuged at 1000 rpm for 1 min. The plate fluorescence was then read at 450 nm after excitation at 430 nm.

Analysis of results:

Percent inhibition was calculated using the Chemical And Biological Information System (CBIS) (ChemInnovation Software Inc.). Curves were plotted by CBIS as percent inhibition versus log[compound concentration] using a 4-parameter inhibition model.

Fit = (A+((B-A)/(1+((C/x)^D))))

Res = (y-fit)

IC ₅₀ values for a representative number of compounds from Table 1 (see above) are given below in Table 4.

(+) IC ₅₀ = 10 µM - 1 µM; (++) IC ₅₀ = 1 µM - 500 nM; (+++) IC ₅₀ = 500 nM - 200 nM; (++++) IC ₅₀ < 200 nM

Table 4 Connection (table 1) IC ₅₀ Compound
(table 1) IC ₅₀ Connection (table 1) IC ₅₀ Connection (table 1) IC ₅₀ 85 >10 196 ++++ 304 ++++ 412 ++++ 86 +++ 197 ++++ 305 >10 413 ++++ 87 ++++ 188 ++ 306 ++++ 414 ++++ 88 ++++ 199 ++++ 307 ++++ 415 ++++ 80 ++++ 200 + 308 ++++ 416 ++++ 90 +++ 201 ++++ 309 + 417 ++++ 91 ++++ 202 >10 310 ++++ 418 ++++ 92 +++ 203 +++ 311 >10 419 ++++ 93 >10 204 ++++ 312 ++++ 420 ++++ 94 ++ 205 ++++ 313 ++ 421 ++++ 94 + 206 >10 314 ++++ 422 ++++ 96 ++++ 207 ++++ 315 ++++ 423 ++++ 97 ++++ 208 >10 316 +++ 424 ++++ 98 ++++ 209 >10 317 ++++ 425 ++++ 99 ++++ 210 >10 318 ++++ 426 ++++ 100 ++++ 211 ++ 319 ++++ 427-776 ++++ 101 ++++ 212 >10 320 ++++ 102 ++++ 213 + 321 ++++ 103 ++++ 214 ++++ 322 ++++ 104 >10 215 >10 323 ++++ 105 +++ 216 ++++ 324 ++++ 106 + 217 +++ 325 ++++ 107 ++++ 218 ++++ 326 ++++ 108 >10 219 +++ 327 ++++ 109 ++++ 220 + 328 ++++ 110 ++++ 221 + 329 ++++ 112 >10 222 ++++ 330 >10 113 >10 223 ++++ 331 ++++ 114 ++++ 224 >10 332 >10 115 ++++ 225 ++++ 333 ++++ 116 >10 226 ++++ 334 ++++ 117 + 227 ++++ 335 ++++ 118 ++++ 228 >10 336 ++++ 119 ++++ 229 >10 337 ++++ 120 + 230 ++++ 338 ++++ 121 +++ 231 + 339 ++++ 122 ++++ 232 ++++ 340 +++ 123 +++ 233 ++++ 341 ++++ 124 ++ 234 ++++ 342 >10 125 ++++ 235 ++++ 343 >10 126 ++++ 236 >10 344 ++++ 127 ++++ 237 ++++ 345 ++++ 128 ++++ 238 ++++ 346 ++++ 129 ++++ 239 ++++ 347 ++++ 130 ++ 240 + 348 ++++ 132 >10 241 + 349 >10 133 ++++ 242 ++ 350 ++++ 134 ++++ 243 >10 351 ++++ 135 ++++ 244 ++++ 352 ++++ 136 ++++ 245 ++++ 353 ++++ 137 ++++ 246 ++++ 354 >10 138 ++++ 247 ++++ 355 ++++ 139 ++++ 248 ++++ 356 >10 140 ++++ 249 >10 357 + 141 ++++ 250 ++ 358 ++++ 142 ++++ 251 + 359 ++++ 143 ++++ 252 >10 360 >10 144 +++ 253 >10 361 >10 145 ++++ 254 ++++ 362 ++++ 146 ++++ 255 ++++ 363 ++++ 147 ++++ 256 ++++ 364 ++++ 148 ++++ 257 ++++ 365 ++++ 149 ++++ 258 ++++ 366 ++++ 150 ++++ 259 ++++ 367 ++++ 151 ++++ 260 ++++ 368 ++++ 152 ++++ 261 ++++ 369 ++++ 153 ++++ 262 ++++ 370 ++++ 154 ++++ 263 ++++ 371 ++++ 155 +++ 264 ++++ 372 ++++ 156 + 265 ++++ 373 ++++ 157 ++++ 266 + 374 ++++ 159 ++++ 267 + 375 >10 160 ++++ 268 ++++ 376 ++++ 161 ++++ 269 ++++ 377 ++++ 162 ++++ 270 ++++ 378 ++++ 163 ++++ 271 ++++ 379 ++++ 164 ++++ 272 ++++ 380 ++++ 165 ++++ one of 273 and 292
the second of 273 and 292 +++++ 381 ++++ 166 +++ 274 ++++ 382 >10 167 ++++ 275 ++ 383 ++ 168 ++++ 276 + 384 ++++ 169 ++++ 277 ++++ 385 ++++ 170 ++++ 278 ++++ 386 ++++ 171 ++++ 279 ++++ 387 + 172 ++++ 280 ++++ 388 ++++ 173 ++++ 281 ++++ 389 ++++ 174 >10 282 ++++ 390 ++++ 175 ++++ 283 ++++ 391 ++++ 176 ++++ 284 ++++ 392 >10 177 ++++ 285 ++++ 393 >10 178 ++++ 286 ++++ 394 ++++ 179 ++++ 287 ++++ 395 ++++ 180 ++++ 288 >10 396 +++ 181 ++++ 289 >10 397 ++++ 182 ++++ 290 >10 398 ++++ 183 ++++ 291 >10 399 ++++ 184 ++++ 400 ++++ 185 ++++ 293 ++++ 401 +++ 186 ++++ 294 ++++ 402 ++ 187 +++ 295 ++++ 403 + 188 +++ 296 ++++ 404 ++++ 189 ++++ 297 ++++ 405 ++++ 190 + 288 ++++ 406 +++ 191 >10 299 +++ 407 ++++ 192 >10 300 ++++ 408 ++ 193 >10 301 ++++ 409 ++++ 194 >10 302 ++++ 410 ++++ 195 >10 303 ++++ 411 ++++

Claims (86)

1. A compound having the formula (IA’) (IA’), where 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, provided that no more than two of w, x, y, and z are N, where R ³ represents a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyl-C _1-6 alkyloxy, cyano, C _1-6 hydroxyalkoxy, C _1-6 aminoalkoxy, heteroaryl, heterocyclyl or heterocyclyloxy, where heterocyclyl or heteroaryl alone or as part of another group is unsubstituted or substituted with R ^a , R ^b and/or R ^c , independently selected from C _1-6 alkyl, halogen and C _1-6 alkoxycarbonyl; R ⁵ is C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _3-6 cycloalkyl, cyano, C _1-6 dialkylamino, C _1-6 alkoxycarbonyl, C _1-6 hydroxyalkyl, heteroaryl or heterocyclyl; R ⁴ and R ⁶ independently represent a hydrogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, halogen, C _1-6 haloalkyl, C _1-6 haloalkoxy or cyano; R ¹ is R ⁷ , wherein R ⁷ is C _3-6 cycloalkyl, C _6-10 aryl or heteroaryl, wherein the C _6-10 aryl or heteroaryl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ; R ² is C _1-6 alkyl, -OR ⁸ , -NR ⁹ R ¹⁰ , or -X ^b -R ¹¹ , where R ⁸ is C _1-6 alkyl or C _3-6 cycloalkyl; R ⁹ represents a hydrogen atom, C _1-6 alkyl, C _1-6 deuteroalkyl or C _3-6 cycloalkyl; R ¹⁰ represents a hydrogen atom, 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, C _1-6 aminosulfonylalkyl, 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, heterocyclyl-C _1-6 alkyl or spiroheterocyclyl, wherein aryl, heteroaryl or heterocyclyl alone or as part of another group is unsubstituted or substituted by R ^j , R ^k and/or R ^l and wherein cycloalkyl in substituted C _3-6 cycloalkyl and substituted C _3-6 cycloalkyl-C _1-6 alkyl is substituted by one, two or three substituents, wherein two of the three substituents are each independently are C _1-6 alkyl, halogen, C _1-6 alkoxy, hydroxy or C _1-6 haloalkyl, and the third substituent is C _1-6 alkyl, halogen, C _1-6 hydroxyalkyl, C _1-6 haloalkyl or cyano; X ^b represents a bond or C _1-6 alkylene; and R ¹¹ is a monocyclic heteroaryl or heterocyclyl selected from oxetanyl, azetidinyl, 2-oxo-azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperidinyl and morpholinyl, wherein the heteroaryl or heterocyclyl is unsubstituted or substituted with R ^m , R ⁿ and/or R ^o ; and R ^d , R ^e , R ^j , R ^k , R ^m and R ⁿ are independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkoxy, hydroxy, C _1-6 alkylsulfonyl, halogen, cyano, carboxy, C _1-6 alkoxycarbonyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy-C _1-6 alkyl, C _1-6 aminoalkyl, aminosulfonyl, C _1-6 alkylaminosulfonyl, C _1-6 dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, C _1-6 alkylaminocarbonyl and C _1-6 dialkylaminocarbonyl; and R ^f , R ^l and R ^o are independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl, hydroxy, halogen, cyano, amino, C _1-6 alkylamino, C _3-6 cycloalkylsulfonylamino, carboxy-C _1-6 alkyl and -X ^c -R ¹² , where X ^c is a bond or C _1-6 alkylene, R ¹² is unsubstituted C _6-10 aryl; or its pharmaceutically acceptable salt, where each heteroaryl has from 5 to 10 ring members and from 1 to 3 ring vertex heteroatoms, each independently selected from N, O, or S; each heterocyclyl has from 4 to 8 ring members and from 1 to 2 ring vertex heteroatoms, each independently selected from N, O, or S(O) _n , where n is 0, 1, or 2; each bridged cycloalkyl has from 5 to 7 ring members in which two non-adjacent ring atoms are linked by a group (CRR') _q , where q is 1-3 and each R and R' is independently H or methyl; and each spiroheterocyclyl is a saturated bicyclic ring having from 6 to 10 ring members and from 1 to 3 heteroatom ring vertices, each independently selected from N, O, or S(O) _n , where n is 0, 1, or 2; and the bicyclic ring is linked through only one atom. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf) or (IIIg): 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIIa). 4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, having a structure represented by formula (IIId). 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ² is -NR ⁹ R ¹⁰ . 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is a hydrogen atom. 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁹ is methyl or ethyl. 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a hydrogen atom, 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 alkyl. 9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is a hydrogen atom. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is C _3-6 cycloalkyl or C _3-6 cycloalkyl-C _1-6 alkyl, each ring independently being unsubstituted or substituted with one or two substituents independently selected from C _1-6 alkyl, halogen and cyano. 11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is chlorine, trifluoromethyl or ethyl. 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁴ and R ⁶ represent a hydrogen atom. 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom. 14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is R ⁷ , wherein R ⁷ is phenyl which is unsubstituted or substituted by R ^f , wherein R ^f is fluorine, chlorine, bromine or methyl and wherein R ^f is attached to a carbon atom of the phenyl ring which is located in the ortho position to the carbon atom of the phenyl ring attached to the quinazolone nitrogen. 15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is pyridinyl which is unsubstituted or substituted with R ^f , wherein R ^f is fluorine, chlorine, bromine or methyl and wherein R ^f is attached to a carbon atom of the pyridinyl ring which is located in the ortho position to the carbon atom of the pyridinyl ring attached to the quinazolone nitrogen. 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from Conn.
No. Structure Conn.
No. Structure Conn.
No. Structure 2 295 548 3 296 549 4 297 550 5 298 551 6 299 552 7 300 553 8 301 554 10 302 555 11 303 556 12 304 557 13 306 558 14 307 559 15 308 560 17 309 561 18 310 562 21 312 563 22 313 564 23 314 565 24 315 566 25 316 567 26 317 568 28 318 569 29 319 570 31 320 571 32 321 572 34 322 573 35 323 574 36 324 575 37 325 576 38 326 577 39 327 578 42 328 579 43 329 580 44 331 581 45 333 582 46 334 583 47 335 584 48 336 585 49 337 586 50 338 587 51 339 588 52 341 589 54 344 590 55 345 591 56 347 592 57 348 593 59 350 594 60 351 595 61 352 596 62 353 597 63 355 598 64 366 599 66 367 600 67 368 601 70 369 602 73 370 603 74 371 604 76 372 605 77 373 606 80 374 607 81 376 608 82 377 609 86 378 610 87 379 611 88 380 612 89 381 613 90 383 614 91 384 615 92 385 616 94 386 617 94 387 618 96 389 619 97 390 620 99 391 621 100 394 622 101 395 623 102 396 624 105 397 625 106 398 626 109 399 627 114 400 628 115 401 629 117 402 630 118 403 631 119 404 632 120 405 633 121 406 634 122 407 635 123 408 636 124 409 637 125 410 638 126 411 639 127 412 640 128 413 641 129 414 642 133 415 643 134 416 644 135 417 645 136 418 646 137 419 647 138 420 648 139 421 649 140 422 650 141 423 651 142 424 652 143 425 653 144 426 654 145 427 655 146 428 656 148 429 657 149 430 658 150 431 659 151 432 660 153 433 661 154 434 662 155 435 663 157 436 664 159 437 665 160 438 666 161 439 667 162 440 668 163 441 669 164 442 670 165 443 671 167 444 672 168 445 673 169 446 674 170 447 675 171 448 676 172 449 677 173 450 678 174 451 679 175 453 680 176 454 681 177 455 682 178 456 683 179 457 684 180 458 685 181 459 686 182 460 687 183 461 688 184 462 689 185 463 690 186 464 691 187 465 692 188 466 693 189 467 694 190 468 695 196 469 197 470 697 188 471 698 199 472 699 200 473 700 201 474 701 203 475 702 204 476 703 205 477 704 207 478 705 211 479 706 214 480 707 216 481 708 217 482 709 218 483 710 219 484 711 220 485 712 221 486 713 487 714 223 488 715 225 490 716 226 491 717 227 492 718 230 493 719 231 494 720 232 495 721 233 496 722 234 497 723 235 498 724 237 499 725 238 500 726 239 501 727 240 502 728 241 503 729 242 504 730 244 505 731 245 506 732 246 507 733 247 508 734 248 509 735 250 510 736 251 511 737 255 512 738 256 513 739 257 514 740 258 515 741 259 516 742 260 517 743 261 518 744 263 519 745 264 520 746 265 521 747 266 522 748 267 523 749 268 524 750 269 525 751 270 526 752 271 527 753 272 528 754 273 530 755 274 531 756 275 532 757 276 533 758 277 534 759 278 535 760 279 536 761 280 537 762 281 538 763 282 539 764 283 540 765 284 541 766 285 542 767 286 543 768 287 544 769 292 545 770 293 546 771 294 547 772 17. A compound according to claim 1, having formula (IIIa) (IIIa), or a pharmaceutically acceptable salt thereof, where R ³ is hydrogen; R ⁵ is C _1-6 haloalkyl, halogen or C _3-6 cycloalkyl; R ⁴ represents hydrogen or cyano; R ⁶ is hydrogen; R ¹ is R ⁷ , wherein R ⁷ is phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ; R ² is -NR ⁹ R ¹⁰ ; R ⁹ is hydrogen; R ¹⁰ is hydrogen, C _1-6 hydroxyalkyl, C _1-6 alkyl or C _3-6 cycloalkyl, wherein C _3-6 cycloalkyl is unsubstituted or substituted with halogen; R ^d and R ^e are independently selected from C _1-6 alkyl, halogen, C _1-6 haloalkoxy, C _1-6 haloalkyl and hydroxy; and R ^f is selected from C _1-6 alkyl, halogen, C _1-6 haloalkoxy, C _1-6 haloalkyl and hydroxy. 18. A compound according to claim 1, having the formula (IIId) (IIId), or a pharmaceutically acceptable salt thereof, where R ³ is hydrogen; R ⁵ is C _1-6 haloalkyl; R ⁴ is hydrogen; R ¹ is R ⁷ , wherein R ⁷ is phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with R ^d , R ^e and/or R ^f ; R ² is -NR ⁹ R ¹⁰ ; 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 halogen; R ^d and R ^e are independently selected from C _1-6 alkyl, halogen, C _1-6 alkoxy and cyano; and R ^f is selected from C _1-6 alkyl, halogen, C _1-6 alkoxy and cyano. 19. The compound according to item 17, selected from: or a pharmaceutically acceptable salt thereof. 20. The compound according to item 18, selected from: or a pharmaceutically acceptable salt thereof. 21. The compound represented by the formula or a pharmaceutically acceptable salt thereof. 22. The compound represented by the formula 23. A pharmaceutical composition having an inhibitory effect on methionine adenosyltransferase 2A (MAT2A), comprising a compound according to any one of claims 1-22 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 24. A method of treating MTAP-null cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-22 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 23. 25. A method of treating cancer in a patient, wherein the cancer is characterized by a decrease or absence of MTAP gene expression, an absence of the MTAP gene, or a decrease in the function of the MTAP protein, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-22 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 23. 26. The method according to any one of claims 24, 25, 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, mesothelioma, or renal cell carcinoma.