2-oxoquinazoline derivatives as methionine adenylyltransferase 2A inhibitors

Abstract

Disclosed herein are certain 2-oxoquinazoline derivatives of Formula (IA), which are inhibitors of methionine adenylyltransferase 2A (MAT2A). Also disclosed herein are pharmaceutical compositions comprising such compounds and methods of treatment of diseases treatable by inhibition of MAT2A, such as cancers, including cancers characterized by reduced or inactive methylthioadenosine phosphorylase (MTAP) activity. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201980081299.9 filed on December 9, 2019, and invention name “2-Oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 777,715 filed on December 10, 2018, U.S. Provisional Application No. 62 / 835,853 filed on April 18, 2019, and U.S. Provisional Application No. 62 / 883,945 filed on August 7, 2019, the contents of each of which are incorporated by reference in their entirety for all purposes.

[0004] STATEMENT REGARDING RIGHTS TO INVENTS UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0005] not applicable

[0006] Reference to a "Sequence Listing", table or computer program listing appendix submitted on a compact disc

[0007] not applicable Background Art

[0008] Cancer is a leading cause of death worldwide. Mainstream treatments such as chemotherapy and immunotherapy are limited in that their cytotoxic effects are not limited to cancer cells, and adverse effects can occur in normal tissues. Therefore, new strategies are needed to better target cancer cells.

[0009] Synthetic lethality occurs when a combination of defects in the expression of two or more genes leads to cell death, whereas defects in only one of these genes do not. The concept of synthetic lethality originates from studies in the fruit fly model system, where a combination of mutations in two or more independent genes leads to cell death (in contrast to viability, which occurs when only one of the genes is mutated or missing). Recently, a large number of studies have explored the maladaptive genetic changes in cancer cells that make them vulnerable to synthetic lethal approaches. These tumor-specific genetic defects have led to the use of targeted drugs that can induce tumor cell death while sparing normal cells.

[0010] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosylmethionine (SAM). SAM is the major methyl donor in cells and is used to methylate a variety of substrates including DNA, RNA, and proteins. One methyltransferase that utilizes SAM as a methyl donor is protein arginine N-methyltransferase 5 (PRMT5). Although SAM is required for PRMT5 activity, PRMT5 is competitively inhibited by 5' methylthioadenosine (MTA). Since MTA is part of the methionine salvage pathway, cellular MTA levels remain low during the initiation of methylthioadenosine phosphorylase (MTAP).

[0011] MTAP is located in a locus on chromosome 9, which is often missing from several tissues of origin in cells of patients with cancer, including the central nervous system, pancreas, esophagus, bladder and lung (cBioPortal database). Compared with cells expressing MTAP, the loss of MTAP leads to the accumulation of MTA, making cells lacking MTAP (MTAP-deleted cells) more dependent on the production of SAM, and then dependent on the activity of MAT2A. In the shRNA cell line screening of about 400 cancer cell lines, compared with MTAP WT cells, MAT2A knockdown leads to a greater percentage of cells lacking MTAP losing viability (see McDonald et al. 2017 Cell 170, 577-592 pages). In addition, the inducible knockdown of MAT2A protein reduces the growth of tumors in vivo (see Marjon et al., Cell Report 15 (3) in 2016, 574-587). These results suggest that MAT2A inhibitors may offer a novel therapeutic approach for cancer patients, including those with tumors that have deleted MTAP. Summary of the invention

[0012] Disclosed herein are certain 2-oxoquinazoline derivatives that are inhibitors of methionine adenosyltransferase 2A (MAT2A). Also disclosed herein are pharmaceutical compositions comprising such compounds and methods of treating diseases treatable by inhibiting MAT2A, such as cancer, including cancers characterized by reduced or inactive methylthioadenosine phosphorylase (MTAP) activity.

[0013] In a first aspect, a compound of formula (IA'), or a pharmaceutically acceptable salt thereof, is provided:

[0014]

[0015] in:

[0016] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0017] R 3 R is hydrogen, 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, heterocyclylalkoxy, heterocyclyloxyalkoxy or heterocyclyloxyalkylamino, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0018] R 5 R is hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0019] R 4 and R 6are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0020] R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 , where X a is a bond or an alkylene group, R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0021] R 2 is hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0022] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0023] R 9 is hydrogen, alkyl, deuterated alkyl or cycloalkyl; and

[0024] R 10R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl by itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0025] X b is a bond or an alkylene group; and

[0026] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0027] R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0028] R f , R i , R l and R o 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 cis a bond, alkylene or heteroalkylene, and R 12 is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic; provided that when R l is a heterocyclic group and one R d and R e When it is hydroxyl, R f Not hydroxyl;

[0029] The premise is:

[0030] (1) When for 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 is hydrogen, R 4 is chlorine, and R 5 When bromine or 5-methylindazol-4-yl, 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 is hydrogen, and R 5 When it is methyl, R 1 is not isopropyl; (c) when R 2 is hydrogen, R 3 , R 5 and R 6 is hydrogen, and R 4 When it is chlorine, R 1 is not benzyl; (d) when R 2 is hydrogen, R 3 , R 5 and R 6 is hydrogen, and R 4 When it is bromine, 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 is hydrogen, and R 4 When it is chlorine or fluorine, 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 is hydrogen, and R 4 When it is chlorine, R 1 is not cyclopropylmethyl; (g) when R2 is hydrogen or thiophen-2-yl, R 3 , R 5 and R 6 is hydrogen, and R 4 When it is methoxy; or R 2 is thiophen-2-yl, R 3 , R 4 and R 6 is hydrogen, and R 5 When it is methyl, R 1 is not cyclopropylmethyl or 2,2,2-trifluoroethyl; (h) when R 2 and R 6 is methyl, and R 3 , R 4 and R 5 When it is hydrogen; or R 2 and R 3 is methyl, and R 4 , R 5 and R 6 When it is hydrogen, R 1 is not 2,5-, 2,6- or 2,8-dimethylquinolin-4-yl or 2-methyl-5-methoxy-, 2-methyl-6-methoxy- or 2-methyl-8-methoxyquinolin-4-yl; (i) when R 2 is trifluoromethyl, R 3 is methoxy or methyl, and R 4 , R 5 and R 6 When it is hydrogen; or R 2 is trifluoromethyl, R 3 is fluorine or hydrogen, R 4 is halogen, methyl, methoxy, isopropyl or trifluoromethyl, and R 5 and R 6 When it is hydrogen, R 1 is not 4-methoxybenzyl or naphth-1-ylmethyl; (j) when R 2 and R 3 is chlorine and R 4 , R 5 and R 6 When it is hydrogen; or R 2 is trifluoromethyl, R 3 is chlorine, and R 4 , R 5 and R 6 When it is hydrogen; or R 4 is amino, R 3 , R 5 and R 6 is hydrogen, and R 2is 1-methyl-1-pyrimidin-2-ylethylamino, 1-cyclopropylethylamino, 1-pyrimidin-2-ylethylamino, 2-hydroxy-1-methylethylamino or 3-hydroxy-1-methylpropylamino; or R 3 is methoxy, R 4 , R 5 and R 6 is hydrogen, and R 2 When it is 2-methyl-2-phenylpropylamino; or R 4 is chlorine, R 3 , R 5 and R 6 is H, and R 2 When it is 1-naphth-2-ylmethylpiperidin-4-ylamino, 1-ethoxycarbonylpiperidin-4-ylamino or 1-quinolin-6-ylmethylpiperidin-4-ylamino, then R 1 is not a methyl group; (k) when R 2 is methyl, R 3 and R 6 is hydrogen, and R 4 and R 5 When it is methoxy, 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 is hydrogen, and R 4 When R is chlorine, methoxy or fluorine, 1 is not benzyl, 4-methylbenzyl or 3,5-dimethylbenzyl; (m) when R 2 is methyl, R 3 , R 5 and R 6 is hydrogen, and R 4 When it is bromine, R 1 Not ethyl; (n) when R 2 is 4-methoxycyclohexylamino, R 3 , R 5 and R 6 is hydrogen, and R 4 When it is iodine; or R 2 is methyl, R 3 and R 4 is a methoxy group, and R 5 and R 6 When it is hydrogen, then R 1 Not a methyl group; (o) when R 2 is amino or acetylamino, R 4 is dimethylamino, and R 3 , R 5 and R 6 When it is hydrogen, then R1 is not 4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (p) when R 4 is chlorine, R 3 , R 5 and R 6 is hydrogen, and R 1 When it 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 is hydrogen, and R 2 When it 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 is hydrogen, and R 2 When it 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 fluorine, and R 3 , R 4 and R 6 When it is hydrogen, 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 is hydrogen, and R 1 When it is pentyl, R 2 It is not 1-naphth-1-ylmethylpiperidin-4-ylamino, 1-naphth-2-ylmethylpiperidin-4-ylamino or 1-ethoxycarbonylpiperidin-4-ylamino.

[0031] (2) When for When (a) R 2 is hydrogen, R 3 and R 5 is methyl, R 4 When it is hydrogen, then R 1 is not 2-dimethylaminoethyl or 2-diisopropylaminoethyl; (b) when R 2 is chlorine, R 3 is 3-pentyloxy, R4 is hydrogen, and R 5 When it is methyl, 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 is hydrogen, and R 5 When it is methyl, hydroxymethyl or ethyl, then R 1 is not ethyl; (d) when R 2 and R 3 is hydrogen, R 4 is cyano, and R 5 When it is an amino group, R 1 not allyl, benzyl, methyl or ethyl;

[0032] (3) When for When (a) R 2 is hydrogen, R 3 is chlorine, and R 5 When R is 1,3-dihydroxypropan-2-ylamino, 3-diethylaminopropylamino or 4-(4-methylpiperidin-1-yl)piperidin-1-yl, 1 is not 2,4-difluorophenyl, 2,6-difluorophenyl or 4-trifluoromethylphenyl; (b) when R 2 and R 3 is hydrogen, and R 5 When it is pyridin-4-ylamino, then R 1 is not a cyclopentyl group; (c) when R 1 is 4-hydroxy-5-hydroxymethylfuran-1-yl, R 5 is an amino group, and R 3 When it is methoxy; or when R 1 is 4-methoxybenzyl, R 3 is a methoxy group, and R 5 When it is an amino group, R 2 It is not amino;

[0033] (4) When for When (a) R 2 and R 5 is a methoxy group, and R 4 is hydrogen; or when R 2 is hydrogen, amino or dimethylamino, R 4 and R 5 One of them is hydrogen, and R 4 and R 5 The other is methyl or R 4 and R 5 When it is methyl, then R1 is not a methyl group; (b) when R 1 is 4-hydroxy-5-hydroxymethylfuran-1-yl, R 4 and R 5 One of them is hydrogen, R 4 and R 5 The other is methyl or R 4 and R 5 When both are methyl, then R 2 Not amino;

[0034] (5) When for When (a) R 2 is 4-hydroxycyclohexylamino, dimethylaminocarbonylmethylamino or 4-(2-hydroxyethyl)piperazine-1-yl, R 5 is chloro or 6-methoxypyridin-3-yl, and R 6 When it is hydrogen, R 1 is not 2-ethoxyethyl; (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 When it is hydrogen, R 1 Not 2-propoxyethyl;

[0035] (6) When for When R 2 is 4-(2-hydroxyethyl)piperazin-1-yl or 4-hydroxycyclohexylamino, R 4 and R 6 is hydrogen, and R 5 When it is chlorine or 6-methoxypyridin-3-yl, then R 1 is not 2-propoxyethyl; and

[0036] (7) When for When R 2 is 2-isopropoxyethylamino, 4-hydroxy-cyclohexylamino, 4-(2-hydroxyethyl)piperazin-1-yl, 2-(morpholin-4-yl)ethylamino, R 3 and R 6 is hydrogen, and R 5 When it is 6-methoxypyridin-3-yl, then R 1 Not 2-propoxyethyl.

[0037] In one embodiment of the first aspect, there is provided a compound of formula (IA):

[0038]

[0039] in,

[0040] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0041] R 3 R is hydrogen, 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, heterocyclylalkoxy, heterocyclyloxyalkoxy or heterocyclyloxyalkylamino, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0042] R 5 R is hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is substituted by R independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c replace;

[0043] R 4 and R 6are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0044] R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 , where X a is a bond or an alkylene group, R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0045] R 2 is hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0046] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0047] R 9 is hydrogen, alkyl, deuterated alkyl or cycloalkyl; and

[0048] R 10R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0049] X b is a bond or an alkylene group; and

[0050] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0051] R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0052] R f , R i , R l and R o 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 R12 is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic; provided that when R 1 is a heterocyclic group and one R d and R e When it is hydroxyl, R f is not a hydroxyl group; or

[0053] or pharmaceutically acceptable salts thereof.

[0054] In another embodiment of the first aspect, there is provided a compound of formula (I):

[0055]

[0056] in,

[0057] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0058] R 3 and R 5 R is independently hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0059] R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0060] R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 , where X a is a bond or an alkylene group and R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0061] R 2 is hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0062] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0063] R 9 is hydrogen, alkyl or cycloalkyl; and

[0064] R 10 R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl by itself or as part of another group is unsubstituted or replaced by R j, R k and / or R l replace;

[0065] X b is a bond or an alkylene group; and

[0066] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0067] R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0068] 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

[0069] or pharmaceutically acceptable salts thereof.

[0070] In a second aspect, a pharmaceutical composition is provided, comprising:

[0071] (a) Compound of formula (IIA'):

[0072]

[0073] in:

[0074] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR6 or N, where:

[0075] R 3 R is hydrogen, 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, heterocyclylalkoxy, heterocyclyloxyalkoxy or heterocyclyloxyalkylamino, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0076] R 5 R is hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0077] R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0078] R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 , where X a is a bond or an alkylene group and R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0079] R 2 is hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0080] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0081] R 9 is hydrogen, alkyl, deuterated alkyl or cycloalkyl; and

[0082] R 10R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl by itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0083] X b is a bond or an alkylene group; and

[0084] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0085] R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0086] R f , R i , R l and R o 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 cis a bond, alkylene or heteroalkylene, and R 12 is optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic; provided that when R 1 is a heterocyclic group and one R d and R e When it is hydroxyl, R f is not a hydroxyl group; or

[0087] (b) Compounds of formula (IIA):

[0088]

[0089] in:

[0090] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0091] R 3 R is hydrogen, 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, heterocyclylalkoxy, heterocyclyloxyalkoxy or heterocyclyloxyalkylamino, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0092] R 5R is hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is substituted by R independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c replace;

[0093] R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0094] R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 , where X a is a bond or an alkylene group and R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0095] R 2 is hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0096] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0097] R 9 is hydrogen, alkyl, deuterated alkyl or cycloalkyl; and

[0098] R 10 R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0099] X b is a bond or an alkylene group; and

[0100] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0101] R d , R e , R g , R h , R j , R k , R m and R nindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0102] R f , R i , R l and R o 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 an optionally substituted aryl group, an optionally substituted heteroaryl group, and an optionally substituted heterocyclic group;

[0103] (c) Compounds of formula (II):

[0104]

[0105] in:

[0106] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0107] R 3 and R 5 R is independently hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0108] R4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0109] R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 , where X a is a bond or an alkylene group, R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0110] R 2 is hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0111] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0112] R 9 is hydrogen, alkyl or cycloalkyl; and

[0113] R 10R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl by itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0114] X b is a bond or an alkylene group; and

[0115] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0116] R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0117] 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 an optionally substituted aryl group, an optionally substituted heteroaryl group, and an optionally substituted heterocyclic group;

[0118] (d) Compounds of formula (IVA):

[0119]

[0120] in:

[0121] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0122] R 3 and R 5 R is independently hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0123] R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of is not hydrogen, and (iii) R 3 , R 4 , R 5 and R 6 At least one of them is hydrogen;

[0124] R 1 is a 5- to 8-membered cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclic group, bridged heterocyclic group, fused heterocyclic group or spiro heterocyclic group, wherein the aryl, heteroaryl, heterocyclic group, bridged heterocyclic group, fused heterocyclic group and spiro heterocyclic group are unsubstituted or replaced by R d , R e and / or Rf Substitution, where R d and R e R is independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; 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 and optionally substituted heterocyclyl; or

[0125] (e) a compound of formula (IA'), (IA), (I) or (IV);

[0126] (or any embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof;

[0127] and at least one pharmaceutically acceptable excipient.

[0128] In a third aspect, a method of treating a disease mediated by MAT2A in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of the third aspect, the patient is considered to be in need of such treatment. In a second embodiment of the third aspect and the first embodiment contained therein, a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition. In a third embodiment of the third aspect and the first and second embodiments contained therein, the disease is mediated by overexpression of MAT2A. In a fourth embodiment of the third aspect and the first, second and third embodiments contained therein, the disease is cancer.

[0129] In a fourth aspect, a method of treating MTAP null cancer in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof. In a first embodiment of the fourth aspect, the patient is considered to be in need of such treatment. In a second embodiment of the fourth aspect and the first embodiment contained therein, a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, is administered in the form of a pharmaceutical composition.

[0130] In a fifth aspect, a method is provided for inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in a cell, comprising contacting the cell with an effective amount of a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof.

[0131] In a sixth aspect, a method for treating cancer in a patient is provided, wherein the cancer is characterized by reduced or no expression of the methylthioadenosine phosphorylase (MTAP) gene, MTAP gene deletion, or reduced MTAP protein function, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein), or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

[0132] In a seventh aspect, a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof is provided for use in inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in a cell.

[0133] In an eighth aspect, a compound of Formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof is provided for use in treating a disease in a patient, wherein the disease is mediated by overexpression of MAT2A.

[0134] In a ninth aspect, a compound of formula (IA'), (IA), (I), (IIA), (II), (IVA) or (IV) (or an embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a patient, wherein the cancer is characterized by reduced or absent expression of the methylthioadenosine phosphorylase (MTAP) gene, MTAP gene deletion or reduced MTAP protein function.

[0135] In the tenth aspect, there is provided a compound of formula (IV), or a tautomeric form thereof; or a pharmaceutically acceptable salt thereof:

[0136]

[0137] in:

[0138] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0139] R 3 and R 5 R is independently hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0140] R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of is not hydrogen, and (iii) R 3, R 4 , R 5 and R 6 At least one of them is hydrogen;

[0141] R 1 is a 5- to 8-membered cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclic group, bridged heterocyclic group, fused heterocyclic group or spiro heterocyclic group, wherein the aryl, heteroaryl, heterocyclic group, bridged heterocyclic group, fused heterocyclic group and spiro heterocyclic group are unsubstituted or replaced by R d , R e and / or R f Substitution, where R d and R e R is independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; 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 an optionally substituted aryl group, an optionally substituted heteroaryl group, and an optionally substituted heterocyclic group;

[0142] Provided that the compound of formula (IV) is not:

[0143] (1)R 1 Not (a) 5-hydroxymethyltetrahydrofuran-2-yl or 5-hydroxymethyltetrahydrofuran-2-yl substituted by hydroxy or fluorine; (b) 3-hydroxy-4-hydroxymethylcyclopentyl; and (c) 5-aminomethyltetrahydrofuran-2-yl substituted by fluorine or hydroxy;

[0144] (2) When for When: (a) when R 3 and R 5 is fluorine, and R 4 and R 6 When it is hydrogen; or R 4 and R 5 is fluorine, R 3 and R 6 When it is hydrogen; or R 5 is fluorine, and R 3 , R 4 and R 6 When it is hydrogen, R 1 is not cyclopentyl or tetrahydrofuran-3-yl; (b) when R 5is chlorine, and R 3 , R 4 and R 6 When it is hydrogen, 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 When it is hydrogen, then R 1 is not 4-chlorophenyl; (d) when R 4 is bromine, and R 3 , R 5 and R 6 When it is hydrogen, 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 When it is hydrogen, 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 When it is hydrogen, 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 When it is hydrogen, R 1 is not piperidin-4-yl; and (h) when R 5 is methoxy and R 3 , R 4 and R 6 When it is hydrogen; or R 4 and R 5 is fluorine, R 3 is hydrogen, and R 6 When it is methyl, R 1 Not phenyl;

[0145] (3) When for Then (a) when R 3 and R 5 is methyl, and R 4 When it is hydrogen, R 1 is not 4-ethoxyphenyl; (b) when R3 is 3-pentyloxy, R 5 is methyl and R 4 When it is hydrogen, R 1 is not 2,4,6-trimethylphenyl; (c) when R 4 and R 5 is chlorine and R 3 When it is hydrogen, R 1 is not 2-isopropyl-6-methylphenyl; (d) when R 5 is trifluoromethyl and R 3 and R 4 When it is hydrogen, 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 When it is hydrogen, R 1 is not phenyl, 2-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 4-ethylphenyl, cyclopentyl, cyclohexyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl, or 2- or 4-methoxyphenyl; (f) when R 4 is bromine, and R 3 and R 5 When it is hydrogen; or R 4 is hydrogen, R 3 and R 5 One of them is methyl, and R 3 and R 5 When the other of is hydrogen; or R 4 is hydrogen, R 3 and R 5 is methyl; or R 5 is amino, R 3 and R 4 When it is hydrogen; or R 5 is amino, R 3 is hydrogen, and R 4 When it is cyano; or R 4 is 2-hydroxyethyl, R 3 is hydrogen, and R 5 When it is methyl, R 1 is not phenyl; and (g) R 3 is furan-2-yl, R 4 and R 5 When it is hydrogen, then R 1 Not cyclohexyl;

[0146] (4) When for Then (a) when R 4 and R 5When it is methyl, R 1 is not phenyl, 2-chlorophenyl, 3-chlorophenyl, 2-methoxyphenyl, 4-methylphenyl or 4-methoxyphenyl; and

[0147] (5) When for Then when R 3 and R 5 When it is ethylamino or chlorine, R 1 Not phenyl.

[0148] In one embodiment of the tenth aspect, w, x, y, z, R in formula (IV) l , R 3 , R 4 , R 5 and R 6 As defined in the following embodiments 5, 21, 22, 23, 27 to 34 and the sub-embodiments contained therein.

[0149] The compound of formula (IV) is useful as an intermediate in the synthesis of compounds of formula (IA), (I), (IIA) and (II), and also inhibits MAT2A. DETAILED DESCRIPTION

[0150] Before further describing the present invention, it is to be understood that the present invention is not limited to the particular embodiments described herein and it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0151] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the claims may be drafted to exclude any optional elements. Thus, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only," and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0152] Where a range of values ​​is provided, it is understood that every intermediate value between the upper and lower limits of the range, to one tenth of the lower limit, unless the context clearly indicates otherwise, and any other stated or intermediate values ​​within the stated range are included in the present invention. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are also included in the present invention, subject to any explicitly excluded limitations within the stated ranges. When the range includes one or two limits, the range excluding any one or two of those included limits is also included in the present invention. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present invention belongs.

[0153] When necessary, any definition herein can be used in combination with any other definition to describe a composite structural group. By convention, any such defined following element is an element attached to the parent moiety. For example, the composite group alkoxyalkyl refers to an alkoxy group connected to the parent molecule via an alkyl group.

[0154] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates and may need to be independently confirmed.

[0155] definition:

[0156] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:

[0157] "Alkyl" refers to a straight chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. Those skilled in the art will recognize that the term "alkyl" may include "alkylene" groups.

[0158] Unless otherwise specified, "alkylene" refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0159] The "alkenyl group" refers to a straight-chain monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched monovalent hydrocarbon group having 3 to 6 carbon atoms containing a double bond, for example, propenyl, butenyl, and the like.

[0160] The "alkynyl group" refers to a linear monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched monovalent hydrocarbon group having 3 to 6 carbon atoms containing a triple bond, for example, ethynyl, propynyl, butynyl and the like.

[0161] "Alkoxy" refers to a -OR group where R is alkyl as defined above, for example methoxy, ethoxy, propoxy or 2-propoxy, n-, iso- or tert-butoxy and the like.

[0162] "Alkoxyalkyl" refers to a linear monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3 to 6 carbon atoms substituted with one alkoxy radical as defined above, for example, 2-methoxyethyl, 1-, 2- or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0163] "Alkoxyalkoxy" means a -OR radical where R is alkoxyalkyl as defined above, eg, methoxyethoxy, ethoxypropoxy, and the like.

[0164] "Alkoxyalkylamino" refers to a -NRR' group where R is hydrogen or alkyl and R' is alkoxyalkyl, each as defined above, for example, methoxyethylamino, methoxypropylamino, and the like.

[0165] "Alkylcarbonyl" means a -C(O)R group where R is alkyl as defined herein, eg, methylcarbonyl, ethylcarbonyl, and the like.

[0166] "Alkoxycarbonyl" refers to a -C(O)OR group where R is alkyl as defined above, for example, methoxycarbonyl, ethoxycarbonyl, and the like.

[0167] "Alkoxycarboxyalkyl" refers to an alkyl group as defined above substituted with an alkoxycarboxy group, for example, methylcarboxymethyl, ethylcarboxyethyl, and the like.

[0168] "Alkylthio" refers to a -SR group where R is alkyl as defined above, eg, methylthio, ethylthio, and the like.

[0169] "Alkylsulfonyl" refers to -SO 2 R group, wherein R is alkyl as defined above, for example, methylsulfonyl, ethylsulfonyl, and the like.

[0170] "Alkylsulfonylalkyl" refers to -(alkylene)-SO 2 R group, wherein R is alkyl as defined above, for example, methylsulfonylethyl, ethylsulfonylmethyl, and the like.

[0171] "Amino" refers to -NH 2 .

[0172] "Alkylamino" refers to a -NHR group where R is alkyl as defined above, for example, methylamino, ethylamino, propylamino, or 2-propylamino and the like.

[0173] "Aminoalkyl" refers to a linear monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3 to 6 carbon atoms substituted by -NR'R", wherein R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or alkylcarbonyl, each as defined herein, for example, aminomethyl, aminoethyl, methylaminomethyl, and the like.

[0174] "Aminoalkoxy" means a -OR radical where R is aminoalkyl as defined above, eg, aminoethoxy, methylaminopropoxy, dimethylaminoethoxy, diethylaminopropoxy, and the like.

[0175] "Aminoalkylamino" refers to a -NRR' group where R is hydrogen or alkyl and R' is aminoalkyl, each as defined above, for example, aminoethylamino, methylaminopropylamino, dimethylaminoethylamino, diethylaminopropylamino and the like.

[0176] "Aminocarbonyl" refers to -CONH 2 Group.

[0177] "Alkylaminocarbonyl" means a -CONHR radical where R is alkyl as defined above, eg, methylaminocarbonyl, ethylaminocarbonyl, and the like.

[0178] "Aminosulfonyl" refers to -SO 2 NH 2 Group.

[0179] "Aminosulfonylalkyl" refers to -(alkylene)SO 2 NRR' groups, wherein R is hydrogen or alkyl, and R' is hydrogen, alkyl or cycloalkyl, or R and R' together with the nitrogen atom to which they are attached form a heterocyclic group, as defined above, for example, methylaminosulfonylethyl, dimethylsulfonylethyl, and the like.

[0180] "Alkylaminosulfonyl" refers to -SO 2 NHR group, wherein R is alkyl as defined above, for example, methylaminosulfonyl, ethylaminosulfonyl, and the like.

[0181] "Aminocarbonylalkyl" refers to a -(alkylene)-CONRR' radical where R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, each as defined herein, for example, aminocarbonylethyl, methylaminocarbonylethyl, dimethylaminocarbonylethyl, and the like.

[0182] "Aminosulfonylalkyl" refers to an -(alkylene)-SO 2 NRR' groups, wherein R' and R" are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl or alkoxyalkyl, each as defined herein, for example, aminosulfonylethyl, methylaminosulfonylethyl, dimethylaminosulfonylethyl, and the like.

[0183] "Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 ring atoms, for example, phenyl or naphthyl.

[0184] "Aralkyl" refers to a -(alkylene)-R radical where R is aryl as defined above, eg, benzyl, phenethyl, and the like.

[0185] "Bridged cycloalkyl" refers to 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 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, hydroxyl or cyano. Examples of bridged cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like.

[0186] "Bridged cycloalkylalkyl" refers to a -(alkylene)-R group, where R is a bridged cycloalkyl as defined above. Examples include, but are not limited to, bicyclo[2.2.1]heptylmethyl and the like.

[0187] "Bridged heterocyclic group" refers to a saturated monocyclic ring having 5 to 7 ring carbon atoms, wherein two non-adjacent ring atoms are linked by a (CRR')n group, wherein n is 1 to 3, and each R is independently H or methyl (also referred to herein as a "bridging" group), and further, wherein one or two ring carbon atoms (including the atoms in the bridging group) are substituted with heteroatoms selected from N, O or S(O)n, wherein n is an integer from 0 to 2. The bridged heterocyclic group may be optionally substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl 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.

[0188] "Bridged heterocyclylalkyl" refers to a -(alkylene)-R radical where R is a bridged heterocyclyl as defined above (including the specific bridged heterocyclyl rings).

[0189] "Cycloalkyl" refers to a monocyclic monovalent hydrocarbon radical having 3 to 6 carbon atoms, which may be saturated or contain a double bond. The cycloalkyl may be unsubstituted or substituted by one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxyl or cyano. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocyclopropyl-1-yl, 1-cyanomethylcyclopropyl-1-yl, 3-fluorocyclohexyl, etc. When the cycloalkyl contains a double bond, it may be referred to as a cycloalkenyl radical in this article.

[0190] "Cycloalkylalkyl" refers to a -(alkylene)-R group, where R is a cycloalkyl group as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, and the like.

[0191] "Cycloalkylalkyloxy" refers to a -OR group where R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethoxy, cyclobutylmethoxy, and the like.

[0192] "Cycloalkyloxyalkyl" refers to a -(alkylene)-OR group where R is a cycloalkyl group as defined above. Examples include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxyethyl, and the like.

[0193] "Cycloalkylsulfonylamino" refers to -NRSO 2 -R' group, wherein R is hydrogen or alkyl, and R' is cycloalkyl, each as defined above. Examples include, but are not limited to, cyclopropylsulfonylamino, N-cyclopropylsulfonylN(CH 3 )wait.

[0194] "Cyanoalkyl" refers to an alkyl group as defined above substituted with a cyano group, for example, cyanomethyl, cyanoethyl, and the like.

[0195] "Carboxy" refers to a -COOH group.

[0196] "Carboxyalkyl" refers to an alkyl group as defined above substituted with a carboxy group, for example, carboxymethyl, carboxyethyl, and the like.

[0197] "Deuterated alkyl" refers to an alkyl group as defined above wherein from 1 to 6 hydrogen atoms in the alkyl chain are replaced by deuterium atoms. Examples include, but are not limited to, -CD 3 、-CH 2 CHD 2 wait.

[0198] "Dialkylamino" refers to a -NRR' group where R and R' are alkyl as defined above, for example, dimethylamino, methylethylamino, and the like.

[0199] "Dialkylaminocarbonyl" refers to a -CONRR' group where R and R' are alkyl as defined above, for example dimethylaminocarbonyl, diethylaminocarbonyl, and the like.

[0200] "Dialkylaminosulfonyl" refers to -SO 2 NRR' groups, wherein R and R' are alkyl as defined above, for example dimethylaminosulfonyl, diethylaminosulfonyl, and the like.

[0201] "Fused cycloalkyl" refers to a saturated monovalent hydrocarbon radical having 3 to 6 carbon atoms fused to a phenyl or five- or six-membered heteroaryl ring as defined herein, and optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, halogen, alkoxy, haloalkyl, haloalkoxy, hydroxyl 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.

[0202] "Fused heterocyclyl" refers to a heterocyclyl as defined herein fused to a cycloalkyl, phenyl, or five- or six-membered heteroaryl ring as defined herein. The fused heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from alkyl, halogen, alkoxy, hydroxyl, 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.

[0203] "Fused heterocyclylalkyl" means a -(alkylene)-R radical where R is a fused heterocyclyloxy radical as defined above (including the specific fused heterocyclyl rings).

[0204] "Halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0205] "Haloalkyl" refers to an alkyl group as defined above substituted with 1 to 5 halogen atoms, such as fluorine or chlorine atoms, including groups substituted with different halogens, such as -CH 2 Cl, -CF 3 , -CHF 2 、-CH 2 CF 3 , -CF 2 CF 3 、-CF(CH 3 ) 2 When an alkyl group is substituted only with fluorine, it may be referred to as a fluoroalkyl group in the present application.

[0206] "Haloalkoxy" refers to a -OR group where R is a haloalkyl group as defined above, e.g., -OCF 3 、-OCHF 2 When R is a haloalkyl group (wherein the alkyl group is substituted only with fluorine), it is referred to herein as a fluoroalkoxy group.

[0207] "Haloalkoxyalkyl" refers to an alkyl group substituted with a haloalkoxy group, each as defined above, for example, trifluoromethoxyethyl and the like.

[0208] "Heteroalkylene" refers to a straight chain saturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms, one of the carbon atoms being replaced by -O-, -NR-, -NR'CO-, -CONR'-, SO 2 NR'-or-NR'SO 2 -substituted, unless otherwise indicated, R and R' are independently H or alkyl as defined herein, e.g., -CH 2 O-、-OCH 2 -、-(CH 2 ) 2 O-、-O(CH 2 ) 2 -、-(CH 2 ) 2 NH-、-NH(CH 2 ) 2 -wait.

[0209] "Hydroxyalkyl" refers to a linear monovalent hydrocarbon radical having 1 to 6 carbon atoms or a branched monovalent hydrocarbon radical having 3 or 6 carbon atoms substituted by one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not simultaneously 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.

[0210] "Hydroxyalkoxy" means a -OR group where R is hydroxyalkyl as defined above, eg, hydroxyethoxy, hydroxypropoxy, and the like.

[0211] "Hydroxyalkylamino" refers to a -NRR' group where R is hydrogen or alkyl and R' is hydroxyalkyl, each as defined above, for example, hydroxyethylamino, hydroxypropylamino, and the like.

[0212] Unless otherwise specified, "heteroaryl" refers to a monovalent monocyclic or bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two or three) of the ring atoms are heteroatoms selected from N, O or S, and the remaining ring atoms are carbon. Non-limiting examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridinyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. As defined herein, the terms "heteroaryl" and "aryl" are independent of each other. When the heteroaryl ring contains 5 or 6 ring atoms, it is also referred to herein as a 5- or 6-membered heteroaryl.

[0213] "Heteroaralkyl" refers to a -(alkylene)-R radical where R is heteroaryl as defined above (including specified rings).

[0214] "Heteroaryloxy" refers to a -OR group where R is heteroaryl as defined above (including specified rings).

[0215] "Heteroaralkyloxy" refers to an -O-(alkylene)-R radical where R is heteroaryl as defined above (including specified rings).

[0216] "Heteroarylcarbonyl" refers to a -COR where R is heteroaryl as defined above (including specified rings).

[0217] "Heteroarylamino" refers to a -NRR' group where R is hydrogen or alkyl and R' is heteroaryl as defined above (including specified rings).

[0218] "Heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic group with 4 to 8 ring atoms, wherein 1 or 2 ring atoms are selected from N, O or S (O) n heteroatoms, wherein n is an integer from 0 to 2, and the remaining ring atoms are C. In addition, 1 or 2 ring carbon atoms in the heterocyclyl ring can be optionally replaced by -CO- groups. More specifically, the term heterocyclyl includes but is not limited to azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, homopiperidinyl (homopiperidino), 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazinyl, tetrahydro-pyranyl, thiomorpholino, etc. When the heterocyclyl ring is unsaturated, it can include one or two ring double bonds, provided that the ring is not an aromatic ring. When the heterocyclyl includes at least one nitrogen atom, it may be referred to as heterocyclic amino in this article.

[0219] "Heterocyclylalkyl" refers to an -(alkylene)-R group where R is heterocyclyl as defined above (including specific heterocyclyl rings). For example, oxetanylethyl, piperidinylethyl, and the like.

[0220] "Heterocyclyloxy" means a -OR group where R is heterocyclyl as defined above (including specific heterocyclyl rings).

[0221] "Heterocyclylalkoxy" refers to an -O-(alkylene)-R radical, where R is a heterocyclyl radical as defined above (including specific heterocyclyl rings). For example, oxetanylethoxy, piperidinylethoxy, and the like.

[0222] "Heterocyclylcarbonyl" means a -COR where R is a heterocyclyl as defined above (including the specified rings).

[0223] "Heterocyclylamino" means a -NRR' group where R is hydrogen or alkyl and R' is heterocyclyl as defined above (including specific heterocyclyl rings).

[0224] "Heterocyclyloxyalkyl" refers to an -(alkylene)-OR group where R is heterocyclyl as defined above (including the specific heterocyclyl rings). For example, oxetanyloxyethyl, piperidinyloxyethyl, and the like.

[0225] "Heterocyclyloxyalkoxy" refers to an -O-(alkylene)-R radical, where R is heterocyclyloxy as defined above (including the specified heterocyclyl rings). For example, oxetanyloxyethoxy, piperidinyloxyethoxy, and the like.

[0226] "Heterocyclyloxyalkylamino" refers to a -NR-(alkylene)-R' group, where R is hydrogen or alkyl, and R' is heterocyclyloxy as defined above (including specific heterocyclyl rings). For example, oxetanyloxyethylamino, piperidinyloxyethylamino, and the like.

[0227] As used herein, "oxo," alone or in combination, means =(O).

[0228] As used herein, "pharmaceutically acceptable salts" are meant to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (either neat or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from the following inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from the following relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids, such as arginine salts, and salts of the following organic acids, such as glucuronic acid or galacturonic acid, etc. (See, for example, Berge, SM, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66, pp. 1-19). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allows the compounds to be converted into base addition salts or acid addition salts.

[0229] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but for the purposes of the present invention, these salts are equivalent to the parent form of the compound.

[0230] The present disclosure also includes protected derivatives of compounds of the present disclosure. For example, when compounds of the present disclosure include groups such as hydroxyl, carboxyl, thiol, or any group including one or more nitrogen atoms, these groups may be protected by suitable protecting groups. A complete list of suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.

[0231] The present disclosure also includes prodrugs of compounds of formula (I), (IA), (II), (IIA), (IVA) and (IV), or pharmaceutically acceptable salts thereof. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide compounds of the present invention. An example of a prodrug, without limitation, is a compound administered as an ester ("prodrug") that is then metabolically hydrolyzed to a carboxylic acid, i.e., the active entity. In addition, the prodrug can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when the prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, it can be slowly converted to the compounds of the present invention.

[0232] Certain compounds of formula (I), (IA), (II), (IIA), (IVA) and (IV) may exist in unsolvated forms as well as solvated forms, including hydrated forms. Typically, the solvated forms are equivalent to the unsolvated forms and are intended to be included within the scope of the present invention. Certain compounds of formula (I), (IA), (II), (IIA), (IVA) and (IV) may exist in a variety of crystalline or amorphous forms. Typically, all physical forms are equivalent for the intended uses of the present disclosure and are intended to fall within the scope of the present disclosure.

[0233] Certain compounds of Formula (I), (IA), (II), (IIA), (IVA) and (IV) have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are intended to be included within the scope of the present invention. When stereochemical descriptions are shown, it refers to compounds in which one isomer is present and substantially free of the other isomer. "Substantially free" of the other isomer means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10, or 95 / 5 or more. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0234] Compounds of formula (I), (IA), (II), (IIA), (IVA) and (IV) may also contain unnatural amounts of isotopes at one or more atoms that constitute such compounds. An unnatural amount of an isotope can be defined as an amount up to 100% of the amount found in nature of the atom in question. It differs only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into compounds of the invention, such as compounds of formula (I), (IA), (II), (IIA), (IVA) and (IV) (and any embodiments thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, for example, respectively 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 123 I and 125 1. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled compounds) can be used in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are useful because of their ease of preparation and detectability. In addition, heavier isotopes such as deuterium (i.e. 2 H) substitution may provide certain therapeutic advantages due to better metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in the compounds disclosed herein, including those in Table 1 below, one or more hydrogen atoms are replaced by 2 H or3 H, or one or more carbon atoms are replaced 13 C- or 14 C-enriched carbon substitution. Positron emitting isotopes (e.g. 15 O. 13 N. 11 C and 15 F) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or Examples herein, substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0235] "Optionally substituted aryl" refers to an aryl group optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halogen, haloalkyl, haloalkoxy and cyano.

[0236] "Optionally substituted heteroaryl" refers to a heteroaryl group as defined above, which is optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halogen, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino and cyano.

[0237] Unless otherwise indicated, "optionally substituted heterocyclyl" refers to a heterocyclyl group as defined above optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, halogen, haloalkyl, haloalkoxy and cyano.

[0238] "Pharmaceutically acceptable carrier or excipient" refers to a carrier or excipient that can be used to prepare a pharmaceutical composition, is generally safe, non-toxic and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient" as used in the specification and claims includes one or more such excipients.

[0239] "Spirocycloalkyl" refers to a saturated bicyclic ring with 6 to 10 ring carbon atoms, wherein the ring is connected by only one atom, the connecting atom is also referred to as a spiro atom, most commonly a quaternary carbon ("spiro carbon"). The spirocycloalkyl ring is optionally substituted by 1 or 2 substituents independently selected from alkyl, halogen, alkoxy, hydroxyl 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) etc.

[0240] "Spirocycloalkylalkyl" refers to a -(alkylene)-R group where R is a spirocycloalkyl as defined above (including specific spirocycloalkyl groups).

[0241] "Spiro heterocyclic group" refers to a saturated bicyclic ring with 6 to 10 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from N, O or S (O) n, wherein n is an integer from 0 to 2, the remaining ring atoms are C, and the ring is connected by only one atom, and the connecting atom is also referred to as a spiral atom, most commonly a quaternary carbon ("spiro carbon"). Spiro heterocyclic group is optionally substituted by 1 or 2 substituents independently selected from alkyl, halogen, alkoxy, hydroxyl and cyano. Examples include, but are not limited to, representative examples include, but are not limited to, 2,6-diazaspiro [3.3] heptane, 2,6-diazaspiro [3.4] octane, 2-azaspiro [3.4] nonane, 2-azaspiro [3.5] nonane, 2,7-diazaspiro [4.4] nonane, etc.

[0242] "Spiroheterocyclylalkyl" refers to a -(alkylene)-R radical where R is a spiroheterocyclyl radical (including specific spiroheterocyclyl radicals) as defined above.

[0243] "Sulfonylamino" refers to -NRSO 2 An R' group, wherein R is hydrogen or alkyl, and R' is alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl, each as defined herein.

[0244] "Substituted cycloalkyl" refers to a saturated monocyclic monovalent hydrocarbon group having 3 to 6 carbon atoms substituted by 1, 2 or 3 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, etc.

[0245] "Substituted cycloalkylalkyl" refers to a cycloalkyl substituted with -(alkylene)-, each term being as defined herein. Examples include, but are not limited to, 1-hydroxymethylcycloprop-1-ylmethyl and the like.

[0246] As used herein, "about" is intended to qualify the modified numerical value so that the value is represented as a variable within a range of error. When a specific error range (such as the standard deviation of the mean value given in a graph or data table) is not listed, the term "about" should be understood to mean a range of ±10%, preferably ±5%, and the values ​​and ranges are all included.

[0247] As used herein, "disease" is intended to be generally synonymous with the terms "disorder," "condition," and "condition" (as in medical condition) and are used interchangeably because they all reflect an abnormal condition of the human or animal body or a part thereof that impairs the normal functioning, usually manifests itself as distinctive signs and symptoms, and results in a shortened life span or reduced quality of life in the human or animal.

[0248] "Patient" is often synonymous with the term "subject" and, as used herein, includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0249] As used herein, "in need of treatment" refers to a judgment made by a physician or other caregiver that a subject requires or will benefit from treatment. This judgment is based on a variety of factors within the physician's or caregiver's expertise.

[0250] "Administering", "dosing", etc., when used for example for a patient, cell, tissue, organ or biological fluid, refers to contacting, for example, a compound of formula (I), a pharmaceutical composition comprising the same or a diagnostic agent with a subject, cell, tissue, organ or biological fluid. In the case of cells, administration includes contact of an agent with a cell (e.g., in vitro or ex vivo), and contact of an agent with a fluid, wherein the fluid is in contact with the cell.

[0251] As used herein, "therapeutically effective amount" refers to an amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment described herein and / or a pharmaceutically acceptable salt thereof, which, when administered alone or as part of a pharmaceutical composition and in a single dose or as part of a series of doses to a patient for whom a disease is to be treated, is sufficient to affect the treatment of such disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated. The therapeutically effective amount can be determined by measuring relevant physiological effects and can be adjusted in conjunction with dosing regimens and diagnostic analysis of the subject's condition, etc. For example, measuring serum levels of a compound of Formula (I) (or its metabolite) at a specific time after administration can indicate whether a therapeutically effective amount has been used.

[0252] "Treatment" or "treatment" of a disease includes:

[0253] (1) preventing a disease, that is, causing clinical symptoms of a disease to not develop in a mammal that may be exposed to or susceptible to the disease but does not yet experience or show symptoms of the disease;

[0254] (2) inhibit the disease, i.e., prevent or alleviate the development of the disease or its clinical symptoms; or

[0255] (3) Relieve the disease, that is, cause the disease or its clinical symptoms to disappear.

[0256] "Inhibition", "reduction" or any variation of these terms with respect to MAT2A includes any measurable reduction or complete inhibition to achieve the desired result. For example, compared to its normal activity, the reduction in MAT2A activity can be reduced by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any derivable range thereof.

[0257] "Urea" refers to a -NHCONRR' group where R and R' are independently hydrogen or alkyl, as defined above, e.g., -NHCONHmethyl, -NHCON(CH 3 ) 2 etc. "Thioureaalkyl" refers to -(alkylene)-NHSO 2 NRR' groups, wherein R and R' are independently hydrogen or alkyl, as defined above, for example, -ethylene-NHSO 2 NHmethyl, -propylene-NHSO 2 NH 2 wait.

[0258] Representative compounds of formula (I) are listed in Table 1 below:

[0259] Table 1

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370] Other compounds of formula (I) contemplated are disclosed in Table 2 below:

[0371] Table 2

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394] Implementation method:

[0395] In the following further embodiments 1 to 34, the present disclosure comprises:

[0396] 1A. In embodiment 1A, a compound of formula (IA'), (IA), (IIA') or (IIA) or a pharmaceutically acceptable salt thereof is provided, wherein w, x, y, z, R 1 and R 2As described above in the Summary of the Invention. In a first sub-embodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (IA). In a second sub-embodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (IIA). In a third sub-embodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (IA'). In a fourth sub-embodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (IIA').

[0397] 1. In embodiment 1, provided is a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA') or a compound of a sub-embodiment as described herein; or a pharmaceutically acceptable salt thereof, wherein w, x, y, z, R 1 and R 2 As described above in the Summary of the Invention. In a first sub-embodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (I). In a second sub-embodiment of the first embodiment, the compound or a pharmaceutically acceptable salt thereof has structure (II).

[0398] 2. In embodiment 2, the compound of any one of embodiments 1A or 1 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein

[0399] R 1 For R 7 , where R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a phenyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f Replacement; and

[0400] 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 sub-embodiment of embodiment 2, R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or R 11 .

[0401] 3. In embodiment 3, the compound of any one of embodiments 1A or 1 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein

[0402] R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl or aminosulfonylalkyl; and

[0403] 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 sub-embodiment of embodiment 3, R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or R 11 .

[0404] 4. In embodiment 4, the compound of any one of embodiments 1A or 1 and the subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein

[0405] R 1 For R 7 , where R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace.

[0406] 5. In embodiment 5, the compound described in any of embodiments 1A and 1-4 and sub-embodiments contained therein, or a pharmaceutically acceptable salt thereof, has a structure represented by the following formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIg):

[0407]

[0408] In the first sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in formula (IIIa). In the second sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in formula (IIIb). In the third sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in formula (IIIc). In the fourth sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in formula (IIId). In the fifth sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in formula (IIIe). In the sixth sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in formula (IIIf). In the seventh sub-embodiment of embodiment 5, the compound or a pharmaceutically acceptable salt thereof has a structure as shown in formula (IIIg).

[0409] 6. In embodiment 6, the compound or pharmaceutically acceptable salt thereof of any one of embodiments 1A and 1-5 and subembodiments contained therein (e.g., compounds of formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), and (IIIg)), wherein R 2 For-NR 9 R 10 .

[0410] 7. In embodiment 7, the compound of any one of embodiments 1A and 1 to 5 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 2 For-OR 8 .

[0411] 8. In embodiment 8, a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A and 1 to 5 and subembodiments contained therein, wherein R 2 For R 11 .

[0412] 9. In embodiment 9, a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A and 1-5 and subembodiments contained therein, wherein R 2 -(alkylene)-R 11 In a first sub-embodiment of embodiment 9, the alkylene group is methylene or ethylene. In a second sub-embodiment of embodiment, the alkylene group is methylene.

[0413] 10. In embodiment 10, a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A and 1 to 6 and subembodiments contained therein, wherein R 9is hydrogen, methyl, ethyl, cyclopropyl or trideuterated methyl. In a first sub-embodiment of embodiment 10, R 9 is hydrogen, methyl, ethyl or cyclopropyl. In a second sub-embodiment of embodiment 10, R 9 is hydrogen, methyl or cyclopropyl. In a third sub-embodiment of embodiment 4, R 9 In a fourth sub-embodiment of embodiment 10, R 9 In a fifth embodiment of embodiment 10, R 9 In a sixth embodiment of embodiment 10, R 9 In a seventh embodiment of embodiment 10, R 9 It is trideuterated methyl.

[0414] 11. In embodiment 11, a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A and 1 to 6 and 10 and subembodiments contained therein, wherein R 10 is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, preferably R 10 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl. In a first sub-embodiment of embodiment 11, R 10 is hydrogen. In a second sub-embodiment of embodiment 11, R 10 is alkyl, preferably methyl, ethyl, isopropyl, isobutyl or tert-butyl, preferably methyl. In a third sub-embodiment of embodiment 11, R 10 is a haloalkyl group, preferably 2,2-difluoroethyl or 2,2,2-trifluoroethyl. In a fourth sub-embodiment of embodiment 11, R 10 is hydroxyalkyl, preferably 2-hydroxyethyl, 3-hydroxypropyl or dihydroxypropyl. In a fifth sub-embodiment of embodiment 5, R 10 is aminoalkyl, preferably aminoethyl, methylaminoethyl, dimethylaminoethyl or diethylaminoethyl. In a sixth embodiment of embodiment 11, R 10 is an alkoxyalkyl group, preferably a methoxyethyl group, an ethoxyethyl group, a methoxypropyl group or an ethoxypropyl group. 10 is alkylcarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, preferably acetyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl. In an eighth sub-embodiment of embodiment 11, R 10is alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, preferably methylaminocarbonylmethyl or dimethylaminocarbonylmethyl. In a ninth sub-embodiment of embodiment 11, R 10 It is trideuterated methyl.

[0415] 12. In embodiment 12, a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A, 1 to 5 and 7 and subembodiments contained therein, wherein R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl. In a first sub-embodiment of embodiment 12, R 8 is alkyl, preferably methyl, ethyl, isopropyl, isobutyl or tert-butyl. In a second sub-embodiment of embodiment 12, R 8 is a haloalkyl group, preferably trifluoromethyl or 2,2,2-trifluoroethyl. In a third sub-embodiment of embodiment 12, R 8 is hydroxyalkyl, preferably 2-hydroxyethyl, hydroxypropyl or dihydroxypropyl. In a fourth sub-embodiment of embodiment 12, R 8 is aminoalkyl, preferably aminoethyl, methylaminoethyl, dimethylaminoethyl or diethylaminoethyl. In a fifth sub-embodiment of embodiment 12, R 8 It is an alkoxyalkyl group, preferably a methoxyethyl group, an ethoxyethyl group, a methoxypropyl group or an ethoxypropyl group.

[0416] 13. In embodiment 13, a compound or a pharmaceutically acceptable salt thereof of any one of embodiments 1A, 1 to 7 and 10 and subembodiments contained therein, wherein R 8 and R 10 is independently cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl or spirocycloalkylalkyl. 8 and R 10 is independently cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, and each ring may be independently unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, halogen, alkoxy, hydroxyl or cyano. In a second sub-embodiment of embodiment 13, R 8 and R 10 is independently cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, and each ring may be independently unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, fluoro or cyano. In a third sub-embodiment of embodiment 13, R 8 and R 10is independently cycloalkylalkyl, preferably cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl, and the ring in each group can be independently unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, halogen, alkoxy, hydroxyl or cyano. In the fourth sub-embodiment of embodiment 13, R 8 and R 10 is independently cycloalkyloxyalkyl, preferably cyclopropyloxyethyl, cyclobutyloxyethyl, cyclopentyloxyethyl or cyclohexyloxyethyl, preferably cyclopropyloxyethyl, and the ring in each group can be independently unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, halogen, alkoxy, hydroxyl or cyano. In the fifth sub-embodiment of embodiment 13, R 8 and R 10 is independently a bridged cycloalkyl group or a bridged cycloalkylalkyl group. In a sixth sub-embodiment of embodiment 13, R 8 and R 10 is independently spirocycloalkyl or spirocycloalkylalkyl. In a seventh sub-embodiment of embodiment 13, R 8 and R 10 is independently cycloalkyl or cycloalkylalkyl, preferably cyclopropyl or cyclopropylmethyl, each ring being independently unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, halogen or cyano. In an eighth sub-embodiment of embodiment 13, R 8 and R 10 is independently cyclopropyl or cyclopropylmethyl, each ring being independently unsubstituted or substituted with 1 or 2 substituents independently selected from methyl, fluoro or cyano. In a ninth embodiment of embodiment 13, R 8 and R 10 Independently for R 8 and R 10are independently cyclopropyl, cyclobutyl, 1-methylcyclopropyl, (cis)-3-hydroxy-3-methylcyclobutyl, (cis)-3-hydroxy-2,2-dimethylcyclobutyl, 1-cyanocyclobutyl, cyclopropylmethyl, 1-hydroxycyclopropylmethyl, 1-fluorocyclopropylmethyl, (trans)-3-hydroxy-1-methylcyclobutyl, (cis)-3-cyanocyclobutyl, 1-methylcyclobutyl, (cis)-3-hydroxycyclobutyl, (trans)-3-hydroxycyclobutyl, (trans)-3-cyanocyclobutyl In a tenth subembodiment 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 the eleventh sub-embodiment of embodiment 13, R 8 and R 10 is independently cyclopropylmethyl, 1-hydroxycyclopropylmethyl, 1-fluorocyclopropylmethyl, 1-fluorocyclopropylmethyl, (R)-1-cyclopropylethyl or 2,2-difluorocyclopropylmethyl.

[0417] 14. In embodiment 14, the compound of any one of embodiments 1A, 1 to 7 and 10 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 10 is independently phenyl or phenylalkyl (preferably benzyl or phenylethyl), wherein the phenyl group itself or as part of the aralkyl group is unsubstituted or replaced by R j , R k and / or R 1 replace.

[0418] 15. In embodiment 15, the compound of any one of embodiments 1 to 7 and 10 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 10 is independently heteroaryl or heteroaralkyl, wherein the heteroaryl itself or as part of the heteroaralkyl is unsubstituted or replaced by R j , R k and / or R 1 In a first sub-embodiment of embodiment 15, R 8 and R 10 is a heteroaryl group independently selected from pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indolyl and indazolyl, preferably pyrazolyl, imidazolyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indolyl and indazolyl, each ring being unsubstituted or replaced by R j , R k and / or R 1 In a second sub-embodiment of embodiment 15, R 8 and R 10 is heteroaralkyl independently selected from pyrazolylmethyl, pyrazolylethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolylmethyl, quinolylethyl, isoquinolylmethyl, isoquinolylethyl, indolylmethyl, indolylethyl, indazolylmethyl and indazolylethyl, Preferably, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimidylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolylmethyl, quinolylethyl, isoquinolylmethyl, isoquinolylethyl, indolylmethyl, indolylethyl, indazolylmethyl and indazolylethyl are preferred, preferably pyrazolylmethyl or pyridylmethyl, each ring is unsubstituted or substituted by R j , R k and / or R 1 In a third sub-embodiment of embodiment 15, R 8 and R 10is 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.

[0419] 16. In embodiment 16, the compound of any one of embodiments 1A, 1 to 7 and 10 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 10 is independently heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the heterocyclyl itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l In a first sub-embodiment of embodiment 16, R 8 and R 10 is independently a heterocyclic group, preferably an oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group, each ring being unsubstituted or substituted by R j , R k and / or R l In a second sub-embodiment of embodiment 16, R 8 and R 10is independently heterocycloalkyl, preferably oxetanylmethyl, oxetanylethyl, azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl or morpholinylethyl, each ring being unsubstituted or replaced by R j , R k and / or R l In a third sub-embodiment of embodiment 16, R 8 and R 10 is independently unsubstituted or replaced by R j , R k and / or R l In a fourth subembodiment of embodiment 16, R 8 and R 10 In a fifth sub-embodiment of embodiment 16, R 8 and R 10 are independently spiroheterocyclyl or spiroheterocycloalkyl.

[0420] 17. In embodiment 17, the compound of any one of embodiments 1A, 1-5, 8 and 9 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 11 is an unsubstituted heterocyclic group or is replaced by R m , R n and / or R o In a first subembodiment of embodiment 17, R 11 is oxetane, 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 replaced by R m , R n and / or R o In a second sub-embodiment of embodiment 17, R 11is 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-embodiment of embodiment 17, R 11 It is 3-hydroxypyrrolidin-1-yl.

[0421] 18. In embodiment 18, a compound of any one of embodiments 1A, 1 to 5, 8 and 9 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 11 In a first sub-embodiment of embodiment 18, R 11 is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl, and each ring may independently be unsubstituted or substituted by 1 or 2 substituents independently selected from alkyl, halogen, alkoxy, hydroxyl or cyano.

[0422] 19. In embodiment 19, a compound of any one of embodiments 1A, 1 to 5, 8 and 9 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 11 is an unsubstituted heteroaryl or is replaced by R j , R k and / or R 1 In a first subembodiment of embodiment 19, R 11 is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indolyl and indazolyl, each ring being unsubstituted or replaced by R j , R k and / or R 1 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.

[0423] 20. In embodiment 20, the compound of any one of embodiments 1A, 1 to 5 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 2It is hydroxyalkyl, aminoalkyl, aminocarbonylalkyl.

[0424] 21. In embodiment 21, a compound of any one of embodiments 1A, 1 to 20, and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 6 R is independently selected from hydrogen, methyl, chloro, fluoro, bromo, methoxy, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, or dimethylaminocarbonyl. 4 is hydrogen, fluorine, methoxy, cyano, and R 6 In a second sub-embodiment of embodiment 21, R 4 and R 6 In a second sub-embodiment of embodiment 21, R 4 and R 6 In a third sub-embodiment of embodiment 21, R 4 and R 6 is independently selected from hydrogen, methyl, chloro, fluoro, methoxy, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, or dimethylaminocarbonyl. In a fifth subembodiment of embodiment 21, R 4 is hydrogen, fluorine, bromine, methyl, methoxy or cyano, and R 6 For hydrogen.

[0425] 22. In embodiment 22, a compound of any one of embodiments 1A, 1 to 21, and subembodiments contained therein, 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 R is alkyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl, heteroaryl, heterocyclyl, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R cIn a first sub-embodiment of embodiment 22, R 5 is methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclopentyl, cyano, methylsulfonyl, methylamino or dimethylamino. In a second subembodiment 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 group, such as pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl or pyrimidinyl, each of which is unsubstituted or substituted independently by R selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c In a fourth sub-embodiment of embodiment 22, R 5 is a 4- or 6-membered heterocyclic group, preferably oxetan-3-yl, pyrrolidin-1-yl, tetrahydrofuranyl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl, each ring is unsubstituted or replaced by R a and / or R b In a fifth sub-embodiment of embodiment 22, R 5 is halogen, alkyl, haloalkyl or cycloalkyl. In a sixth sub-embodiment of embodiment 22, R 5 is chloro, methyl, ethyl, trifluoromethyl or cyclopropyl. In a seventh sub-embodiment of embodiment 22, R 5 is trifluoromethyl, 1,1-difluoroethyl or cyclopropyl. In an eighth sub-embodiment of embodiment 22, R 5 is chloro, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or cyclopropyl.

[0426] 23. In embodiment 23, a compound of any one of embodiments 1A, 1 to 23, and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 3R 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, heterocyclylaminoalkoxy, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c In a first sub-embodiment of embodiment 23, R 3 is hydrogen. In a second sub-embodiment of embodiment 23, R 3 is methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, 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 a heteroaryl group, preferably a 5- or 6-membered heteroaryl group, such as pyrazolyl, imidazolyl, triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl or pyrimidinyl, each ring being unsubstituted or substituted by 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or replaced by R a , 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-ylethoxy. In a fifth subembodiment of embodiment 23, R 3 In an eighth sub-embodiment of embodiment 23, when R 3When it is a group as described in the second, third, fourth, fifth or sixth embodiment, then R 2 is amino or methylamino, R 4 and R 6 is hydrogen and R 5 Not hydrogen.

[0427] 24. In embodiment 24, a compound of any one of embodiments 1A, 1, 3, 5 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 It is an alkyl group, preferably a methyl group, an ethyl group or an isopropyl group.

[0428] 25. In embodiment 25, a compound of any one of embodiments 1A, 1, 3, 5 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a halogenated alkyl group, preferably a trifluoromethyl group.

[0429] 26. In embodiment 26, a compound of any one of embodiments 1A, 1, 3, 5 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, an aminocarbonylalkyl group or an aminosulfonylalkyl group.

[0430] 27. In embodiment 27, a compound of any one of embodiments 1A, 1, 2, 4 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 YesR 7 , where R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group or a spirocycloalkyl group. 7 is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which is unsubstituted or substituted by 1 or 2 substituents independently selected from alkyl, hydroxy, alkoxy, cyano or halogen. In a first sub-embodiment of embodiment 27, R 7 is a cycloalkenyl, cyclopentenyl or cyclohexenyl group which is unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, hydroxy, alkoxy, cyano or halogen.

[0431] 28. In embodiment 28, a compound of any one of embodiments 1A, 1, 2, 4 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 YesR 7 , where R 7 is an unsubstituted aryl group or is replaced by R d , R e and / or R f Substituted aryl, wherein Rf is selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl. In a first subembodiment of embodiment 28, R 7 is unsubstituted phenyl or is replaced by R d , R e and / or R f In a second subembodiment of embodiment 28, R 7 is unsubstituted phenyl or is replaced by R d , R e and / or R f Substituted phenyl, 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, fluorine, chlorine, cyano or methyl. In a third sub-embodiment of embodiment 28, R 7 Is R d , R e and / or R f Substituted phenyl, 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 is attached to a carbon atom of the benzene ring that is located in the ortho or meta position to the carbon atom of the benzene ring attached to the quinazolinone nitrogen. In a fourth sub-embodiment of embodiment 28, R 7 is unsubstituted phenyl or is replaced by R e and / or R f Substituted phenyl, 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 fluorine, chlorine, cyano or methyl, and wherein R f is attached to a carbon atom on the benzene ring that is ortho to the carbon atom on the benzene ring attached to the quinazolinone nitrogen. In a fifth sub-embodiment of embodiment 28, R 7 is unsubstituted phenyl or is replaced by R f Substituted phenyl, wherein R f is fluorine, chlorine, bromine or methyl, and wherein R fThe carbon atom on the benzene ring is attached to the carbon atom on the benzene ring which is ortho to the carbon atom on the benzene ring attached to the quinazolinone nitrogen.

[0432] 29. In embodiment 28, a compound of any one of embodiments 1A, 1, 2, and 4 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 YesR 7 , where R 7 is an unsubstituted heteroaryl or is replaced by R d , R e and / or R f Substituted heteroaryl, 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, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, which is unsubstituted or replaced by 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, fluorine, chlorine, cyano or methyl. In a third sub-embodiment of embodiment 29, R d , R e and / or R f Where R d and R e R is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, f is selected from hydroxy, fluoro, chloro, cyano or methyl, and wherein R d , R e and / or R f is attached to a carbon atom of the heteroaryl ring that is located in the ortho or meta position to the carbon atom of the heteroaryl ring attached to the quinazolinone nitrogen. In a fourth subembodiment of embodiment 29, R 7 is pyridyl or pyrimidinyl, preferably pyridin-3-yl or pyrimidin-4-yl, which is unsubstituted or substituted by R e and / or R f Substitution, where R eis methyl, ethyl, fluorine, chlorine, bromine, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, R f is fluorine, chlorine, cyano or methyl, and wherein R f is attached to a carbon atom of the pyridyl or pyrimidyl group that is ortho to the carbon atom of the benzene ring attached to the quinazolinone nitrogen. In a fifth subembodiment of embodiment 29, R 7 is pyridinyl, preferably pyridin-2-yl or pyridin-3-yl, which is unsubstituted or substituted by R f Substitution, where R f is fluorine, chlorine or methyl, and wherein R f The bond is to the carbon atom of the pyridyl group which is ortho to the carbon atom of the benzene ring which is attached to the quinazolinone nitrogen.

[0433] 30. In embodiment 30, a compound of any one of embodiments 1A, 1, 2, and 4 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 YesR 7 , where R 7 is a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f Substitution, where 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 being independently unsubstituted or substituted by 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 being independently unsubstituted or substituted by R d , R e and / or substituted, wherein R d , R e and / or R f Independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, hydroxy, methylsulfonyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl.

[0434] 31. In embodiment 31, a compound of any one of embodiments 1A, 1, 2, and 4 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 YesR 7 , where R 7 Is R d , R e and / or R f Substituted aryl, wherein R f -X c -R 12 , where X c is alkylene or heteroalkylene, R 12 is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl. In a first sub-embodiment of embodiment 28, R 7 Is R d , R e and / or R f In a second subembodiment of embodiment 28, R 7 is unsubstituted phenyl or is replaced by R d , R e and / or R f Substituted phenyl, 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 2-phenoxyethyl, 2-phenylaminoethyl, 2-phenylethoxy or 2-phenylaminoethyl, wherein the phenyl group is optionally substituted with 1 or 2 substituents independently selected from methyl, fluoro, chloro, methoxy, hydroxyl, trifluoromethyl or trifluoromethoxy. In a third subembodiment of embodiment 31, R f The carbon atom is attached to the benzene ring and is located in the ortho or meta position to the carbon atom of the benzene ring attached to the quinazolinone nitrogen.

[0435] 32. In embodiment 32, a compound of any one of embodiments 1A, 1, 2, and 4 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 YesR 7 , where R 7 For R d , R e and / or R f Substituted heteroaryl, wherein R f -X c -R 12 , where X c is alkylene or heteroalkylene, R 12is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl. In a first sub-embodiment of embodiment 32, R 7 is a 5- or 6-membered heteroaryl ring, such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, which is unsubstituted or replaced by 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, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, and R f is selected from 2-phenoxyethyl, 2-phenylaminoethyl, 2-phenylethoxy or 2-phenylaminoethyl, wherein the phenyl group is optionally substituted with 1 or 2 substituents independently selected from methyl, fluoro, chloro, methoxy, hydroxyl, trifluoromethyl or trifluoromethoxy. In a third subembodiment of embodiment 32, R f The bond is to a carbon atom on the heteroaryl ring that is ortho or meta to the carbon atom on the heteroaryl ring that is attached to the quinazolinone nitrogen.

[0436] 33. In embodiment 33, a compound of any one of embodiments 1A, 1, 2, 4 to 23 and subembodiments contained therein, or a pharmaceutically acceptable salt thereof, wherein R 1 Yes-X a -R 7 , where X a is an alkylene group, R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace.

[0437] It should be understood that the embodiments described above include all combinations of the embodiments and sub-embodiments listed therein. 1 The groups and / or the first and / or second sub-embodiments therein can be independently combined with one or more of embodiments 1-28 and 31 to 33 and / or the sub-embodiments contained therein.

[0438] The present disclosure includes the following additional embodiments 35 to 90.

[0439] 35. A compound of formula (IA), or a pharmaceutically acceptable salt thereof:

[0440]

[0441] in:

[0442] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0443] R 3 R is hydrogen, 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, heterocyclylalkoxy, heterocyclyloxyalkoxy or heterocyclyloxyalkylamino, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c replace;

[0444] R 5 R is hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is substituted by R independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c replace;

[0445] R 4 and R 6are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0446] R 1 For R 7 , where R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0447] R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0448] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0449] R 9 is hydrogen, alkyl, deuterated alkyl or cycloalkyl; and

[0450] R 10R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0451] X b is a bond or an alkylene group; and

[0452] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0453] R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0454] R f , R i , R l and R o 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 R12 is an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocyclic group; provided that:

[0455] (1) When for 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 is hydrogen, R 4 is chlorine, R 5 When bromine or 5-methylindazol-4-yl, R 1 is not 2-isopropylphenyl; (b) when R 2 and R 6 is methyl and R 3 , R 4 and R 5 When it is hydrogen; or R 2 and R 3 is methyl and R 4 , R 5 and R 6 When it is hydrogen, R 1 is not 2,5-, 2,6- or 2,8-dimethylquinolin-4-yl or 2-methyl-5-methoxy-, 2-methyl-6-methoxy- or 2-methyl-8-methoxyquinolin-4-yl; (c) when R 2 is amino or acetylamino, R 4 is dimethylamino, and R 3 , R 5 and R 6 When it is hydrogen, R 1 is not 4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (d) when R 5 is fluorine, R 3 , R 4 and R 6 is hydrogen and R 2 When it 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 is hydrogen, and R 2 When it is 4-aminocarbonylmethyl-2-methylphenylamino, then R 1 is not 4-fluoro-2-methoxyphenyl; (f) when R 1 is 4-chloro-2-ethoxyphenyl, R 5is fluorine, and R 3 , R 4 and R 6 When it is hydrogen, then R 2 Not 3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino;

[0456] (2) When for When R 1 When it is 4-hydroxy-5-hydroxymethylfuran-1-yl, R 5 is amino, R 3 is methoxy; then R 2 is not amino; and

[0457] (3) When for When R 1 When it is 4-hydroxy-5-hydroxymethylfuran-1-yl, R 4 and R 5 One of them is hydrogen, R 4 and R 5 The other is methyl or R 4 and R 5 If both are methyl, then R 2 Not amino.

[0458] 36. The compound of embodiment 35, wherein the compound has a structure as shown in formula (I):

[0459]

[0460] in:

[0461] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0462] R 3 and R 5R is independently hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b , and / or R c replace;

[0463] R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0464] R 1 For R 7 , where R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a phenyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0465] R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0466] R 8is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0467] R 9 is hydrogen, alkyl or cycloalkyl; and

[0468] R 10 R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0469] X b is a bond or an alkylene group; and

[0470] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0471] R d , R e , R g , R h , R j , R k , R m and R nindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0472] 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

[0473] or pharmaceutically acceptable salts thereof.

[0474] 37. The compound or pharmaceutically acceptable salt thereof according to embodiment 35 or 36, which has a structure represented by the following formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIg):

[0475]

[0476] 38. The compound according to embodiment 35 or 36 or a pharmaceutically acceptable salt thereof, which has a structure as shown in formula (IIIa).

[0477] 39. The compound or pharmaceutically acceptable salt thereof according to embodiment 35 or 36, which has a structure as shown in formula (IIIb).

[0478] 40. The compound according to embodiment 35 or 36 or a pharmaceutically acceptable salt thereof, which has a structure as shown in formula (IIIc).

[0479] 41. The compound or pharmaceutically acceptable salt thereof according to embodiment 35 or 36, which has a structure as shown in formula (IIId).

[0480] 42. The compound or pharmaceutically acceptable salt thereof according to embodiment 35 or 36, which has a structure as shown in formula (IIIe).

[0481] 43. The compound or pharmaceutically acceptable salt thereof according to embodiment 35 or 36, which has a structure as shown in formula (IIIf).

[0482] 44. The compound or pharmaceutically acceptable salt thereof according to embodiment 35 or 36, which has a structure as shown in formula (IIIg).

[0483] 45. A compound as described in any one of embodiments 35 to 44, wherein R 2 For-NR 9 R 10 .

[0484] 46. ​​A compound as described in any one of embodiments 35 to 44, wherein R 2 For-OR 8 .

[0485] 47. A compound as described in any one of embodiments 35 to 44, wherein R 2 For R 11 .

[0486] 48. A compound as described in any one of embodiments 35 to 45, wherein R 9 It is a deuterated alkyl group, preferably a trideuterated methyl group.

[0487] 49. A compound as described in any one of embodiments 35 to 45, wherein R 9 For hydrogen.

[0488] 50. A compound as described in any one of embodiments 35 to 45, wherein R 9 It is an alkyl group, preferably a methyl group or an ethyl group.

[0489] 51. A compound as described in any one of embodiments 35 to 45, wherein R 9 It is a cycloalkyl group, preferably a cyclopropyl group.

[0490] 52. A compound as described in any one of embodiments 35 to 45 and 49 to 51, wherein R 10 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl.

[0491] 53. The compound or pharmaceutically acceptable salt thereof as described in embodiment 52, wherein R 10 For hydrogen.

[0492] 54. A compound or a pharmaceutically acceptable salt thereof as described in embodiment 46 or 52, wherein R 8 and R 10 It is an alkyl group, preferably a methyl group.

[0493] 55. The compound of claim embodiment 52 or a pharmaceutically acceptable salt thereof, wherein R10 It is an alkylaminocarbonylalkyl group or a dialkylaminocarbonylalkyl group, preferably a methylaminocarbonyl-methyl group or a dimethylaminocarbonylmethyl group.

[0494] 56. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 46 and 49 to 51, wherein R 8 and R 10 is independently phenyl or phenylalkyl, preferably benzyl or phenylethyl, wherein the phenyl itself or as part of the benzyl and phenylethyl groups is unsubstituted or replaced by R j , R k and / or R 1 replace.

[0495] 57. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 46 and 49 to 51, wherein R 8 and R 10 Independently being cycloalkyl or cycloalkylalkyl, each ring may independently be unsubstituted or substituted with 1 or 2 substituents independently selected from alkyl, halogen or cyano.

[0496] 58. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 46 and 49 to 51, wherein R 8 and R 10 is independently heteroaryl or heteroaralkyl, wherein the heteroaryl itself or as part of the heteroaralkyl is unsubstituted or replaced by R j , R k and / or R 1 replace.

[0497] 59. The compound or pharmaceutically acceptable salt thereof as described in embodiment 58, wherein R 8 and R 10 is a heteroaryl group independently selected from pyrazolyl, imidazolyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indolyl and indazolyl, each ring being unsubstituted or replaced by R j , R k and / or R 1 replace.

[0498] 60. The compound or pharmaceutically acceptable salt thereof as described in embodiment 58, wherein R 8 and R 10is heteroaralkyl independently selected from pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimidylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolylmethyl, quinolylethyl, isoquinolylmethyl, isoquinolylethyl, indolylmethyl, indolylethyl, indazolylmethyl and indazolylethyl, each ring being unsubstituted or substituted by R j , R k and / or R 1 replace.

[0499] 61. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 46 and 49 to 51, wherein R 8 and R 10 is independently a heterocyclic group, preferably an oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group, each ring being unsubstituted or substituted by R j , R k and / or R 1 replace.

[0500] 62. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 46 and 49 to 51, wherein R 8 and R 10 is independently heterocyclylalkyl, preferably oxetanylmethyl, oxetanylethyl, azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, piperidinylethyl, morpholinylmethyl or morpholinylethyl, each ring being unsubstituted or replaced by R j , R k and / or R 1 replace.

[0501] 63. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 44 and 47, wherein R 2 For R 11 , where R 11 is an unsubstituted heterocyclic group or is replaced by R m , R n and / or R o Substituted heterocyclic group.

[0502] 64. The compound or pharmaceutically acceptable salt thereof as described in embodiment 63, wherein R 11is oxetane, 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 replaced by R m , R n and / or R o Substituted, preferably R 11 is azetidin-1-yl, 4-hydroxyazetidin-1-yl, 4-methylaminocarbonylazetidin-1-yl, 4-dimethylaminocarbonylazetidin-1-yl, 2-hydromethyl-azetidin-1-yl, 2-methylazetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, piperidin-1-yl, 2-carboxypiperidin-1-yl, 2-aminocarbonylpiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl or morpholin-4-yl.

[0503] 65. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 44 and 47, wherein R 2 For R 11 , where R 11 is an unsubstituted heteroaryl or is replaced by R m , R n and / or R o Substituted heteroaryl, preferably R 11 is pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indolyl and indazolyl, each ring being unsubstituted or replaced by R m , R n and / or R o replace.

[0504] 66. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 44, wherein R 2 It is hydroxyalkyl, aminoalkyl or aminocarbonylalkyl.

[0505] 67. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 66, wherein R 5R is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl, heteroaryl, heterocyclyl, wherein the heterocyclyl or heteroaryl is unsubstituted or independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c replace.

[0506] 68. The compound or pharmaceutically acceptable salt thereof as described in embodiment 67, wherein R 5 R is methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, 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 ring is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c replace.

[0507] 69. The compound or pharmaceutically acceptable salt thereof as described in embodiment 67, wherein R 5 is chloro, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or cyclopropyl.

[0508] 70. The compound of embodiment 68, wherein R 5 is chloro, trifluoromethyl or ethyl.

[0509] 71. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 70, wherein R 4 and R 6 are independently selected from hydrogen, methyl, chloro, fluoro, methoxy, methanesulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl or dimethylaminocarbonyl.

[0510] 72. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 70, wherein R 4 is hydrogen, fluorine, methoxy, cyano, R 6 For hydrogen.

[0511] 73. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 70, wherein R 4is hydrogen or bromine, R 6 For hydrogen.

[0512] 74. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 35 to 70, wherein R 4 and R 6 For hydrogen.

[0513] 75. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 74, wherein R 3 is hydrogen, alkyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.

[0514] 76. A compound as described in embodiment 75 or a pharmaceutically acceptable salt thereof, wherein

[0515] R 3 It's hydrogen.

[0516] 77. The compound or pharmaceutically acceptable salt thereof as described in embodiment 75, wherein R 3 It is methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano, methylsulfonyl, aminocarbonyl, methylamino or dimethylamino.

[0517] 78. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 74, wherein R 3 is a heteroaryl group, preferably a 5- or 6-membered heteroaryl group, such as pyrazolyl, imidazolyl, triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl or pyrimidinyl, each ring being unsubstituted or substituted by R a , R b and / or R c replace.

[0518] 79. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 74, wherein R 3 It is a heterocyclic group, preferably oxopyrrolidinyl, morpholin-4-yl or 2-morpholin-4-ylethoxy.

[0519] 80. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 79, wherein R 1 For R 7 , where R 7 is cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each ring being unsubstituted or substituted by 1 or 2 substituents independently selected from alkyl, hydroxy, alkoxy, cyano or halogen.

[0520] 81. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 79, wherein R 1 For R 7 , where R 7 is unsubstituted phenyl or R d , R e and / or R f Substituted phenyl, wherein R d and R e R is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, f Selected from hydroxy, fluoro, chloro, cyano and methyl.

[0521] 82. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 79, wherein R 1 For R 7 , where R 7 is unsubstituted phenyl or R f Substituted phenyl, wherein R f is fluorine, chlorine, bromine or methyl, and wherein R f The carbon atom of the benzene ring is attached to the carbon atom of the benzene ring which is located in the ortho position to the carbon atom of the benzene ring attached to the quinazolinone nitrogen.

[0522] 83. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 79, wherein R 1 For R 7 , where R 7 is a 5- or 6-membered heteroaryl ring, such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl or pyrazinyl, which is unsubstituted or R is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl d and / or R e and / or R is selected from hydroxy, fluorine, chlorine, cyano and methyl f replace.

[0523] 84. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35 to 79, wherein R 1 For R 7 , where R 7 For R d , R e and / or R f Substituted phenyl, wherein R d and R eR is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, f Selected from -X c R 12 , where X c It is an alkylene group or a heteroalkylene group, preferably a heteroalkylene group.

[0524] 85. A compound or a pharmaceutically acceptable salt thereof as described in any one of embodiments 35-79, wherein R 1 For R 7 , where R 7 For R d , R e and / or R f substituted 5- or 6-membered heteroaryl ring, such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, wherein R d and R e R is independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl, f Selected from -X c R 12 , where X c is an alkylene group or a heteroalkylene group, preferably a heteroalkylene group.

[0525] 86. A pharmaceutical composition comprising a compound described in any one of embodiments 35 to 85 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0526] 87. A method for treating a disease mediated by MAT2A in a patient, comprising administering to the patient a therapeutically effective amount of:

[0527] (a) Compound of formula (IIA):

[0528]

[0529] in:

[0530] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0531] R 3R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkoxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy or heterocyclyloxyalkylamino, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c replace;

[0532] R 5 R is hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is substituted by R independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl a , R b and / or R c replace;

[0533] R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0534] R 1 For R 7 , where R 7is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0535] R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0536] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0537] R 9 is hydrogen, alkyl, deuterated alkyl or cycloalkyl; and

[0538] R 10 R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0539] X b is a bond or an alkylene group; and

[0540] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0541] R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0542] R f , R i , R l and R o 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 an optionally substituted aryl group, an optionally substituted heteroaryl group, and an optionally substituted heterocyclic group;

[0543] (b) a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0545]

[0546] in:

[0547] w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where:

[0548] R 3 and R 5R is independently hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace;

[0549] R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen;

[0550] R 1 is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, or -X a -R 7 , where X a is a bond or an alkylene group, R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace;

[0551] R 2 is hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in:

[0552] R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace;

[0553] R 9 is hydrogen, alkyl or cycloalkyl; and

[0554] R 10 R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl by itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace;

[0555] X b is a bond or an alkylene group; and

[0556] R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and

[0557] R d , R e , R g , R h , R j , R k , R m and R nindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and

[0558] 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

[0559] (c) The compound of any one of Embodiments 35 to 85, or a pharmaceutically acceptable salt thereof.

[0560] 88. The method of embodiment 87, wherein the disease is cancer.

[0561] 89. A method of treating MTAP-deficient cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (IIA) or (II) as defined in claim 87, or a pharmaceutically acceptable salt thereof; or

[0562] A compound of any one of Embodiments 35-85, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

[0563] 90. A method for treating cancer in a patient, wherein the cancer is characterized by reduced or absent MTAP gene expression, MTAP gene deletion, or reduced MTAP protein function, comprising administering to the subject a therapeutically effective amount of a compound of formula (IIA) or (II) as defined in embodiment 87, or a pharmaceutically acceptable salt thereof; or

[0564] A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 35-85, optionally in a pharmaceutical composition.

[0565] The compounds of the present disclosure can be prepared by the methods described in the reaction schemes shown below.

[0566] Starting materials and reagents used to prepare these compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Mich.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1-17 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, Vols. 1-41 (John Wiley and Sons, 1991), and March's Advanced Organic Chemistry. Chemistry" (John Wiley & Sons, 4th edition) and Larock's Comprehensive Organic Transformations (VCH Publishing Co., Ltd., 1989). These schemes are merely illustrative of some of the methods by which the compounds of the present invention may be synthesized, and various modifications may be made to these schemes, and those skilled in the art will be inspired by reading the present invention. If desired, the starting materials and intermediates of the reaction and the final products may be separated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0567] Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure at a temperature range of about -78°C to about 150°C, such as about 0°C to about 125°C, further such as at about room temperature (or ambient temperature), such as about 20°C.

[0568] The compounds of formula (I) and (II) and subembodiments described herein can be prepared as illustrated and described in Scheme 1 below, wherein w, x, y and z are not nitrogen, R 2 is not hydrogen, and other groups are as defined in the Summary of the Invention.

[0569] Solution 1

[0570]

[0571] The 2,4-dioxoquinazoline compound shown in Formula 1, wherein R 1 , R 3 , R 4 , R 5 and R 6 As described in the Summary of the Invention or its precursor group, it can be easily converted to R by methods well known in the art 2 For example, in an inert organic solvent, in the presence of an organic base (such as triethylamine), POCl 3 Compound 1 was treated to give R 2 The compound of formula (I) is chloro and can then be converted to R by methods well known in the art. 2 A compound of formula (I) which is not a halogen. For example, R 2 For-NR 9 R 10 The compound of formula (I) containing at least one nitrogen-containing heterocyclic ring and a basic nitrogen-containing heteroaryl group can be prepared by reacting the compound with a compound of formula -NR 9 R 10 The amine, the heterocyclic ring containing at least one nitrogen and the heteroaryl containing a basic nitrogen are treated with R 2 The corresponding compound of formula (I) is prepared by 9 R 10 The amines or heterocycles containing at least one nitrogen are commercially available. For example, methylamine, dimethylamine, ethylamine, dimethylamine, cyclopropylamine, 2-aminooxetane, tetrahydrofuran-2-amine, benzylamine, azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyrazole, 2-pyridinamine, 3-pyridinamine, 3-pyridinamine and cyclopropylmethylamine are commercially available.

[0572] Alternatively, by methods well known in the art, under alkylation or arylation conditions, a -NR 9 R 10 The compounds can be derived from R 2 For -NH 2 A compound of formula (I).

[0573] R 2 For R 11 , where R 11 The compound of formula (I) where R is a heteroaryl group can be reacted under Suzuki reaction conditions by 2 The method is prepared by using a compound of formula (I) which is halogen.

[0574] The compounds of formula 1 can be prepared by methods known in the art. Such methods are illustrated and described below.

[0575] Synthesized from 2-halogenated benzamide:

[0576] Method (a)

[0577]

[0578] In the presence of an inorganic base such as potassium carbonate, cesium carbonate, etc. and copper, a solution of formula R 1 NH 2 The amine shown, wherein R 1 Compounds of formula 2, wherein X is halogen (e.g., chlorine) and other groups as defined in the invention or their precursor groups, are treated as defined in the invention summary or their precursor groups to obtain compounds of formula 3. Compounds of formula 2 are commercially available or can be prepared by methods well known in the art. Compounds of formula 2 can be converted to compounds of formula 1 by treatment with a base such as sodium hydride in the presence of N,N-carbonyldiimidazole under conditions well known in the art.

[0579] Alternatively, the compound of formula 1 can be prepared from compound 2 as shown in method b below.

[0580] Method (b)

[0581]

[0582] In a chlorinated organic solvent or a 1 Isocyanate represented by NCO, where R 1 As defined in the invention or its precursor group, in the presence of oxalyl chloride, with formula R 1 NH 2 The compound of formula 2, wherein X is a halogen (preferably chlorine) and other groups or precursor groups as defined in the present invention, is treated with an amine as shown to obtain an ureide compound of formula 4, which is then cyclized in the presence of a base such as sodium hydride or KHMDS under conditions well known in the art to obtain a compound of formula 1.

[0583] Synthesized from 2-halogenated benzoic acid:

[0584] Method (c)

[0585]

[0586] In the presence of an inorganic base such as potassium carbonate, cesium carbonate, etc. and copper, a solution of formula R 1 NH 2 The amine shown, wherein R 1The benzoic acid compound shown in formula 5 is treated as defined in the invention or its precursor group, wherein X is a halogen (preferably chlorine) and other groups as defined in the invention or its precursor group, thereby obtaining a compound of formula 6. Alternatively, an amination reaction can be carried out in THF at -78°C in the presence of LDA. The compound of formula 5 is commercially available or can be prepared by methods well known in the art. The compound of formula 6 is converted into a compound of formula 1 by treating with urea under conditions well known in the art.

[0587] Alternatively, in an organic solvent (such as THF, etc.), in the presence of an organic base (such as diisopropylethylamine), treating 6 with HATU or EDCI / HOBt and ammonium chloride can convert the compound of formula 6 into the amide compound shown in formula 3. Compound 6 is then converted into compound 1, which can be prepared as shown in method a or method b above.

[0588] Synthesized from 2-aminobenzoic acid:

[0589] Method (d)

[0590]

[0591] In the presence of copper acetate, in a base such as triethylamine, pyridine, etc., use R 1 Br halide, where R 1 The 2-aminobenzoic acid compound of formula 7 is treated as defined in the invention or its precursor group, wherein R 3 To R 6 As defined in the Summary of the Invention or its precursor group to give compound 6 which can then be converted to a compound of formula 1 as described above.

[0592] Synthesized from 2-aminobenzamide:

[0593] Method (e)

[0594]

[0595] In the presence of copper (I) chloride, in the presence of a base such as triethylamine, pyridine, etc., a compound of formula R 1 B(OH) 2 The boronic acid shown, where R 1 The 2-aminobenzamide compound of formula 8 is treated as defined in the invention or its precursor group, wherein R 3 To R 6 or a precursor group thereof as defined in the Summary of the Invention, thereby obtaining a compound of formula 3 which can then be converted to a compound of formula 1 as described above.

[0596] The compounds of formula (I) and (II) and sub-embodiments described herein can be converted to other compounds of formula (I) and (II), respectively, by methods well known in the art. For example, by treating R with sodium methoxide in the presence of CuI in DMF 5 Compounds of formula (I) or (II) which are halogen (precursor groups) can be converted into R 5 The corresponding compound of formula (I) or (II) is methoxy. 3 ) 4 ) can be treated with zinc cyanide in the presence of R 5 The compound of formula (I) or (II) is halogen (precursor group) and is converted into R 5 The corresponding compound of formula (I) or (II) is cyano. By treating R with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate in the presence of CuI in DMF 5 Compounds of formula (I) which are halogen (progenitor groups) can be converted to R 5 The corresponding compound of formula (I) is trifluoromethyl.

[0597] applicability

[0598] Overexpression of the enzyme MAT2A has been shown to mediate certain cancers. In one embodiment, the cancer is neuroblastoma, intestinal cancer (e.g., rectal cancer, colon cancer, familial adenomatous polyposis and hereditary non-polyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urethral cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor), hormonal cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urethral cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor), ... Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal myoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma and plasmacytoma.

[0599] In another embodiment, the cancer is lung cancer, non-small cell lung cancer (NSLC), bronchioloalveolar lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, vaginal cancer, vulvar cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, mesothelioma, hepatocellular carcinoma, biliary tract cancer, chronic or acute leukemia, lymphocytic lymphoma, central nervous system tumor (CNS), spinal cord tumor, brain stem glioma, glioblastoma multiforme, astrocytoma, neurilemmoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, pituitary adenoma, including refractory forms of any of the above cancers, or a combination of one or more of the above cancers.

[0600] Methylthioadenosine phosphorylase (MTAP) is an enzyme found in all normal tissues that catalyzes the conversion of methylthioadenosine (MTA) into adenine and 5-methylthioribose-1-phosphate. Salvage adenine to produce adenosine monophosphate, 5-methylthioribose-1-phosphate is converted into methionine and formate. Due to this salvage pathway, when de novo purine synthesis is blocked by, for example, antimetabolites such as L-alanosine, MTA can be used as an alternative purine source.

[0601] Many human and mouse malignant cells lack MTAP activity. MTAP deficiency is not only present in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma and mesothelioma. K. Marjon et al. reported in Cell Reports Vol. 15 (2016) pp. 574-587 (incorporated herein by reference), and the proliferation of cancer cells with MTAP deletion can be inhibited by knocking down MAT2A expression with shRNA. MTAP-deficient cancer is a cancer in which the MTAP gene has been deleted or lost or otherwise inactivated or a cancer in which the function of the MTAP protein is reduced or impaired.

[0602] Thus, in one embodiment of the present invention, a method for treating a MTAP-deficient cancer in a patient is provided, wherein the cancer is characterized by reduced or absent MTAP expression or MTAP gene absence or reduced MTAP protein function compared to a cancer 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') as described herein, or a sub-embodiment, or a pharmaceutically acceptable salt thereof. In another embodiment, a method for treating a MTAP-deficient 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') as described herein, or a sub-embodiment, or a pharmaceutically acceptable salt thereof. In one embodiment, the MTAP-deficient cancer is a leukemia, a glioma, a melanoma, a pancreatic cancer, a non-small cell lung cancer (NSLC), a bladder cancer, an astrocytoma, an osteosarcoma, a head and neck cancer, a myxoid chondrosarcoma, an ovarian cancer, an endometrial cancer, a breast cancer, a soft tissue sarcoma, a non-Hodgkin lymphoma, or a mesothelioma. In another embodiment, the MTAP-deficient cancer is pancreatic cancer. In another embodiment, the MTAP-deficient 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-deficient cancer is gastric cancer. In another embodiment, the cancer is colon cancer. In another embodiment, the MTAP-deficient cancer is liver cancer. In yet another embodiment, the MTAP-deficient cancer is glioblastoma multiforme (GBM). In another embodiment, the MTAP-deficient cancer is bladder cancer. In another embodiment, the MTAP-deficient cancer is esophageal cancer. In another embodiment, the MTAP-deficient cancer is breast cancer. In another embodiment, the MTAP-deficient cancer is NSCLC. In another embodiment, the MTAP-deficient cancer is MCL. In another embodiment, the MTAP-deficient cancer is DLBCL. In another embodiment, the MTAP-deficient cancer is ALL.

[0603] Genomic analysis of MTAP-null cell lines revealed that cell lines that also incorporated KRAS mutations or p53 mutations were sensitive to MAT2A inhibition.

[0604] Thus, also provided is a method of treating a cancer in a patient, wherein the cancer is characterized by reduced or absent MTAP expression or MTAP gene deletion or reduced MTAP protein function (i.e., MTAP deletion), further characterized by the presence of mutant KRAS and / or mutant p53, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment as described herein. In one embodiment, the cancer is MTAP deletion and KRAS mutation. In another embodiment, the cancer is MTAP deletion and p53 mutation. In another embodiment, the cancer is MTAP deletion, KRAS mutation, and p53 mutation.

[0605] The term "mutant KRAS" or "KRAS mutation" refers to a KRAS protein (or a gene encoding the protein) that has incorporated an activating mutation that alters its normal function. For example, a mutated KRAS protein may incorporate a single amino acid substitution at position 12 or 13. In a specific embodiment, the KRAS mutant incorporates a G12X or G13X substitution, where X represents any amino acid change at the indicated position. In a specific embodiment, the substitution is G12V, G12R, G12C, or G13D. In another embodiment, the substitution is G13D. "Mutant p53" or "p53 mutation" refers to a p53 protein (or a gene encoding the protein) that has incorporated a mutation that inhibits or eliminates 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 aforementioned cancer is non-small cell lung cancer (NSLCC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer or ovarian cancer.

[0606] test

[0607] Compounds of the present disclosure can be tested for their ability to inhibit MAT2A as described in Biological Example 1 below.

[0608] Pharmaceutical composition

[0609] The compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments described herein, or pharmaceutically acceptable salts thereof, may be in the form of a composition suitable for administration to a subject. Typically, such compositions are pharmaceutical compositions comprising compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments described herein, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable or physiologically acceptable excipients. In certain embodiments, the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments described herein, or pharmaceutically acceptable salts thereof, are present in a therapeutically effective amount. The pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions may be administered to a subject ex vivo or in vivo to practice the methods of treatment and uses described herein.

[0610] The pharmaceutical composition can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are described herein. In addition, the pharmaceutical composition can be used in combination with other therapeutically active agents or compounds described herein to treat the diseases, disorders and conditions contemplated by the present invention.

[0611] Pharmaceutical compositions comprising an active ingredient (e.g., a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment as described herein, or a pharmaceutically acceptable salt thereof) may be in a form suitable for oral use, such as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions for oral use may be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions may include one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets, capsules, and the like contain the active ingredient in admixture with a nontoxic pharmaceutically acceptable excipient suitable for preparing tablets, capsules, and the like. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc.

[0612] Tablets suitable for oral administration, capsules etc. can be uncoated or coated by known technology to delay disintegration and absorption in the gastrointestinal tract, thereby providing a lasting effect.For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, can be used.Tablets can also be coated by technology known in the art to form an osmotic therapeutic tablet for controlled release.Extra reagents include biodegradable or biocompatible particles or polymeric substances, such as polyester, polyamino acid, hydrogel, polyvinyl pyrrolidone, polyanhydride, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethyl cellulose, protamine sulfate or a copolymer of lactide and glycolide, a copolymer of polylactide and glycolide or ethylene vinyl acetate copolymer, to control the delivery of the composition used.For example, oral agents can be embedded in microcapsules prepared by coacervation technology or by interfacial polymerization (respectively by using hydroxymethyl cellulose or gelatin-microcapsules or poly (methyl methacrylate) microcapsules), or embedded in a colloidal drug delivery system. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles and liposomes. Methods for preparing the above formulations are known in the art.

[0613] Oral preparations can also be presented in the form of hard gelatin capsules, in which the active ingredient 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 ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0614] Aqueous suspensions include active substances mixed with excipients suitable for their manufacture. These excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl) methylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth and gum arabic; dispersants or wetting agents, such as natural phosphatides (such as lecithin), or condensation products of alkylene oxide and fatty acids (such as polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain aliphatic alcohols (such as, heptadecaethyleneoxycetanol), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol (such as, polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (such as, polyethylene sorbitan monooleate). Aqueous suspensions may also include one or more preservatives.

[0615] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavoring agents such as those mentioned above may be added to provide a palatable oral preparation.

[0616] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0617] The pharmaceutical composition can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (e.g., olive oil or peanut oil), or a mineral oil (e.g., liquid paraffin) or a mixture thereof. Suitable emulsifiers can be natural gums, such as gum arabic or tragacanth; natural phospholipids, such as soybean, lecithin, and esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0618] The pharmaceutical composition generally comprises a therapeutically effective amount of a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA') as described herein or a sub-embodiment 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, methyl paraben, ethyl or n-propyl paraben), emulsifiers, suspending agents, dispersants, solvents, fillers, bulking agents, detergents, buffers, vehicles, diluents and / or adjuvants. For example, a suitable vehicle may be a physiological saline solution or citric acid buffered saline, which may be supplemented with other substances commonly found in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin is a further exemplary vehicle. Those skilled in the art will readily recognize a variety of buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, the buffer component can be a water-soluble material, such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid and salts thereof. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS) and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0619] After the pharmaceutical composition is formulated, it can be stored in a sterile vial in the form of a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such a formulation can be stored in a ready-to-use form, a lyophilized form that requires reconstitution before use, a liquid form that requires dilution before use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a disposable container (e.g., a disposable vial, ampoule, syringe, or autoinjector (similar to, for example, )), while multiple-use containers (e.g., multiple-use vials) are provided in other embodiments.

[0620] The preparation can also include a carrier to protect the composition from rapid degradation or removal from the body, such as a controlled release formulation, including liposomes, hydrogels, prodrugs and microcapsule delivery systems. For example, a time-delay material (such as glyceryl monostearate or glyceryl stearate) can be used alone or in combination with wax. Any drug delivery device can be used to deliver formula (I), (IA), (IA'), (II), (IIA), (IIA') compounds or sub-embodiments or salts thereof as described herein, including implants (such as implantable pumps) and catheter systems, slow injection pumps and devices, all of which are well known to technicians.

[0621] Depot injections, which are typically administered subcutaneously or intramuscularly, can also be used to release a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment or a salt thereof as described herein over a certain period of time. Depot injections are typically solid-based or oil-based and typically include at least one of the formulation ingredients described herein. Those of ordinary skill in the art are familiar with possible formulations and uses of depot injections.

[0622] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. The suspension may be prepared according to known techniques using suitable dispersants or wetting agents and suspending agents as mentioned herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable diluents, solvents and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL TM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used to prepare injections. Prolonged absorption of a particular injectable formulation may be achieved by including an agent that delays absorption, such as aluminum monostearate or gelatin.

[0623] The compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof described herein can also be administered in the form of suppositories for rectal administration or sprays for nasal or inhalation administration. Suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0624] Route of administration

[0625] The compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof described herein and compositions comprising the same may be administered in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisternal, intraarticular, intraperitoneal, intracerebral (intraparenchymal) and intraventricular), nasal, vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), oral, and inhalation. Reservoir injections, which are typically administered subcutaneously or intramuscularly, may also be used to administer the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof described herein over a certain period of time. Specific embodiments of the invention contemplate oral administration.

[0626] Combination therapy

[0627] The present invention contemplates the use of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment as described herein, or a salt thereof, in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other preventive or therapeutic modalities (e.g., radiation). In such combination therapies, the various active agents often have different complementary mechanisms of action. Such combination therapies may be particularly beneficial by allowing the dosage of one or more agents to be reduced, thereby reducing or eliminating adverse effects associated with one or more agents. In addition, such combination therapies may have a synergistic therapeutic or preventive effect on the underlying disease, disorder, or condition.

[0628] As used herein, "combination" is meant to include therapies that can be administered separately, e.g., therapies formulated separately for separate administration (e.g., as provided in a kit), as well as therapies that can be administered together in a single formulation (i.e., a "co-formulation").

[0629] In certain embodiments, the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof described herein are administered or applied sequentially, for example, one agent is administered prior to one or more other agents. In other embodiments, the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof described herein are administered simultaneously, for example, two or more agents are administered simultaneously or approximately simultaneously; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Regardless of whether the two or more agents are administered sequentially or simultaneously, for purposes of this disclosure, they are considered to be administered in combination.

[0630] In this case, the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof as described herein may be used in combination with at least one other (active) agent in any suitable manner. In one embodiment, treatment with at least one active agent and at least one compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof as described herein is maintained over a period of time. In another embodiment, treatment with at least one active agent is reduced or interrupted (e.g., when the subject is stable), while treatment with the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof as described herein is carried out at a constant dosage regimen. In another embodiment, treatment with at least one active agent is reduced or interrupted (e.g., when the subject is stable), while treatment with the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof as described herein is reduced (e.g., lower doses, less frequent dosing, or shorter treatment regimens). In yet another embodiment, treatment with at least one active agent is reduced or discontinued (e.g., when the subject is stable), and treatment with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment as described herein, or a salt thereof, is increased (e.g., a higher dose, more frequent dosing, or a longer treatment regimen). In yet another embodiment, treatment with at least one active agent is maintained, and treatment with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment as described herein, or a salt thereof, is reduced or discontinued (e.g., a lower dose, less frequent dosing, or a shorter treatment regimen). In yet another embodiment, treatment with at least one active agent and a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment as described herein, or a salt thereof, is reduced or discontinued (e.g., a lower dose, less frequent dosing, or a shorter treatment regimen).

[0631] The present disclosure provides methods of treating cancer using a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or subembodiments described herein, or a salt thereof, and at least one additional therapeutic or diagnostic agent.

[0632] In some embodiments, the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or subembodiments described herein or salts thereof are 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, venetoclax (Bcl2 inhibitor), 5-azacytidine, anti-CD20 therapeutic agents such as rituximab and obinutuzumab, hormonal agents (anastrazole, exemestand, letrozole, sireloide, lupon acetate (lupon eligard), CDK4 / 6 inhibitors, palbociclib, abemaciclib, CPIs (avelumab, cemiplimab-rwlc and bevacizumab).

[0633] In certain embodiments, the present disclosure provides a method for treating cancer comprising administering a compound of formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment or a salt thereof as described herein in combination with a signal transduction inhibitor (STI) to achieve additive inhibition or synergistic inhibition of tumor growth. As used herein, the term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signaling pathway. Examples of signal transduction inhibitors (STIs) that can be used in the methods described herein include, but are not limited to: (i) bcr / abl kinase inhibitors (e.g., Gleevec); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) her-2 / neu receptor inhibitors (e.g., Herceptin); (iv) inhibitors of Akt family kinases or Akt pathways (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); (vi) phosphatidylinositol kinase inhibitors. Agents involved in immunomodulation can also be used in combination with one or more compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or subembodiments described herein, or salts thereof, to inhibit tumor growth in cancer patients.

[0634] In certain embodiments, the present disclosure provides a method of treating cancer comprising administering a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment as described herein, or a salt thereof, in combination with a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, piposulfan; aziridines such as benzodopa, carboquinone, meturedopa, and uredopa; ethyleneimines and methylamelamines including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide, and trimethylolmelamine; Nitrogen mustards, such as chlorambucil, naphthyl mustard, cholophosphamide, estramustine, ifosfamide, dichloromethyl diethylamine, methoxychlor hydrochloride, melphalan, nembice, phenylephrine, prednimustine, trolofosamide, uracil mustard; nitrosoureas, such as carmustine, pyrglucose, fotemustine, lomustine, nimustine, ranimustine; antibiotics, such as aclarubicin, actinomycin, anthramycin, azaserine, bleomycin, C-actinomycin, calicheamicin, carabicin, carminomycin, carmomycin, chromomycin, D-actinomycin, daunomycin, detoxibacin, 6-diazo-5-oxo- L-norleucine, doxorubicin, epirubicin, esorubicin, idambicin, marsalamycin, mitomycin, mycophenolic acid, noramycin, olive mycin, peplomycin, potfiromycin, puromycin, triferric doxorubicin, rhodorubicin, streptozocin, streptozocin, truffles, ubenimex, netastatin, daunorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as dimethylfolate, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiopurine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine glycosides, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens, such as captestosterone, drostanolone propionate, cyclothiocarb, melastane, testolactone; antiadrenergic agents, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folic acid; aceglucuronolide; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; idatrexate; defofamine; colcemid; diazocone; elfornithine; eliritamide; etoglu; gallium nitrate; hydroxyurea; mushroom polysaccharides; lonidamine;Mitoguanidine; mitoxantrone; mopidarol; diamine nitrazol; pentostatin; methamine nitrogen mustard; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofran; spirogermanium; tricholomanic acid; triazoquinone; 2,2',2"-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; piperobroman; cytosine; arabinosylcytidine (Ara-C); cyclophosphamide; thiotepa; taxanes, such as paclitaxel and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin and carboplatin; vinblastine; Trastuzumab; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; noantor; teniposide; daunomycin; aminopterin; sildenafil; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; ramycin; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above drugs. In a specific embodiment, the compounds of the present disclosure are co-administered with a cell inhibitory compound selected from cisplatin, doxorubicin, paclitaxel (taxol), docetaxel and mitomycin C. In a specific embodiment, the cell inhibitory compound is doxorubicin. ;

[0635] Chemotherapeutic agents also include anti-hormonal agents for regulating or inhibiting the hormonal effects of tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibition of 4 (5) -imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone and toremifene; anti-androgens, such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide and goserelin; and any pharmaceutically acceptable salts, acids or derivatives of any of the above drugs. In certain embodiments, the combination therapy includes the administration of hormones or related hormone agents.

[0636] The present disclosure also contemplates the use of compounds of formula (I), (IA), (IA'), (II), (IIA), (IIA') as described herein or sub-embodiments or salts thereof in combination with immune checkpoint inhibitors. The large number of genetic and epigenetic changes that are characteristic of all cancers provide a diverse set of antigens that the immune system can use to distinguish tumor cells from their normal counterparts. In the case of T cells, the ultimate amplitude (e.g., the level of cytokine production or proliferation) and quality (e.g., the type of immune response produced, such as the pattern of cytokine production) of the response initiated by T cell receptor (TCR) antigen recognition are regulated by the balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are essential for preventing autoimmunity (i.e., maintaining self-tolerance) and protecting tissues from damage when the immune system responds to pathogen infection. The expression of immune checkpoint proteins may be dysregulated by tumors as an important immune resistance mechanism. Examples of immune checkpoint inhibitors include, but are not limited to, CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFβ, CD73, CD39, A2AR, A2BR, IDO1, TDO2, arginase, B7-H3, B7-H4. Cell-based anticancer immunomodulators are also contemplated herein. Examples of such modulators include, but are not limited to, chimeric antigen receptor T cells, tumor infiltrating T cells, and dendritic cells.

[0637] The present disclosure contemplates the use of compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or sub-embodiments or salts thereof described herein in combination with the above-mentioned immune checkpoint receptor and ligand inhibitors (e.g., ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab and durvalumab).

[0638] Other treatment modalities that can be combined with a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment or a salt thereof as described herein include radiation therapy, monoclonal antibodies directed against tumor antigens, complexes of monoclonal antibodies and toxins, T cell adjuvants, bone marrow transplantation, or antigen presenting cells (e.g., dendritic cell therapy).

[0639] The present disclosure contemplates the use of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or an embodiment described herein, or a salt thereof, alone or in combination with radiation therapy and / or temozolomide (TMZ), Avastin or lomustine for the treatment of glioblastoma.

[0640] The present disclosure includes pharmaceutically acceptable salts, acids or derivatives of any of the above drugs.

[0641] Drug administration

[0642] The amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment or salt thereof as described herein that can be administered to a subject depends on, for example, the target of administration (e.g., the resolution required); the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered; the route of administration; and the nature of the disease, disorder, condition, or symptom. The dosage regimen may also take into account the presence, nature, and extent of any side effects associated with the administered agent. The effective dose and dosage regimen can be readily determined from, for example, safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0643] Typically, dosing parameters specify that the dose should be lower than the amount that may produce irreversible toxicity to the subject (maximum tolerated dose (MTD)) and not less than the amount required to produce a measurable effect on the subject. This amount is determined by, for example, pharmacokinetic and pharmacodynamic parameters related to ADME, taking into account the route of administration and other factors.

[0644] The effective dose (ED) is the dose or amount of a drug that produces a therapeutic response or desired effect in a subset of subjects taking the drug. The median effective dose or ED of a drug is 50 Refers to 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. 50 It is often used as a reasonable estimate of the effect of a drug, but it is not necessarily the dose that a clinician would consider appropriate, taking into account all relevant factors. Therefore, in some cases, the effective dose is greater than the calculated ED. 50 , while in still other cases the effective amount is less than the calculated ED 50 In some cases, the effective dose is different from the calculated ED 50 same.

[0645] In addition, an effective dose of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment or a salt thereof as described herein can be an amount that produces a desired result relative to a healthy subject when administered to a subject in one or more doses. For example, for a subject experiencing a particular condition, an effective dose can be a dose that improves a diagnostic parameter, measurement, marker, etc. of the condition 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 greater than 90%, where 100% is defined as a diagnostic parameter, measurement, marker, etc. exhibited by a normal subject.

[0646] In certain embodiments, a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment or a salt thereof as described herein may be administered (e.g., orally) once or more per day at a dosage level of about 0.01 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg of the subject's body weight to achieve the desired therapeutic effect.

[0647] For oral administration, the composition can be provided in the form of tablets, capsules, etc., containing 1.0 to 1000 mg of the active ingredient, especially 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 1.00.0 mg of the active ingredient.

[0648] In certain embodiments, dosages of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment or a salt thereof as described herein are contained in a "unit dosage form". The phrase "unit dosage form" refers to physically discrete units, each unit containing a predetermined amount of a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA') or a sub-embodiment or a salt thereof as described herein, alone or in combination with one or more additional agents, sufficient to produce the desired effect. It will be understood that the parameters of the unit dosage form will depend on the specific agent and the effect to be achieved.

[0649] Reagent test kit

[0650] The present invention also contemplates kits comprising a compound of Formula (I), (IA), (IA'), (II), (IIA), (IIA'), or a sub-embodiment, or a salt thereof, as described herein, and a pharmaceutical composition thereof. As described below, the kit is generally in the form of a physical structure that houses the various components and can be used, for example, to perform the above-described methods.

[0651] The kit may include one or more compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') as described herein, or sub-embodiments, or salts thereof (provided, for example, in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') as described herein, or sub-embodiments, or salts thereof may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form that requires, for example, reconstitution or dilution prior to administration (e.g., powder). When the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') as described herein, or sub-embodiments, or salts thereof are in a form that requires reconstitution or dilution by the user, the kit may also include a diluent (e.g., sterile water), a buffer, a pharmaceutically acceptable excipient, etc., packaged together or separately from the compounds of Formula (I), (IA), (IA'), (II), (IIA), (IIA') as described herein, or sub-embodiments, or salts thereof. When combination therapy is contemplated, the kit may contain several agents individually, or they may already be combined in the kit. Each component of the kit may be enclosed in a separate container, and all of the various containers may be in a single package.The kits of the present invention may be designed to properly maintain the conditions necessary for the components contained therein (eg, refrigeration or freezing).

[0652] The kit may include a label or package insert including identification information of the components therein and instructions for their use (e.g., dosage parameters, clinical pharmacology of one or more active ingredients, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse reactions, contraindications, etc.). The label or insert may include manufacturer information, such as a batch number and expiration date. The label or package insert may, for example, be integrated into a physical structure that houses the components, be contained separately within a physical structure, or be attached to a component of the kit (e.g., an ampoule, tube, or vial).

[0653] The label or insert may additionally include or be incorporated into a computer-readable medium, such as a disk (e.g., hard disk, card, storage disk), an optical disk such as CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or an electronic storage medium (e.g., RAM and ROM) or a combination thereof, such as a magnetic / optical storage medium, a flash memory medium, or a memory card. In some embodiments, the actual instructions are not present in the kit, but a means of obtaining the instructions from a remote source is provided, such as via the Internet.

[0654] Example

[0655] The following examples and references (intermediates) are intended to provide a person of ordinary skill in the art with a complete disclosure and description of how to prepare and use the invention, and are not intended to limit the scope of what the inventors believe to be their invention, nor are they intended to represent that the following experiments were performed or that these experiments are all experiments that can be performed. It should be understood that the exemplary descriptions written in the present tense are not necessarily performed, but rather that these descriptions can be performed to generate the properties described herein, such as data. Every effort has been made to ensure the accuracy of the numbers used (e.g., quantities, temperatures, etc.), but some experimental errors and deviations should be considered.

[0656] Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius (°C), and pressure is at or near atmospheric. Standard abbreviations are used, including the following: μg = microgram; μl or μL = microliter; mM = millimole; μM = micromole; aa = amino acid; Ac = amino acid. 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; DEAD = diethyl azodicarboxylate; DIBAL = diisobutylaluminum hydride; DIEA = N,N-diisopropylethylamine; DIPEA = N,N-diisopropylethylamine; dl or dL = deciliter; DMA = dimethylacetamide; DMAP = dimethylaminopyridine; DME = 1,2-dimethoxyethane; DMEM = Dulbecco's Modification of Eagle Medium 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; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HEPES = 4-(2 -hydroxyethyl)-1-piperazineethanesulfonic acid; HOAc = acetic acid; HPLC = high performance liquid chromatography; HPLC = high pressure liquid chromatography; im = intramuscular (Im); ip = intraperitoneal (Im); IHC = immunohistochemistry; IPA = isopropanol; kb = kilobase; kDa = kilodalton; kg = kilogram; l or L = liter; LC = liquid chromatography; LCMS = liquid chromatography and mass spectrometry; m / z = mass-to-charge ratio; M = mole; m = multiplicity; MeCN = acetonitrile; MeOH = methanol; MeSO2 Cl = methanesulfonyl chloride; mg = milligram; min = minute; min = minute; ml or mL = milliliter; mM = millimole; MS = mass spectrometry; MsCl = methanesulfonyl chloride; N = normal; NADPH = nicotinamide adenine dinucleotide phosphate; NBS = N-bromosuccinimide; ng = nanogram; nm = nanometer; nM = nanomolar; NMP = N-methylpyrrolidone; NMR = nuclear magnetic resonance; ns = not statistically significant; nt = nucleotide; PBS = phosphate-buffered saline; Pd / C = palladium on carbon; Pd 2 (dba) 3 = tris(dibenzylideneacetone)dipalladium; Pd(dppf)Cl 2 =1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride; PE = petroleum ether; QD = daily; QM = monthly; QW = weekly; rac = racemic; Rt = retention time; s = singlet; s or sec = seconds; sat. = saturated; SC or SQ = subcutaneous (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 = unit; wt = wild type.

[0657] Synthesis Example

[0658] Reference 1

[0659] Synthesis of 7-Chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one

[0660]

[0661] Step 1: Synthesis of 4-chloro-2-(phenylamino)benzoic acid

[0662]

[0663] To a stirred solution of 2,4-dichlorobenzoic acid (1 eq.) in DMF (0.5 M) was added aniline (1.5 eq.), copper (0) powder (0.5 eq.) and potassium carbonate (2 eq.) and the reaction mixture was stirred at 150 °C for 5 hours. After the reaction was complete, the reaction mixture was brought to room temperature and filtered through a pad of celite. The resulting filtrate was acidified with 2N HCl. The solid formed was filtered and dried under vacuum to give 4-chloro-2-(phenylamino)benzoic acid as a brown solid.

[0664] Step 2: Synthesis of 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one

[0665]

[0666] A mixture of 4-chloro-2-(phenylamino)benzoic acid (1 equivalent) and urea (5 equivalents) was charged into a round-bottom flask equipped with a stirring bar and heated at 200°C for 2 hours. The crude product was poured into water and extracted with EtOAc. The combined organic layers were separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (20-30% EtOAc / hexanes) 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=8.3Hz,1H),7.66-7.56(m,3H),7.48-7.44(m,2H),7.31(dd,J=8.3,1.9Hz,1H),6.31(d,J=1.8Hz,1H).m / z[M+H] + 273.18

[0667] Reference 2

[0668] Synthesis of 7-chloro-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione

[0669]

[0670] Step 1: Synthesis of 4-chloro-2-(pyridin-3-ylamino)benzamide

[0671]

[0672] To a stirred solution of 2,4-dichlorobenzamide (1 eq.) in DMF (0.5 M) were added 3-aminopyridine (1.5 eq.), copper (0) powder (0.5 eq.) and potassium carbonate (2 eq.) and the reaction mixture was stirred at 150 °C for 5 hours. After the reaction was complete, the reaction mixture was brought to room temperature and filtered through a pad of celite. The resulting filtrate was acidified with 2N HCl. The solid formed was filtered and dried in vacuo to afford the title compound as a brown solid. m / z[M+H] + 249.1

[0673] Step 2: Synthesis of 7-chloro-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione

[0674]

[0675] The vial was charged with 4-chloro-2-(pyridin-3-ylamino)benzamide (1.0 eq.) and DMF (0.2 M). NaH (60% in mineral oil, 3.0 eq.) was added to the reaction vessel at 0°C and the reaction mixture was stirred at room temperature for 10 minutes. CDI (1.5 eq.) was added to the container and the reaction mixture was stirred at room temperature for 20 minutes. The reaction was quenched by adding MeOH (0.5 mL) and AcOH (0.2 mL). The crude reaction mixture was directly purified by reverse phase column chromatography (20-75% MeCN / water, 0.1% formic acid). 1 H NMR (400 MHz, DMSO-d 6 )δ11.82(s,1H),8.69(d,J=4.9Hz,1H),8.61(s,1H),7.99(d,J=8.4Hz,1H),7.91( d,J=7.9Hz,1H),7.68-7.50(m,1H),7.27(d,J=8.6Hz,1H),6.32(s,1H).m / z[M+H] + 274.0

[0676] 2-((2-chlorophenyl)amino)-6-cyclopropyl-nicotinamide was prepared as described in step 1 of reference 2 using 2-chloroaniline and 2-chloro-6-cyclopropylnicotinamide in place of 3-aminopyridine and 2,4-dichlorobenzamide, respectively.

[0677]

[0678] Proceeding as described above in Step 2, the following compounds were prepared:

[0679] 7-Chloro-1-(pyridin-4-yl)quinazoline-2,4(1H,3H)-dione was prepared using 4-chloro-2-(pyridin-4-ylamino)benzamide.

[0680]

[0681] 1-(2-Chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinamide.

[0682]

[0683] 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.

[0684]

[0685] 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.

[0686]

[0687] 3-(7-Chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile was prepared using 4-chloro-2-((3-cyanophenyl)amino)benzamide. 1 H NMR (400 MHz, DMSO-d 6 )δ11.92(s,1H),8.13-8.00(m,3H),7.85(dd,J=8.3,1.7Hz,2H),7.34(dt,J=8.5,1.7Hz,1H),6.43(d,J=1.7Hz,1H).

[0688]

[0689] Reference 3

[0690] Synthesis of 7-Chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

[0691]

[0692] Step 1: Synthesis of 4-chloro-2-fluoro-6-(phenylamino)benzoic acid

[0693]

[0694] To a stirred solution of aniline (2 eq.) in THF (1 M) was added LDA (3 eq.) at 78°C and the reaction mixture was stirred for 10 minutes. A solution of 4-chloro-2,6-difluorobenzoic acid (1 eq.) in THF (1 M) was added at 78°C and the reaction mixture was stirred at room temperature for 48 hours. After completion of the reaction, the crude product was poured into 1N HCl solution and extracted with EtOAc. The combined organic layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the desired 4-chloro-2-fluoro-6-(phenylamino)benzoic acid as a light yellow solid.

[0695] Step 2: Synthesis of 4-chloro-2-fluoro-6-(phenylamino)benzamide

[0696]

[0697] To a stirred solution of 4-chloro-2-fluoro-6-(phenylamino)benzoic acid (1 eq) in DMF (0.4 M) was added HATU (1.5 eq), DIPEA (5 eq) and stirred for 30 minutes at room temperature. Ammonium chloride (5 eq) was added to the reaction mixture and stirring was continued for 16 hours at room temperature. After completion, the crude product was poured into ice-cold water and stirred for 30 minutes, the solid was filtered and dried in vacuo to give 4-chloro-2-fluoro-6-(phenylamino)benzamide as an off-white solid.

[0698] Step 3: Synthesis of 7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

[0699]

[0700] 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 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 crude product was poured into ice-cold water and the mixture was stirred for 30 min. The solid 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 )δ11.77(br s,1H),7.61(m,3H),7.44(m,2H),7.29(dd,J=10.8,1.8Hz,1H),6.10(s,1H).m / z[M+H] + 291.3

[0701] Proceeding as described above in reference 3, step 2, the following compound was prepared:

[0702] 2-Chloro-4-methoxy-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinic acid.

[0703]

[0704] 2,6-Dichloro-4-(trifluoromethyl)benzamide was prepared using 2,6-dichloro-4-(trifluoromethyl)benzoic acid.

[0705]

[0706] 5-Bromo-2-fluoro-4-(trifluoromethyl)benzamide was prepared using 5-bromo-2-fluoro-4-(trifluoromethyl)benzoic acid.

[0707]

[0708] Reference 4

[0709] Synthesis of 7-Chloro-1-[3-(methoxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione

[0710]

[0711] Step 1: Synthesis of 4-chloro-2-((3-(methoxymethyl)phenyl)amino)benzamide

[0712]

[0713] 2-Amino-4-chlorobenzamide (1.0 equiv), cupric chloride (0.15 equiv), 3-(methoxymethyl)phenylboronic acid (1.5 equiv) and triethylamine (0.5 equiv) were placed in a vial in air. MeOH (0.4 M) was added to the reaction vessel and the reaction mixture was stirred at room temperature for 3-12 hours. The crude reaction mixture was directly purified by reverse phase chromatography (20-65% MeCN / water) to afford the title compound. m / z [M+H] + 291.1

[0714] Step 2: Synthesis of 7-chloro-1-[3-(methoxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione

[0715]

[0716] 4-Chloro-2-((3-(methoxymethyl)phenyl)-amino)benzamide (1.0 eq.) and DMF (0.2 M) were loaded into a vial under nitrogen. NaH (60% in mineral oil, 3.0 eq.) was added to the reaction mixture at 0°C and the reaction mixture was stirred at room temperature for 10 minutes. CDI (1.5 eq.) was added and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched by adding MeOH and AcOH. The crude reaction mixture was directly purified by reverse phase column chromatography (20-75% MeCN / water, 0.1% formic acid) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 )δ11.80(s,1H),8.03(dd,J=8.4,1.3Hz,1H),7.60(t,J=7.6Hz,1H),7.50(d,J=7.8Hz,1H), 7.41-7.34(m,2H),7.30(dt,J=8.4,1.7Hz,1H),6.30(t,J=1.6Hz,1H),4.50(s,2H)m / z[M+H] + 317.1

[0717] Proceeding similarly as above, the following compounds were prepared:

[0718] 7-Chloro-1-(3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting 3-hydroxyphenylboronic acid for 3-(methoxymethyl)phenylboronic acid.

[0719]

[0720] 7-Chloro-1-[3-(2-hydroxyethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-(methoxymethyl)phenylboronic acid with (3-(2-hydroxyethyl)phenyl)boronic acid.

[0721]

[0722] 7-Chloro-1-(3-fluorophenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting (3-fluorophenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid.

[0723]

[0724] 7-Chloro-1-(3-methylphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-(methoxymethyl)phenylboronic acid with m-tolylboronic acid.

[0725]

[0726] 7-Chloro-1-[3-(3-hydroxypropyl)phenyl]-1,3-dihydroquinazoline-2,4-dione was prepared by replacing 3-(methoxymethyl)phenylboronic acid with 3-(3-hydroxypropyl)phenylboronic acid.

[0727]

[0728] 7-Chloro-1-(3-chlorophenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting (3-chlorophenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid.

[0729]

[0730] 7-Chloro-1-[3-(hydroxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione was prepared by substituting (3-(hydroxymethyl)phenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid.

[0731]

[0732] 3-(7-Chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile was prepared by substituting (3-cyanophenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid.

[0733]

[0734] Tert-butyl (3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzyl)carbamate was prepared by substituting 3-((tert-butoxycarbonylamino)methyl)phenylboronic acid for 3-(methoxymethyl)phenylboronic acid.

[0735]

[0736] 7-Chloro-1-(3-methoxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting (3-methoxyphenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid.

[0737]

[0738] 7-Chloro-1-(5-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting 3-fluoro-5-hydroxyphenylboronic acid for 3-(methoxymethyl)phenylboronic acid.

[0739]

[0740] 7-Chloro-1-(4-fluorophenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting (4-fluorophenyl)boronic acid for 3-(methoxymethyl)phenylboronic acid.

[0741]

[0742] 7-Chloro-1-(2-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting 2-fluoro-3-hydroxyphenylboronic acid for 3-(methoxymethyl)phenylboronic acid.

[0743]

[0744] 7-Chloro-1-(4-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione was prepared by substituting 4-fluoro-3-hydroxyphenylboronic acid for 3-(methoxymethyl)phenylboronic acid.

[0745]

[0746] Reference 5

[0747] Synthesis of 1-[3-(Aminomethyl)phenyl]-7-chloro-1,3-dihydroquinazoline-2,4-dione

[0748]

[0749] A vial was charged with tert-butyl (3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzyl)carbamate (1.0 equiv) and MeCN (0.2 M) under nitrogen, 4N HCl / dioxane (10 equiv) was added and the reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated and the crude reaction mixture was directly purified by reverse phase purification (10-45% MeCN / water, 0.1% formic acid) to give the title compound. 1 H NMR (400 MHz, DMSO-d 6 )δ8.30(s,1H),8.05(d,J=8.4Hz,1H),7.60(d,J=7.3Hz,2H),7.44(s,1H),7.39-7.23(m,2H),6.35(s,1H),3.93(s,3H).m / z[M+H] + 302.0

[0750] Reference 6

[0751] Synthesis of 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

[0752]

[0753] Step 1: Synthesis of 2,4-dichloro-N-(o-tolylcarbamoyl)benzamide

[0754]

[0755] A slurry of 2,4-dichlorobenzamide (1 eq.) in DCE (0.5 M) was treated dropwise with oxalyl chloride (1.35 eq.) at room temperature. The reaction mixture was warmed to 55 °C for 1 hour and then further warmed to reflux for 20 hours. The reaction mixture was concentrated in vacuo to give a crude yellow oil. A solution of this crude isocyanate in DCE (1.2 M) was added dropwise to a cooled solution of o-toluidine in DCE (0.4 M) at 0 °C. The ice bath was removed and the reaction mixture was stirred at room temperature for 45 minutes. The solid was filtered, washed with DCM and dried to give the title compound as a white solid. m / z[M+H] + 324.0

[0756] Step 2: Synthesis of 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

[0757]

[0758] A slurry of 2,4-dichloro-N-(o-tolylcarbamoyl)benzamide in DME:toluene (0.06M, 1:1 v / v) was cooled to 0°C and treated with NaH (60%, dispersed in oil, 3.1 eq) in batches. After addition, the ice bath was removed and the reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and poured into 20% aqueous hydrochloric acid. The resulting mixture was stirred vigorously and the off-white solid was filtered and washed with Et 2 O washing and drying to obtain the crude product, which was used in the next step without purification. m / z[M+H] + 287.0

[0759] Proceeding similarly as described above in Step 1, the following compounds were prepared:

[0760] 4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide was prepared by replacing o-toluidine with imidazo[1,2-a]pyridin-5-amine and 2,4-dichlorobenzamide with 4-(1,1-difluoroethyl)-2-fluorobenzamide.

[0761]

[0762] 5-Cyano-4-cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide was prepared by substituting 5-cyano-4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide.

[0763]

[0764] N-((2-chlorophenyl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide was prepared by replacing o-toluidine with 2-chloroaniline and 2,4-dichlorobenzamide with 4-(1,1-difluoroethyl)-2-fluorobenzamide (Pharmablock, PBU1050).

[0765]

[0766] 4-Chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide was prepared by substituting imidazo[1,2-a]pyridin-5-amine for o-toluidine and 4-chloro-2-fluorobenzamide for 2,4-dichlorobenzamide.

[0767]

[0768] 4-Chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide was prepared by substituting imidazo[1,2-a]pyridin-7-amine for o-toluidine and 4-chloro-2-fluorobenzamide for 2,4-dichlorobenzamide.

[0769]

[0770] N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was synthesized by using 4-cyclopropyl-2-fluorobenzamide instead of 2,4-dichlorobenzamide and 2-chloroaniline instead of o-toluidine.

[0771]

[0772] 2,4-Dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide in place of 2,4-dichlorobenzamide and pyrimidin-2-amine.

[0773]

[0774] 4-Cyclopropyl-2-fluoro-N-((3-methylpyrazin-2-yl)carbamoyl)benzamide was synthesized by using 4-cyclopropyl-2-fluorobenzamide to replace 2,4-dichlorobenzamide and 3-methylpyrazin-2-amine to replace o-toluidine.

[0775]

[0776] 4-Cyclopropyl-2-fluoro-N-(pyrazin-2-ylcarbamoyl)benzamide was synthesized by using 4-cyclopropyl-2-fluorobenzamide to replace 2,4-dichlorobenzamide and pyrazin-2-amine to replace o-toluidine.

[0777]

[0778] 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.

[0779]

[0780] N-((3-chloropyridin-2-yl)carbamoyl)-4-ethyl-2-fluorobenzamide was prepared by substituting 3-chloropyridin-2-amine for o-toluidine and 4-ethyl-2-fluorobenzamide for 2,4-dichlorobenzamide.

[0781]

[0782] N-((3-chloropyridin-2-yl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide was prepared by substituting 3-chloropyridin-2-amine for o-toluidine and 4-(1,1-difluoroethyl)-2-fluorobenzamide for 2,4-dichlorobenzamide.

[0783]

[0784] 4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide was prepared by substituting imidazo[1,2-a]pyridin-7-amine for o-toluidine and 4-(1,1-difluoroethyl)-2-fluorobenzamide for 2,4-dichlorobenzamide.

[0785]

[0786] 2-Fluoro-N-(pyrazin-2-ylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and pyrazin-2-amine for o-toluidine.

[0787]

[0788] 2-Fluoro-N-(pyridazin-3-ylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and pyridazin-3-amine for o-toluidine.

[0789]

[0790] 2-Fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared by substituting 2-fluoro-4-(trifluoromethoxy)benzamide for 2,4-dichlorobenzamide and imidazo[1,2-a]pyridin-5-amine for o-toluidine.

[0791]

[0792] 2-Chloro-4-cyclopropyl-N-((3-(trifluoromethyl)pyrazin-2-yl)carbamoyl)benzamide was prepared by substituting 2-chloro-4-cyclopropylbenzamide for 2,4-dichlorobenzamide and 3-(trifluoromethyl)pyrazin-2-amine for o-toluidine.

[0793]

[0794] 5-Bromo-2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared by substituting 5-bromo-2-fluoro-4-(trifluoromethoxy)benzamide for 2,4-dichlorobenzamide.

[0795]

[0796] 5-Bromo-2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethoxy)benzamide was prepared by substituting 5-bromo-2-fluoro-4-(trifluoromethoxy)benzamide for 2,4-dichlorobenzamide and aniline for o-toluidine.

[0797]

[0798] 4-Bromo-N-((2-chlorophenyl)carbamoyl)-2,5-difluorobenzamide was prepared by substituting 4-bromo-2,5-difluorobenzamide for 2,4-dichlorobenzamide and 2-chloroaniline for o-toluidine.

[0799]

[0800] 2,6-Difluoro-4-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide was prepared by substituting 2,6-difluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine for o-toluidine.

[0801]

[0802] 4-Cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and imidazo[1,2-a]pyridin-7-amine for o-toluidine.

[0803]

[0804] 2-Chloro-N-((2-chloropyridin-3-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared by substituting 2-chloro-6-(trifluoromethyl)nicotinamide for 2,4-dichlorobenzamide and 2-chloropyridin-3-amine for o-toluidine.

[0805]

[0806] 2-Chloro-6-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)nicotinamide was prepared by substituting 2-chloro-6-(trifluoromethyl)nicotinamide for 2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine for o-toluidine.

[0807]

[0808] 5-Bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)phenyl)carbamoyl)benzamide was prepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-(trifluoromethyl)aniline for o-toluidine.

[0809]

[0810] 5-Bromo-4-cyclopropyl-N-((2-cyclopropylphenyl)carbamoyl)-2-fluorobenzamide was prepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-cyclopropylaniline for o-toluidine.

[0811]

[0812] 5-Bromo-N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-bromoaniline for o-toluidine.

[0813]

[0814] 5-Bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide was prepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine for o-toluidine.

[0815]

[0816] 5-Bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by substituting 5-bromo-2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and 2-chloroaniline for o-toluidine.

[0817]

[0818] 5-Bromo-N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-chloropyridin-3-amine for o-toluidine.

[0819]

[0820] N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide was prepared by substituting 4-cyclopropyl-2-fluoro-6-methoxybenzamide for 2,4-dichlorobenzamide and 2-chloropyridin-3-amine for o-toluidine.

[0821]

[0822] N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-chloropyridin-3-amine for o-toluidine.

[0823]

[0824] 2-Fluoro-4-(trifluoromethyl)-N-(((1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)carbamoyl)benzamide was prepared by replacing 2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-amine for o-toluidine.

[0825]

[0826] 2-Fluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and aniline for o-toluidine.

[0827]

[0828] N-((3-chloropyridin-2-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 3-chloropyridin-2-amine for o-toluidine.

[0829]

[0830] 4-Cyclopropyl-2-fluoro-N-(pyrimidin-5-ylcarbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and pyrimidin-5-amine for o-toluidine.

[0831]

[0832] 4-Cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide.

[0833]

[0834] 2-Fluoro-4-(trifluoromethyl)-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide was prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamide and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine for o-toluidine.

[0835]

[0836] 4-Cyclopropyl-2-fluoro-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine for o-toluidine.

[0837]

[0838] N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-bromoaniline for o-toluidine.

[0839]

[0840] 4-Cyclopropyl-2-fluoro-6-methoxy-N-(pyridin-3-ylcarbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluoro-6-methoxybenzamide for 2,4-dichlorobenzamide and pyridin-3-amine for o-toluidine.

[0841]

[0842] 4-Cyclopropyl-2-fluoro-6-methoxy-N-(o-tolylcarbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluoro-6-methoxybenzamide for 2,4-dichlorobenzamide.

[0843]

[0844] 4-Chloro-N-((2-chlorophenyl)carbamoyl)-2,6-difluorobenzamide was prepared by substituting 4-chloro-2,6-difluorobenzamide for 2,4-dichlorobenzamide and 2-chloroaniline for o-toluidine.

[0845]

[0846] 4-Chloro-2,6-difluoro-N-(o-tolylcarbamoyl)benzamide was prepared by substituting 4-chloro-2,6-difluorobenzamide for 2,4-dichlorobenzamide.

[0847]

[0848] N-(Benzylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide was prepared by substituting 2-chloro-6-(trifluoromethyl)nicotinamide for 2,4-dichlorobenzamide and benzylamine for o-toluidine.

[0849]

[0850] 4-Cyclopropyl-2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide was prepared by substituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and 2-methylpyridin-3-amine for o-toluidine.

[0851]

[0852] 2-Chloro-N-((2-chloro-6-fluorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared by substituting 2-chloro-6-(trifluoromethyl)nicotinamide for 2,4-dichlorobenzamide and 2-chloro-6-fluoroaniline for o-toluidine.

[0853]

[0854] Proceeding similarly as described above in Step 2, the following compounds were prepared:

[0855] 7-Chloro-1-(2-fluorophenyl)quinazoline-2,4(1H,3H)-dione was prepared by replacing o-toluidine with 2-fluoroaniline.

[0856]

[0857] 1-(3-Bromophenyl)-7-chloroquinazoline-2,4(1H,3H)-dione was prepared by replacing o-toluidine with 3-bromoaniline.

[0858]

[0859] 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.

[0860]

[0861] 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.

[0862]

[0863] 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.

[0864]

[0865] 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.

[0866]

[0867] 1-(2-Chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared using N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide.

[0868]

[0869] Reference 7

[0870] Synthesis of 6-Bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

[0871]

[0872] Step 1: Synthesis of 4-cyclopropyl-2-fluorobenzamide

[0873]

[0874] A vial was charged with 4-bromo-2-fluorobenzamide (1 eq.), cyclopropylboronic acid (3 eq.) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (0.1 eq.). A 1:1 mixture of toluene: tert-butanol (0.1 M) was added, followed by an aqueous solution of potassium carbonate (2 M, 4 eq.). The reaction mixture was heated to 100 °C for 2 hours and then cooled. The crude reaction mixture was diluted with ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-100% ethyl acetate / hexane) to give the title compound.

[0875] Step 2: Synthesis of 5-bromo-4-cyclopropyl-2-fluorobenzamide

[0876]

[0877] A vial was charged with 4-cyclopropyl-2-fluorobenzamide (1 eq.) and N-bromo-succinimide (1.2 eq.). Trifluoroacetic acid (0.5 M) was added, followed by a catalytic amount of sulfuric acid. The reaction mixture was heated to 40 °C for 2 hours, then cooled. The crude reaction mixture was poured into water and the title compound was collected by filtration.

[0878] Step 3: Synthesis of 5-bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide

[0879]

[0880] The slurry of 5-bromo-4-cyclopropyl-2-fluorobenzamide (1 equivalent) in DCE (0.5M) was dropwise treated with oxalyl chloride (1.35 equivalents) at room temperature. The reaction mixture was warmed to 55 ° C for 1 hour, and then further heated to reflux for 20 hours. The reaction mixture was concentrated in vacuo to obtain a yellow oily crude product. At 0 ° C, a DCE (1.2M) solution of this thick isocyanate was added dropwise to a DCE (0.4M) cooling solution of 2-chloroaniline. The ice bath was removed and the reaction mixture was stirred at room temperature for 45 minutes. The solid was filtered, washed with DCM, and dried to obtain the title compound as a white solid.

[0881] Step 4: Synthesis of 6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

[0882]

[0883] A slurry of 5-bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide in DME:toluene (0.06M, 1:1 v / v) was cooled to 0°C and treated with NaH (60%, dispersed in oil, 3.1 eq) in batches. After addition, the ice bath was removed and the reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and poured into 20% aqueous hydrochloric acid. The resulting mixture was stirred vigorously and the off-white solid was filtered and washed with Et 2 O washing and drying to obtain the crude product, which was used in the next step without purification. m / z[M+H] + 392.0.

[0884] Reference 8

[0885] Synthesis of 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide

[0886]

[0887] A slurry of 2,4-dichlorobenzoyl (1 eq.) in DCE (0.5 M) was treated dropwise with oxalyl chloride (1.35 eq.) at room temperature. The reaction mixture was then warmed to 55 °C for 1 hour and then further warmed to reflux for 20 hours. The reaction mixture was concentrated in vacuo to give crude 2,4-dichlorobenzoyl isocyanate as a yellow oil. A solution of the crude product in DCE (1.2 M) was added dropwise to a cooled solution of pyrazine-2-amine in DCE (0.4 M) at 0 °C. The ice bath was removed and the reaction mixture was stirred at room temperature for 45 minutes. The solid was then filtered, washed with DCM and dried to give the title compound as a white solid. m / z[M+H] + 311.0.

[0888] Proceeding similarly as above, the following compounds were prepared.

[0889] 2,4-Dichloro-N-(pyridin-2-ylcarbamoyl)benzamide

[0890]

[0891] 2,4-Dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyridin-2-amine.

[0892]

[0893] 2,4-Dichloro-N-(pyridazin-3-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyridazin-3-amine.

[0894]

[0895] 2,4-Dichloro-N-(pyrimidin-5-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and pyrimidin-5-amine.

[0896]

[0897] N-((1H-pyrazol-4-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using 2,4-dichlorobenzamide and 1H-pyrazol-4-amine.

[0898]

[0899] N-((1H-imidazol-2-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using 2,4-dichlorobenzamide and 1H-imidazol-2-amine.

[0900]

[0901] 2,4-Dichloro-N-(thiazol-2-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and thiazol-2-amine.

[0902]

[0903] 2,4-Dichloro-N-(thiazol-5-ylcarbamoyl)benzamide was prepared using 2,4-dichlorobenzamide and thiazol-5-amine.

[0904]

[0905] N-((1H-pyrazol-5-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using 2,4-dichlorobenzamide and 1H-pyrazol-5-amine.

[0906]

[0907] 2-Chloro-N-((2-chlorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and 2-chloroaniline.

[0908]

[0909] 2-Chloro-N-((3-methylpyridin-2-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and 3-methylpyridin-2-amine.

[0910]

[0911] 2-Chloro-N-((3-chloropyridin-2-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and 3-chloropyridin-2-amine.

[0912]

[0913] 2-Chloro-6-isopropyl-N-(phenylcarbamoyl)nicotinamide was prepared using 2-chloro-6-isopropylnicotinamide and aniline.

[0914]

[0915] 2,6-Difluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2,6-difluoro-4-(trifluoromethyl)benzamide and aniline.

[0916]

[0917] 2-Fluoro-N-((2-methylpyridin-3-yl)carbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2-fluoro-4-(trifluoromethyl)benzamide and 2-methylpyridin-3-amine.

[0918]

[0919] N-((2-chlorophenyl)carbamoyl)-2-fluoro-4-(trifluoromethoxy)benzamide was prepared using 2-fluoro-4-(trifluoromethoxy)benzamide and 2-methylpyridin-3-amine.

[0920]

[0921] 4-Bromo-5-chloro-N-((2-chlorophenyl)carbamoyl)-2-fluorobenzamide was prepared using 4-bromo-5-chloro-2-fluorobenzamide and 2-chloroaniline.

[0922]

[0923] 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.

[0924]

[0925] 4-Cyclopropyl-N-((2-(difluoromethoxy)pyridin-3-yl)carbamoyl)-2-fluorobenzamide was prepared using 4-cyclopropyl-2-fluorobenzamide and 2-(trifluoromethoxy)pyridin-3-amine.

[0926]

[0927] Reference 9

[0928] Synthesis of 7-Chloro-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione

[0929]

[0930] A slurry of 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide in DMF (0.06 M) was treated dropwise with KHMDS (3 eq.) at room temperature. The reaction mixture was heated to 95° C. for 18 hours. Upon completion, water was added to the reaction mixture to completely dissolve the product, which was immediately purified by reverse phase column chromatography (20-

[0931] 60% MeCN / water, 0.1% formic acid) to give the title compound. m / z[M+H] + 276.0

[0932] Proceeding similarly as above, the following compound was prepared by substituting 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide:

[0933] 7-Chloro-1-(pyridin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(pyridin-2-ylcarbamoyl)benzamide.

[0934]

[0935] 7-Chloro-1-(pyrimidin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide.

[0936]

[0937] 7-Chloro-1-(pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(pyridazin-3-ylcarbamoyl)benzamide.

[0938]

[0939] 7-Chloro-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(pyrimidin-5-ylcarbamoyl)benzamide.

[0940]

[0941] 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.

[0942]

[0943] 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.

[0944]

[0945] 7-Chloro-1-(thiazol-2-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(thiazol-2-ylcarbamoyl)benzamide.

[0946]

[0947] 7-Chloro-1-(thiazol-5-yl)quinazoline-2,4(1H,3H)-dione was prepared using 2,4-dichloro-N-(thiazol-5-ylcarbamoyl)benzamide.

[0948]

[0949] 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.

[0950]

[0951] 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.

[0952]

[0953] 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.

[0954]

[0955] 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.

[0956]

[0957] 7-Isopropyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 2-fluoro-6-isopropyl-N-(phenylcarbamoyl)nicotinamide.

[0958]

[0959] 5-Fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared using 2,6-difluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide.

[0960]

[0961] 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.

[0962]

[0963] 1-(2-Chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione was prepared using N-((2-chlorophenyl)carbamoyl)-2-fluoro-4-(trifluoromethoxy)benzamide.

[0964]

[0965] 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.

[0966]

[0967] 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.

[0968]

[0969] 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.

[0970]

[0971] 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.

[0972]

[0973] 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.

[0974]

[0975] 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.

[0976]

[0977] 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.

[0978]

[0979] 7-Chloro-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using 2,6-dichloro-N-(phenylcarbamoyl)nicotinamide.

[0980]

[0981] 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.

[0982]

[0983] 6-Bromo-1-phenyl-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione was prepared using 5-bromo-2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethoxy)benzamide.

[0984]

[0985] 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.

[0986]

[0987] 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.

[0988]

[0989] 1-(Imidazolo[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.

[0990]

[0991] 1-(Pyridazin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared using 2-fluoro-N-(pyridazin-3-ylcarbamoyl)-4-(trifluoromethyl)benzamide.

[0992]

[0993] 1-(Pyrazin-2-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared using 2-fluoro-N-(pyrazin-2-ylcarbamoyl)-4-(trifluoromethyl)benzamide.

[0994]

[0995] 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.

[0996]

[0997] 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.

[0998]

[0999] 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.

[1000]

[1001] 7-Cyclopropyl-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared using 4-cyclopropyl-2-fluoro-N-(pyrazin-2-ylcarbamoyl)benzamide.

[1002]

[1003] 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.

[1004]

[1005] 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.

[1006]

[1007] 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.

[1008]

[1009] 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.

[1010]

[1011] 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.

[1012]

[1013] 7-Bromo-1-(2-chlorophenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione was prepared using 4-bromo-N-((2-chlorophenyl)carbamoyl)-2,5-difluorobenzamide.

[1014]

[1015] 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.

[1016]

[1017] 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.

[1018]

[1019] 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.

[1020]

[1021] 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.

[1022]

[1023] 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.

[1024]

[1025] 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.

[1026]

[1027] 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.

[1028]

[1029] 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.

[1030]

[1031] 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.

[1032]

[1033] 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.

[1034]

[1035] 1-Phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared using 2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide.

[1036]

[1037] 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.

[1038]

[1039] 7-Cyclopropyl-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione was prepared from 4-cyclopropyl-2-fluoro-N-(pyrimidin-5-ylcarbamoyl)benzamide.

[1040]

[1041] 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.

[1042]

[1043] 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.

[1044]

[1045] 1-(2-Bromophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was prepared using N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide.

[1046]

[1047] 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.

[1048]

[1049] 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.

[1050]

[1051] 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.

[1052]

[1053] 1-Benzyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was prepared using N-(benzylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide.

[1054]

[1055] 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.

[1056]

[1057] 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.

[1058]

[1059] 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.

[1060]

[1061] Reference 10

[1062] Synthesis of 7-Chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

[1063]

[1064] Step 1: Synthesis of 4-chloro-2,5-difluorobenzamide

[1065]

[1066] To a stirred solution of 4-chloro-2,5-difluorobenzoic acid (1 eq.) in THF (0.9 M) at 0 °C in a sealed flask was added DIPEA (5 eq.), HATU (1.2 eq.) and NH 3 (0.4 M in THF, 3 eq.). The resulting reaction mixture was stirred at room temperature for 16 hours and the progress of the reaction was monitored by TLC. The reaction mixture was stirred with crushed ice for 2 hours and then filtered and dried under high vacuum to give 4-chloro-2,5-difluorobenzamide as a white solid.

[1067] Step 2: Synthesis of 4-chloro-2,5-difluoro-N-(phenylcarbamoyl)benzamide.

[1068]

[1069] Phenyl isocyanate (1 equivalent) was added to a stirred solution of 4-chloro-2,5-difluorobenzamide (1 equivalent) in toluene (0.5M) and the resulting reaction mixture was refluxed for 16 hours. The reaction mixture was diluted with EtOAc and then washed with water. The combined organic layers were separated, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by column chromatography (10% EtOAc / hexane) to give the title compound as an off-white solid.

[1070] Step 3: Synthesis of 7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

[1071]

[1072] To a stirred solution of 4-chloro-2,5-difluoro-N-(phenylcarbamoyl)benzamide (1 eq.) in THF (0.25 M) was added KHMDS (1 M in THF, 1 eq.) at 0 °C. The resulting reaction mixture was warmed to room temperature and 18-crown-6 (0.01, g, catalyst) was added. After heating at 75 °C for 4 hours, the reaction mixture was diluted with EtOAc and then washed with water. The organic layer was dried over sodium sulfate and concentrated. The crude solid was washed with diethyl ether and n-pentane, then filtered and dried under high vacuum to give the title compound as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 )δppm 12.13-11.95(m,1H),7.96(d,J=8.61Hz,1H),7.77-7.55(m,3H),7.46(m,2H),6.43(d,J=5.89Hz,1H).m / z[M+H] + 291.13.

[1073] Proceeding similarly as described above in reference 10, step 2, the following compound was prepared:

[1074] 2,6-Dichloro-N-((2-fluorophenyl)carbamoyl)nicotinamide was prepared using 1-fluoro-2-phenylisocyanic acid and 2,6-dichloronicotinamide.

[1075]

[1076] 2,6-Dichloro-N-((2-chlorophenyl)carbamoyl)nicotinamide was prepared using 1-chloro-2-phenylisocyanic acid and 2,6-dichloronicotinamide.

[1077]

[1078] 2,6-Dichloro-N-(o-tolylcarbamoyl)nicotinamide was prepared using 1-isocyanato-2-toluene and 2,6-dichloronicotinamide.

[1079]

[1080] 2,6-Dichloro-N-(phenylcarbamoyl)nicotinamide was prepared using 2,6-dichloronicotinamide.

[1081]

[1082] 2,6-Dichloro-N-(pyridin-3-ylcarbamoyl)nicotinamide was prepared using 3-isocyanatopyridine and 2,6-dichloronicotinamide.

[1083]

[1084] 2,6-Dichloro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using 2,6-dichloro-4-(trifluoromethyl)benzamide and 1-isocyanato-2-toluene.

[1085]

[1086] 2-Chloro-4-methoxy-N-(phenylcarbamoyl)-6-(trifluoromethyl)nicotinamide was prepared using 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinamide and phenyl isocyanate.

[1087]

[1088] Proceeding similarly as described above in step 3 of reference 10, the following compound was prepared:

[1089] 7-Cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

[1090]

[1091] 6-Bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

[1092]

[1093] 6-Bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

[1094]

[1095] Reference 11

[1096] Synthesis of 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione

[1097]

[1098] Step 1: Synthesis of 3,4-dichloro-2-(phenylamino)benzoic acid

[1099]

[1100] 2-Amino-3,4-dichlorobenzoic acid (1 eq.), triethylamine (4 eq.) and bromobenzene (1 eq.) were loaded into a flask. Dioxane (1 M) and copper (II) acetate (1 eq.) were added, and the reaction mixture was heated to 110 ° C for 18 hours. The reaction mixture was cooled, additional bromobenzene (1 eq.) was added, and then heated to 110 ° C for 24 hours. The crude reaction mixture was diluted with saturated ammonium chloride solution and extracted with dichloromethane. The organic layer was washed with 1N HCl and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-50% ethyl acetate / hexane) to give the title compound.

[1101] Step 2: Synthesis of 3,4-dichloro-2-(phenylamino)benzamide

[1102]

[1103] To a stirred solution of 3,4-dichloro-2-(phenylamino)benzoic acid (1 eq) in THF (0.9 M) at 0 °C in a sealed flask was added DIPEA (5 eq), HATU (1.2 eq) followed by NH 3 (0.4 M in THF, 3 equiv.). The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was stirred with crushed ice for 2 h, then filtered and dried under high vacuum to afford the title compound as a white solid.

[1104] Step 3: Synthesis of 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione

[1105]

[1106] 3,4-dichloro-2-(phenylamino)benzamide (1.0 eq.) and DMF (0.2M) were loaded into a vial under nitrogen. NaH (60% in mineral oil, 3.0 eq.) was added to the reaction vessel at 0°C and the reaction mixture was stirred at room temperature for 10 minutes. CDI (1.5 eq.) was added and the reaction mixture was stirred at room temperature for 20 minutes. MeOH (0.5 mL) and AcOH (0.2 mL) were added to quench the reaction. The crude reaction mixture was directly purified by reverse phase column chromatography (20-75% MeCN / water, 0.1% formic acid). 1 H NMR (400 MHz, chloroform-d) δ 8.29 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.48-7.43 (m, 3H), 7.29 (d, J = 7.8 Hz, 2H). m / z [M+H] + 307.0

[1107] Reference 12

[1108] Synthesis of 7-Chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione

[1109]

[1110] Step 1: Synthesis of 4-chloro-2-fluoro-3-methylbenzamide

[1111]

[1112] 4-Chloro-2-fluoro-3-methylbenzoic acid (1 equivalent), hydroxybenzotriazole (0.2 equivalent) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.5 equivalent) were loaded into a flask. DMF (0.5M) was added, followed by diisopropylethylamine (2 equivalents). The reaction mixture was stirred for 15 minutes, and then ammonium chloride (5 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours. The crude reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with 1N HCl and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound.

[1113] Step 2: Synthesis of 4-chloro-2-fluoro-3-methyl-N-(phenylcarbamoyl)benzamide

[1114]

[1115] At room temperature, oxalyl chloride (1.35 equivalents) is dropwise processed into the slurries of 4-chloro-2-fluoro-3-methylbenzamide (1 equivalent) in DCE (0.5M).Then the reaction mixture is warming up to 55 ℃ and kept for 1 hour, then further heated to reflux for 20 hours.The reaction mixture is concentrated in vacuo to obtain a yellow oily crude product.At 0 ℃, DCE (1.2M) solution of this rough 4-chloro-2-fluoro-3-methylbenzoyl isocyanate is added dropwise in DCE (0.4M) solution of cooling aniline.Remove ice bath and the reaction mixture is stirred at room temperature for 45 minutes.Then filter solid, wash with DCM, dry to obtain title compound, is white solid.

[1116] Step 3: Synthesis of 7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione

[1117]

[1118] A slurry of 4-chloro-2-fluoro-3-methyl-N-(phenylcarbamoyl)benzamide in DMF (0.06 M) was cooled to 0°C and treated with NaH (60% dispersion in oil, 3.1 eq.) in portions. After the addition was complete, the ice bath was removed and the reaction mixture was refluxed for 18 hours. The reaction mixture was cooled to room temperature and poured into 20% aqueous hydrochloric acid. The resulting mixture was stirred vigorously, the off-white solid was filtered, and the mixture was washed with Et 2 O and dried to give the title compound, which was used directly in the next step without purification. 1 HNMR (400 MHz, chloroform-d) δ8.21 (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.

[1119] Proceeding similarly as above, the following compound was prepared by substituting 4-chloro-2-fluoro-3-methylbenzamide:

[1120] 2-Fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide was prepared using o-toluidine and 2-fluoro-4-(trifluoromethyl)benzamide.

[1121]

[1122] 1-(o-Tolyl)-7-trifluoromethylquinazoline-2,4(1H,3H)-dione was prepared using 2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide.

[1123]

[1124] Reference 13

[1125] Synthesis of 1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

[1126]

[1127] Step 1: Synthesis of 2-(phenylamino)-6-(trifluoromethyl)nicotinamide

[1128]

[1129] A round bottom flask was purged with nitrogen and a solution of KHMDS (2.5 eq., 1 M THF) was added to a vigorously stirred suspension of 2-chloro-6-(trifluoromethyl)nicotinamide (1 eq.) and aniline (1.1 eq.) in toluene or THF (0.4 M) at room temperature. After 2 h, the reaction mixture was evaporated to half volume to remove THF. The solid portion was filtered, washed with additional toluene, and dried under vacuum to give the title compound. m / z [M+H] + 282.1

[1130] Step 2: Synthesis of 1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

[1131]

[1132] Proceeding analogously as described above in reference 2, but substituting 2-(phenylamino)-6-(trifluoromethyl)nicotinamide for 4-chloro-2-(pyridin-3-ylamino)benzamide, the title compound was obtained.

[1133] Proceeding similarly as described above in reference 13, step 1, the following compound was prepared:

[1134] 2-((2-Fluorophenyl)amino)-6-(trifluoromethyl)nicotinamide was prepared by replacing aniline with 2-fluoroaniline.

[1135]

[1136] 2-((2-bromophenyl)amino)-6-(trifluoromethyl)nicotinamide was prepared by replacing aniline with 2-bromoaniline.

[1137]

[1138] Reference 14

[1139] Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile

[1140]

[1141] 6-Bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione (1 eq) and cupric cyanide (2 eq) were placed in a vial. Dimethylformamide (0.5 M) was added and the reaction mixture was heated to 120 °C for 18 hours and then cooled. The crude reaction mixture was filtered and purified by reverse phase purification (30-60% MeCN / water, 0.1% formic acid) to give the title compound. m / z[M+H] + 338.0.

[1142] Proceeding similarly as described above in reference 14, the following compounds were prepared:

[1143] 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.

[1144]

[1145] 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.

[1146]

[1147] 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.

[1148]

[1149] 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.

[1150]

[1151] 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.

[1152]

[1153] 1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydroquinazoline-6-carbonitrile was prepared from 6-bromo-1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-hydroxyquinazolin-2(1H)-one.

[1154]

[1155] Reference 15

[1156] Synthesis of 7-chloro-1-(3-vinylphenyl)quinazoline-2,4(1H,3H)-dione

[1157]

[1158] 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) was added potassium fluoride (3 eq.) and tributyl(vinyl)stannane (1.5 eq.) in a sealed tube at room temperature. The reaction mixture was degassed with argon for 20 min. Pd(OAc) was added 2 (10 mol%), the reaction mixture was degassed again for 5 minutes. The resulting reaction mixture was stirred at 100 °C for 16 hours. After completion, the reaction mixture was filtered through a celite bed. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine solution, Na 2 SO 4 Dry. The organics were then filtered and concentrated under reduced pressure to give the crude compound. The crude product was purified by column chromatography (1:6 EtOAc / hexane) to give the title compound as a yellow solid. m / z [MH] + 298.73.

[1159] Reference 16

[1160] Synthesis of 7-cyclopropyl-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

[1161]

[1162] Step 1: Synthesis of 2-bromo-4,6-dichlorobenzoic acid

[1163]

[1164] Butyl nitrite (2 equivalents) was added dropwise to CuBr at 0°C. 2 (1.2 equiv.) in a suspension of acetonitrile (0.25 M). The reaction was stirred for 10 minutes and 2-amino-4,6-dichlorobenzoic acid (1 equiv.) was added in portions. The reaction mixture was stirred at 0 ° C for 2 hours, then warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0 ° C, and the reaction mixture was quenched with 1N HCl. The solution was then extracted with ether. The pH of the organic phase was adjusted to pH 12 with 2N NaOH. The aqueous phase was adjusted to pH 2 with 2N HCl and then extracted with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-bromo-4,6-dichlorobenzoic acid as an off-white solid.

[1165] Step 2: Synthesis of 2,4-dichloro-6-vinylbenzoic acid

[1166]

[1167] To a stirred solution of 2-bromo-4,6-dichlorobenzoic acid (1 eq.) in DMSO:H 2 Vinylboronic acid pinacol ester (1.2 equivalents), K 2 CO 3 (3 equiv.) and Pd(dppf)Cl 2 The reaction mixture was purged under argon for 10 minutes, then heated to 120 ° C and stirred for 16 hours. The reaction mixture was diluted with 1N HCl and EtOAc, then washed with brine solution. The combined organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc / hexane) and then concentrated under reduced pressure to give 2,4-dichloro-6-vinylbenzoic acid as an off-white semi-solid.

[1168] Step 3: Synthesis of 2,4-dichloro-6-ethylbenzoic acid

[1169]

[1170] 10% Pd / C (10 mol%) was added to a stirred solution of 2,4-dichloro-6-vinylbenzoic acid (1 equivalent) in EtOAc (0.3 M) at room temperature. The reaction mixture was stirred for 16 hours under a hydrogen atmosphere (1 atm), then filtered through a celite bed and washed several times with ethyl acetate. The filtrate was concentrated under reduced pressure to give 2,4-dichloro-6-ethylbenzoic acid as a viscous liquid, which was further used in the next step without any purification.

[1171] Step 4: Synthesis of 2,4-dichloro-6-ethylbenzamide

[1172]

[1173] To a stirred solution of 2,4-dichloro-6-ethylbenzoic acid (1 eq.) in DMF (0.4 M) was added HATU (1.5 eq.), DIPEA (5 eq.), and then NH 4 Cl (5 equivalents). The reaction mixture was then stirred at room temperature for 16 h, then diluted with EtOAc and washed with water. The combined organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (30% EtOAc / hexane) and concentrated under reduced pressure to give the title compound, a pale solid.

[1174] Step 5: Synthesis of 2,4-dichloro-6-ethyl-N-(o-tolylcarbamoyl)benzamide

[1175]

[1176] 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 was stirred at 100 °C for 16 hours and then concentrated to give crude 2,4-dichloro-6-ethylbenzoyl isocyanate as a colloidal liquid. To a stirred solution of o-toluidine (1.2 eq.) in DCE (1.4 M) at 0 °C was slowly added a suspension of the crude isocyanate in DCE (1.5 M) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The solid residue was washed with pentane and dried in vacuo to give the title compound as an off-white solid.

[1177] Step 6: Synthesis of 7-chloro-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

[1178]

[1179] 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 dropwise KHMDS (2 eq., 1.0 M in THF) at 0°C. The reaction was stirred at 100°C for 1 h, then diluted with water and 1 N HCl was slowly added. The precipitated solid was filtered and washed with water and dried in vacuo to give the title compound as a light yellow solid.

[1180] Step 7: Synthesis of 7-cyclopropyl-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

[1181]

[1182] To a stirred solution of 7-chloro-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one (1 equivalent) in toluene:H 2 O (8:2, 0.6 M) solution was added with cyclopropylboronic acid (10 equivalents), K 3 PO 4 (3 equiv.). The reaction mixture was purged with argon for 5 min and Pd(PPh 3 ) 4(10 mol%). After the reaction mixture was stirred at 150 °C in a microwave for 1 hour, it was diluted with water and extracted with EtOAc. The combined organic layers were separated, washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (10-20% EtOAc / hexanes) and concentrated under reduced pressure to give the title compound as an off-white solid. m / z[M+H] + 321.41.

[1183] Reference 17

[1184] Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione

[1185]

[1186] Step 1: Synthesis of 4-bromo-2-fluoro-6-hydroxybenzoic acid

[1187]

[1188] 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 at 120 °C for 45 minutes, then cooled to room temperature and ice water was added. The mixture was acidified with 2N HCl (100 mL) until pH was about 1, the precipitate was filtered and washed with water to give the title compound as an off-white solid.

[1189] Step 2: Synthesis of methyl 4-bromo-2-fluoro-6-hydroxybenzoate

[1190]

[1191] 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 hours and then concentrated under reduced pressure. The residue was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM. The combined organic layers were washed with brine solution and anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to afford the title compound as an off-white solid.

[1192] Step 3: Synthesis of methyl 4-bromo-2-(difluoromethoxy)-6-fluorobenzoate

[1193]

[1194] To a stirred solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1 eq.) in acetonitrile / water (1:1, 0.2 M) at room temperature was added potassium hydroxide (20 eq.). The solution was cooled to -78 °C and diethyl (bromodifluoromethyl)phosphonate (2 eq.) was added. The reaction mixture was stirred at room temperature for 20 minutes, then diluted with water and extracted with ether. The combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the crude product. Purify by column chromatography (5% EtOAC / hexanes) to give the title compound as a colorless liquid.

[1195] Step 4: Synthesis of methyl 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoate

[1196]

[1197] To a stirred solution of methyl 4-bromo-2-(difluoromethoxy)-6-fluorobenzoate (1 eq) in toluene / water (1:1, 0.2 M) was added cyclopropylboronic acid (1.5 eq) and Na 2 CO 3 The resulting reaction mixture was degassed under argon for 20 minutes before adding PdCl 2 (dppf)·DCM (10 mol%). After stirring at 120°C for 16 h, the reaction mixture was filtered through celite, and the filtrate was extracted with EtOAc. The combined organic layers were washed with brine solution and anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure afforded the crude product. Purification by column chromatography using silica gel (5% EtOAc / hexanes) and concentrating under reduced pressure afforded the title compound as a colorless liquid.

[1198] Step 5: Synthesis of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoic acid

[1199]

[1200] To a stirred solution of methyl 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoate (1 eq.) in MeOH / THF / H 2 O (2:2:1, 0.17 M) solution was added with LiOH. 2 O (2 equiv.). The reaction mixture was stirred at room temperature for 16 h. Methanol was removed under reduced pressure and water was added to the remaining residue, and the solution was acidified to about pH 1 with 2N HCl. The precipitate was filtered and dried to give the title compound as an off-white solid.

[1201] Step 6: Synthesis of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide

[1202]

[1203] To a stirred solution of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoic acid (1 eq.) in DMF (0.4 M) was added NH 4 Cl (5 eq.), DIPEA (3 eq.) and HATU (1.5 eq.). The reaction mixture was stirred at room temperature for 16 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with cold water and brine. The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound as a light yellow solid.

[1204] Step 7: Synthesis of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide

[1205]

[1206] 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 hours. The reaction mixture was concentrated 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 mixture of the crude isocyanate in THF (1 M) at 0 ° C, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate. The crude product is purified by column chromatography (10% EtOAc / hexanes) and concentrated under reduced pressure to afford the title compound as a light brown solid.

[1207] Step 8: Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione

[1208]

[1209] To a stirred solution of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-(difluoro-methoxy)-6-fluorobenzamide (1 eq) in DMF (0.5 M) was added KHMDS (2 eq, 1 M in THF) dropwise at 0 °C. The reaction mixture was stirred at 100 °C for 2 h, then cooled to room temperature and acidified to about pH 1 with 2N HCl. 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.

[1210] Reference 18

[1211] Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione

[1212]

[1213] Step 1: Synthesis of 4-bromo-2-fluoro-6-methoxybenzamide

[1214]

[1215] 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 reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (40% EtOAc / hexane) and concentrated under reduced pressure to give the title compound as a white solid.

[1216] Step 2: Synthesis of 4-cyclopropyl-2-fluoro-6-methoxybenzamide

[1217]

[1218] 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.), K 2 CO 3 (3 equivalents), tributylphosphine (20 mol%), Pd 2 (dba) 3The mixture was stirred at 115°C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic layers were separated, washed with brine, and dried over anhydrous sodium sulfate. The solution was then filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (30% EtOAc / hexane) and concentrated under reduced pressure to give the title compound as an off-white solid.

[1219] Step 3: Synthesis of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxy-benzamide

[1220]

[1221] 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 and the reaction mixture was stirred at 55°C for 1 hour and then refluxed for 20 hours. A solution of 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 hours. The solid was filtered, washed with ether and dried in vacuo to give the title compound as a brown solid.

[1222] Step 4: Synthesis of 1-(2-chlorophenyl)-7-cyclopropyl-4-hydroxy-5-methoxyquinazolin-2(1H)-one

[1223]

[1224] To a stirred solution of N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide (1 eq) in DMF (0.05 M) was added KHMDS (1 M in THF, 2.5 eq) dropwise at 0 °C and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water and acidified to about pH 1 with 2N HCl. The solid was filtered and dried in vacuo to give the title compound as an off-white solid. m / z [M+H] + 343.34.

[1225] Reference 19

[1226] Synthesis of (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)...

Claims

1. A compound of formula (IA'), or a pharmaceutically acceptable salt thereof: in: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where: R 3 R is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkoxy, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkoxy, heterocyclyloxyalkoxy or heterocyclyloxyalkylamino, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace; R 5 R is hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen; R 1 For R 7 , where R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace; R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace; R 9 is hydrogen, alkyl, deuterated alkyl or cycloalkyl; and R 10 R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl by itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace; X b is a bond or an alkylene group; and R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and R f , R i , R l and R o 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 heterocyclic; provided that when R 1 When it is a heterocyclic group, R f Not hydroxyl; The premise is: (1) When yes 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 is hydrogen, R 4 is chlorine, R 5 When it is bromine or 5-methylindazol-4-yl, then R 1 is not 2-isopropylphenyl; (b) when R 2 and R 6 is methyl and R 3 , R 4 and R 5 When it is hydrogen; or R 2 and R 3 is methyl and R 4 , R 5 and R 6 When it is hydrogen, 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; (c) when R 2 is amino or acetylamino, R 4 is dimethylamino, and R 3 , R 5 and R 6 When it is hydrogen, then R 1 is not 4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (d) when R 5 is fluorine, R 3 , R 4 and R 6 is hydrogen and R 2 When it 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 is hydrogen, and R 2 When it 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 fluorine, and R 3 , R 4 and R 6 When it is hydrogen, then R 2 Not 3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino; (2) When yes When R 1 is 4-hydroxy-5-hydroxymethylfuran-1-yl, R 5 is amino, R 3 When it is methoxy, then R 2 is not amino; and (3) When yes When R 1 is 4-hydroxy-5-hydroxymethylfuran-1-yl, R 4 and R 5 One of them is hydrogen, R 4 and R 5 The other is a methyl group or R 4 and R 5 When both are methyl, then R 2 Not amino.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which has a structure as shown in formula (IA): in: R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen; R 10 R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l Replacement; and R f , R i , R l and R o 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 heterocyclic; provided that when R 1 When it is a heterocyclic group, R f Not hydroxyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in formula (I): in: R 3 and R 5 R is independently hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace; R 1 For R 7 , where R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a phenyl group, a heteroaryl group, a heterocyclyl group, a bridged heterocyclyl group, a fused heterocyclyl group or a spiro heterocyclyl group, wherein the phenyl group, the heteroaryl group or the heterocyclyl group is unsubstituted or replaced by R d , R e and / or R f replace; R 9 is hydrogen, alkyl or cycloalkyl; and R 10 R is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl by itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace; R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; 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 an optionally substituted aryl group, an optionally substituted heteroaryl group and an optionally substituted heterocyclic group.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, having a structure represented by the following formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIg):

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, which has a structure represented by formula (IIIa).

6. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, which has a structure represented by formula (IIId).

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R 2 For-NR 9 R 10 .

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R 2 is - OR 8 .

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R 2 For R 11 .

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: R 9 A deuterated alkyl.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: R 9 For hydrogen.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: R 9 It is an alkyl group.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, characterized in that: R 9 It is methyl or ethyl.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 and 11 to 13, characterized in that: R 10 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonylalkyl or dialkylaminocarbonylalkyl.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, characterized in that: R 10 For hydrogen.

16. The compound according to claim 8 or 14 or a pharmaceutically acceptable salt thereof, characterized in that: R 8 and R 10 It is an alkyl group.

17. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, characterized in that: R 8 and R 10 It is methyl.

18. The compound according to claims 1 to 8 and 11 to 13 or a pharmaceutically acceptable salt thereof, characterized in that R 8 and R 10 Independently being cycloalkyl or cycloalkylalkyl, each ring may independently be unsubstituted or substituted with one or two substituents independently selected from alkyl, halo or cyano.

19. The compound according to claim 18, characterized in that 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.

20. The compound according to claim 18, characterized in that 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.

21. The compound according to claim 18, characterized in that R 8 and R 10 are independently cyclopropylmethyl, 1-hydroxycyclopropylmethyl, 1-fluorocyclopropylmethyl, 1-fluorocyclopropylmethyl, (R)-1-cyclopropylethyl or 2,2-difluorocyclopropylmethyl.

22. The compound according to claims 1 to 8 and 11 to 13 or a pharmaceutically acceptable salt thereof, characterized in that R 8 and R 10 is independently heteroaryl or heteroaralkyl, wherein the heteroaryl group itself or as part of the heteroaralkyl group is unsubstituted or replaced by R j , R k and / or R 1 replace.

23. The compound according to claim 22, characterized in that R 8 and R 10 is a heteroaryl group independently selected from pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indolyl and indazolyl, each ring being unsubstituted or replaced by R j , R k and / or R 1 replace.

24. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, characterized in that R 8 and R 10 is a heteroaryl group independently selected from pyrazolyl, imidazolyl, thienyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, indolyl and indazolyl, each ring being unsubstituted or replaced by R j , R k and / or R 1 replace.

25. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, characterized in that R 8 and R 10 is heteroaralkyl independently selected from pyrazolylmethyl, pyrazolylethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimidylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolylmethyl, quinolylethyl, isoquinolylmethyl, isoquinolylethyl, indolylmethyl, indolylethyl, indazolylmethyl and indazolylethyl, each ring being unsubstituted or substituted by R j , R k and / or R 1 replace.

26. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, characterized in that R 8 and R 10 is heteroaralkyl independently selected from pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridylmethyl, pyridylethyl, pyrimidylmethyl, pyrimidylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolylmethyl, quinolylethyl, isoquinolylmethyl, isoquinolylethyl, indolylmethyl, indolylethyl, indazolylmethyl and indazolylethyl, each ring being unsubstituted or substituted by R j , R k and / or R 1 replace.

27. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, characterized in that R 8 and R 10 is 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.

28. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R 2 For R 11 , where R 11 is an unsubstituted heterocyclic group or is replaced by R m , R n and / or R o Substituted heterocyclic group.

29. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, characterized in that R 11 is oxetane, azetidinyl, 2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, each ring being unsubstituted or substituted by R m , R n and / or R o replace.

30. The compound according to claim 28 or a pharmaceutically acceptable salt thereof, characterized in that R 11 is azetidin-1-yl, 4-hydroxyazetidin-1-yl, 4-methylaminocarbonylazetidin-1-yl, 4-dimethylaminocarbonylazetidin-1-yl, 2-hydromethyl-azetidin-1-yl, 2-methylazetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3,3-dimethylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, piperidin-1-yl, 2-carboxypiperidin-1-yl, 2-aminocarbonylpiperidin-1-yl, piperazin-1-yl, 4-methylpiperazin-1-yl or morpholin-4-yl.

31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, characterized in that: R 5 R is alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl, heteroaryl, heterocyclyl, wherein the heterocyclyl or heteroaryl is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace.

32. The compound according to claim 31 or a pharmaceutically acceptable salt thereof, characterized in that R 5 is methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, 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 is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace.

33. The compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein R 5 is chloro, methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl or cyclopropyl.

34. The compound according to claim 32, characterized in that R 5 is chloro, trifluoromethyl or ethyl.

35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, characterized in that R 4 and R 6 are independently selected from hydrogen, methyl, chloro, fluoro, bromo, methoxy, methylthio, methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino, dimethylamino, methylaminocarbonyl or dimethylaminocarbonyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, fluorine, bromine, methyl, methoxy or cyano, and R 6 For hydrogen.

37. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, characterized in that R 4 and R 6 For hydrogen.

38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, characterized in that R 3 is hydrogen, alkyl, alkoxy, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.

39. The compound according to claim 38 or a pharmaceutically acceptable salt thereof, characterized in that R 3 It is hydrogen or methoxy.

40. The compound according to claim 38 or a pharmaceutically acceptable salt thereof, wherein R 3 For hydrogen.

41. The compound according to claim 38 or a pharmaceutically acceptable salt thereof, wherein R 3 It is methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano, methylsulfonyl, aminocarbonyl, methylamino or dimethylamino.

42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, characterized in that R 1 For R 7 , where R 7 is unsubstituted phenyl or R d , R e and / or R f Substituted phenyl, wherein R d and R e R is independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; f is selected from the group consisting of alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen and cyano.

43. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, characterized in that R 1 For R 7 , where R 7 is unsubstituted phenyl or R d , R e and / or R f Substituted phenyl, 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 Selected from hydroxy, fluoro, chloro, cyano and methyl.

44. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, characterized in that R 1 For R 7 , where R 7 is unsubstituted phenyl or R f Substituted phenyl, wherein R f is fluorine, chlorine, bromine or methyl, and wherein R f The carbon atom attached to the benzene ring is located in the ortho position to the carbon atom of the benzene ring attached to the quinazolone nitrogen.

45. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, characterized in that R 1 For R 7 , where R 7 is an unsubstituted heteroaryl or is replaced by R d , R e and / or R f Substituted heteroaryl, wherein R d and R e R is independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; f is selected from the group consisting of alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen and cyano.

46. ​​The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein: R 1 For R 7 , where 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 by R independently selected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl or 3-hydroxypropyl d and / or R e R is substituted and / or selected from hydroxy, fluorine, chlorine, cyano and methyl f replace.

47. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein: R 1 is unsubstituted pyridyl or is replaced by R f Substituted pyridyl, wherein R f is fluorine, chlorine, bromine or methyl, and wherein R f The carbon atom attached to the pyridine ring is located in the ortho position to the carbon atom of the pyridine ring attached to the quinazolone nitrogen.

48. The compound of claim 1, wherein The compound is selected from the group consisting of compounds 2-52, 54-83, 85-97, 99-102, 104-106, 109, 112-129, 132-146, 148-151, 153-155, 157, 159-165, 167-190, 192, 195-209, 211, 214, 216-228, 230-252, 255-287, 289-304, 306-310, 312-339, 341-353, 355, 366-374, 376-387, 389-528, 530-772 in Table 1 or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

50. A method of treating a disease mediated by MAT2A in a patient, the method comprising administering to the patient a therapeutically effective amount of: (a) Compound of formula (IIA') in: w is CR 3 or N; x is CR 4 or N; y is CR 5 or N; z is CR 6 or N, where: R 3 R is hydrogen, 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, heterocyclylalkoxy, heterocyclyloxyalkoxy or heterocyclyloxyalkylamino, wherein the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace; R 5 R is hydrogen, 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 the heterocyclyl or heteroaryl group itself or as part of another group is unsubstituted or is independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halogen, cyano, hydroxyalkyl, alkoxyalkyl or aminoalkyl. a , R b and / or R c replace; R 4 and R 6 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfonyl, halogen, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) up to two of w, x, y, and z may be N, and (ii) R 3 , R 4 , R 5 and R 6 At least one of them is not hydrogen; R 1 For R 7 , where R 7 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, an aryl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the aryl group, the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R d , R e and / or R f replace; R 2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, -OR 8 、-NR 9 R 10 or -X b -R 11 ,in: R 8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein the aryl, heteroaryl or heterocyclyl group itself or as part of another group is unsubstituted or replaced by R g , R h and / or R i replace; R 9 is hydrogen, alkyl, deuterated alkyl or cycloalkyl; and R 10 R is hydrogen, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl, substituted cycloalkylalkyl, cycloalkyloxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, spiroheterocyclyl or spiroheterocyclylalkyl, wherein aryl, heteroaryl or heterocyclyl by itself or as part of another group is unsubstituted or replaced by R j , R k and / or R l replace; X b is a bond or an alkylene group; and R 11 is a cycloalkyl group, a bridged cycloalkyl group, a fused cycloalkyl group, a spirocycloalkyl group, a heteroaryl group, a heterocyclic group, a bridged heterocyclic group, a fused heterocyclic group or a spiro heterocyclic group, wherein the heteroaryl group or the heterocyclic group is unsubstituted or replaced by R m , R n and / or R o Replacement; and R d , R e , R g , R h , R j , R k , R m and R n independently selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, alkylsulfonyl, halogen, cyano, carboxyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl and urea; and R f , R i , R l and R o 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 heterocyclic; provided that when R 1 When it is a heterocyclic group, R f is not a hydroxyl group; or (b) a compound as claimed in any one of claims 2 to 47; or pharmaceutically acceptable salts thereof.

51. The method of claim 50, wherein: The disease is cancer.

52. A method of treating MTAP-deficient cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IA') as defined in claim 48 or a compound as described in any one of claims 2 to 48; A pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

53. A method for treating cancer in a patient, wherein the cancer is characterized by reduced or absent MTAP gene expression, MTAP gene deletion, or reduced MTAP protein function, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (IA') as defined in claim 48 or a compound as described in any one of claims 2 to 48; A pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

54. The method according to any one of claims 51 to 53, characterized in that 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 or mesothelioma.

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