Mat2a inhibitor and use thereof

Abstract

The present invention belongs to the technical field of pharmaceuticals, and relates to a MAT2A inhibitor and the use thereof, in particular to a compound represented by general formula (I), or an isomer or pharmaceutically acceptable salt thereof, and the use thereof, in particular for the prevention or treatment of diseases related to the expression or activity of MAT2A. The diseases or conditions are selected from tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases.

Description

A MAT2A inhibitor and its use

[0001] The present invention claims priority to the prior application filed with the State Intellectual Property Office of China on January 15, 2024, with patent application number 202410055937.2 and entitled “A MAT2A inhibitor and its use”. Technical Field

[0002] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a MAT2A inhibitor and uses thereof. Background Art

[0003] Synthetic lethality refers to the phenomenon in which two genes in a cell mutate or lose their biological function simultaneously, causing cell death. Mutation of either gene alone will not cause cell death. Compared to normal cells, tumor cells often harbor more mutated genes. Identifying lethal gene pairs in these cells and then exogenously regulating them can specifically induce tumor cell death while leaving normal cells unaffected.

[0004] Methionine adenosyltransferase 2A (MAT2A) is the rate-limiting enzyme in the methionine (Met) cycle, converting Met into S-adenosylmethionine (SAM), a highly dependent methylation donor in cells. Protein arginine methyltransferase 5 (PRMT5) epigenetically regulates multiple biological processes, including RNA transcription and splicing, protein translation, and the DNA damage response, by catalyzing SAM-mediated methyl transfer reactions. Upregulation of its expression and activity often accompanies tumor development and progression. 5'-Methylthioadenosine (MTA), an endogenous inhibitor of PRMT5, is metabolized by methylthioadenosine phosphatase (MTAP) via the methionine recycling pathway to generate Met, a substrate for MAT2A. Aberrant MTAP gene expression (e.g., mutation or deletion) in tumor cells leads to intracellular accumulation of MTA. In such cases, exogenous MAT2A inhibitors can reduce SAM production. The accumulation of MTA and the restricted production of SAM methyl sources will simultaneously inhibit the activity of PRMT5, triggering the "synthetic lethality" mechanism, thereby killing tumor cells.

[0005] The MTAP gene is located on chromosome 9. Due to its proximity to the tumor suppressor gene CDKN2A, it is often deleted concomitantly with CDKN2A in tumor cells. According to incomplete statistics, MTAP deletion phenotypes are quite common in glioblastoma (37.2%), pancreatic cancer (27.2%), melanoma (26.2%), bladder cancer (26.1%), head and neck squamous cell carcinoma (19.2%), esophageal cancer (17.4%), and non-small cell lung cancer (16.7%). As previously mentioned, MAT2A and MTAP form an ideal "synthetic lethal" gene pair, and MAT2A inhibitors are an effective strategy for treating malignant tumors, especially MTAP-dull tumors.

[0006] The present invention designs compounds having structures represented by general formulae (I) and (II), and finds that compounds having such structures exhibit potent MAT2A inhibitory activity and outstanding in vivo pharmacokinetic properties, and show good in vivo pharmacodynamic responses in animal models. Summary of the Invention

[0007] The present invention discloses a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, and finds that compounds having such structures exhibit potent MAT2A inhibitory activity and outstanding in vivo pharmacokinetic properties, and show good in vivo pharmacodynamic responses in animal models.

[0008] A compound represented by formula (I), its isomer or a pharmaceutically acceptable salt thereof:

[0009] in:

[0010] Ring A is selected from * indicates that they are independently * end connected, # indicates that they are connected independently The # end connection;

[0011] R1 is selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C1-6 alkyl)2-aminocarbonyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, 3-8 membered cycloalkylcarbonyl, 3-8 membered cycloalkenylcarbonyl, 3-8 membered heterocyclylcarbonyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkenyloxy or 3-8 membered heterocyclyloxy, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1- 6-alkylamino, halogenated C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, 3-8 membered cycloalkylcarbonyl, 3-8 membered cycloalkenylcarbonyl, 3-8 membered heterocyclylcarbonyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkenyloxy or 3-8 membered heterocyclyloxy are unsubstituted or optionally substituted by one to four radicals independently selected from hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1- 6-alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkylcarbonyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the heteroatoms of the heterocyclic group and heteroaryl group are selected from one or more combinations of N, O or S;

[0012] R2 and R3 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1- 6 alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl is unsubstituted or optionally substituted by one to four independently selected radicals selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein the heteroatoms of the heterocyclyl and heteroaryl groups are selected from one or more combinations of N, O or S;

[0013] or R2 and R3 form a ring with the connected N atom to form a 3-8 membered N-containing heterocyclic group, wherein the 3-8 membered N-containing heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1- 6-alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl or C 2-8 The 3-8 membered N-containing heterocyclic group may further contain one or more combinations of heteroatoms N, O or S;

[0014] Ar1 and Ar 11 Each is independently selected from a 3-8 membered cycloalkyl group which is unsubstituted or optionally substituted by one to four Ra, a 3-8 membered heterocyclyl group which is unsubstituted or optionally substituted by one to four Ra, a 3-8 membered cycloalkenyl group which is unsubstituted or optionally substituted by one to four Ra, a phenyl group which is unsubstituted or optionally substituted by one to four Ra, or a 5-6 membered heteroaryl group which is unsubstituted or optionally substituted by one to four Ra, wherein the heteroatoms of the heterocyclyl and heteroaryl groups are selected from one or more combinations of N, O or S;

[0015] Each Ra is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 3-6 Cycloalkylcarbonyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S;

[0016] Ar2 and Ar 22 Each is independently selected from a 3-8 membered monocyclic radical which is unsubstituted or optionally substituted by one to four Rb, a 6-13 membered bicyclic condensed cyclic radical which is unsubstituted or optionally substituted by one to four Rb, a 6-13 membered bicyclic spirocyclic radical which is unsubstituted or optionally substituted by one to four Rb, an 8-21 membered polycyclic condensed cyclic radical which is unsubstituted or optionally substituted by one to four Rb, an 8-21 membered polycyclic spirocyclic radical which is unsubstituted or optionally substituted by one to four Rb, and an 8-21 membered polycyclic spirocyclic radical which is unsubstituted or optionally substituted by one to four Rb;

[0017] Each Rb is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl-R X -, 3-8 membered cycloalkenyl-R X - or 3-8 membered heterocyclic group-R X -, wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl-R X -, 3-8 membered cycloalkenyl-R X - or 3-8 membered heterocyclic group-R X - is unsubstituted or optionally substituted by one to four substituted radicals independently selected from hydrogen, deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 3-6 Cycloalkylcarbonyloxy, C 1-6 Alkylcarbonyloxy, C 1- 6-Alkylaminocarbonyloxy, C 2-8 Alkynyl, C 2-8 Alkenyl, C 1-6 Alkylsulfonyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl are substituted, wherein the heteroatoms of the heterocyclyl and heteroaryl groups are selected from one or more combinations of N, O or S;

[0018] Each Rx is independently selected from -C 1-6 Alkyl-, -C 1-6 Alkylamino C 1-6 Alkyl-, -C 1-6 Alkoxy-, -C 1-6 Alkoxy C 1-6 Alkyl- or -(C 1- 6-alkyl)2-amino C 1-6 alkyl-.

[0019] In one embodiment, the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof:

[0020] Ar2 and Ar 22and each independently selected from 3-8 membered cycloalkyl which is unsubstituted or optionally substituted by one to four Rb, 3-8 membered heterocyclyl which is unsubstituted or optionally substituted by one to four Rb, 3-8 membered cycloalkenyl which is unsubstituted or optionally substituted by one to four Rb, phenyl which is unsubstituted or optionally substituted by one to four Rb, 5-6 membered heteroaryl which is unsubstituted or optionally substituted by one to four Rb, 6-13 membered bicyclic and cycloalkyl which is unsubstituted or optionally substituted by one to four Rb, or a 6-13 membered bicyclic alkenyl group optionally substituted by one to four Rb, a 6-13 membered bicyclic heterocyclic group unsubstituted or optionally substituted by one to four Rb, a 6-13 membered bicyclic aryl group unsubstituted or optionally substituted by one to four Rb, a 6-13 membered bicyclic heteroaryl group unsubstituted or optionally substituted by one to four Rb, a 6-13 membered bicyclic spiroalkyl group unsubstituted or optionally substituted by one to four Rb, a 6- 13-membered bicyclic spirocycloalkenyl, 6-13-membered bicyclic spiro heterocyclyl which is unsubstituted or optionally substituted by one to four Rb, 8-21-membered tricyclic and cycloalkyl which is unsubstituted or optionally substituted by one to four Rb, 8-21-membered tricyclic and cycloalkenyl which is unsubstituted or optionally substituted by one to four Rb, 8-21-membered tricyclic and heterocyclyl which is unsubstituted or optionally substituted by one to four Rb, 8-21-membered tricyclic and aryl which is unsubstituted or optionally substituted by one to four Rb, 8-21 membered tricyclic heteroaryl optionally substituted by one to four Rb, 8-21 membered polycyclic spiroalkyl unsubstituted or optionally substituted by one to four Rb, 8-21 membered polycyclic spiroalkenyl unsubstituted or optionally substituted by one to four Rb, 8-21 membered polycyclic spiroheterocyclyl unsubstituted or optionally substituted by one to four Rb, the heteroatoms of the heterocyclyl and heteroaryl are selected from one or more combinations of N, O or S, and the C atoms on the ring can be oxidized to C(O).

[0021] In one embodiment, the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof:

[0022] Ring A is selected from * indicates that they are independently * end connected, # indicates that they are connected independently The # end connection;

[0023] R1 is selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl is unsubstituted or optionally substituted by one to four independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the heteroatoms of the heterocyclic group and heteroaryl group are selected from one or more combinations of N, O or S;

[0024] R2 and R3 are independently selected from hydrogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, the C 1-6 Alkyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl is unsubstituted or optionally substituted by one to four independently selected radicals selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl or C 2-8 The heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S;

[0025] or R2 and R3 form a ring with the connected N atom to form a 3-8 membered N-containing heterocyclic group, wherein the 3-8 membered N-containing heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1- 6-alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl or C 2-8 The 3-8 membered N-containing heterocyclic group may further contain one or more combinations of heteroatoms N, O or S;

[0026] Ar1 and Ar 11 Each is independently selected from phenyl which is unsubstituted or optionally substituted by one to four Ra, and a 5-6 membered heteroaryl which is unsubstituted or optionally substituted by one to four Ra, wherein the heteroatom of the heteroaryl is selected from one or more combinations of N, O or S;

[0027] Each Ra is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl or C 2-8 The heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S;

[0028] Ar2 and Ar 22 Each is independently selected from a 5-6 membered heterocyclyl which is unsubstituted or optionally substituted with one to four Rb, a phenyl which is unsubstituted or optionally substituted with one to four Rb, a 5-6 membered heteroaryl which is unsubstituted or optionally substituted with one to four Rb, a 6-13 membered bicyclic heterocyclyl which is unsubstituted or optionally substituted with one to four Rb, a 6-13 membered bicyclic heteroaryl which is unsubstituted or optionally substituted with one to four Rb, a 6-13 membered bicyclic heteroaryl which is unsubstituted or optionally substituted with one to four Rb, an 8-21 membered tricyclic heterocyclyl which is unsubstituted or optionally substituted with one to four Rb, and an 8-21 membered tricyclic spiroheterocyclyl which is unsubstituted or optionally substituted with one to four Rb, and the heteroatoms of the heterocyclyl and heteroaryl are selected from one or more combinations of N, O and S;

[0029] Each Rb is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl is unsubstituted or optionally substituted by one to four independently selected radicals selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkynyl, C 2-8 Alkenyl or C 1-6 The heterocyclic group is substituted with an alkylsulfonyl group, and the heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S.

[0030] In one embodiment, the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof:

[0031] Ring A is selected from * indicates that they are independently * end connected, # indicates that they are connected independently The # end connection;

[0032] R1 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, halogenated C 1-6 Alkyl, C 2-8 Alkenyl, C 1-6 Alkylthio, 3-8 membered cycloalkyl or amino substituted by 3-8 membered cycloalkyl;

[0033] R2 and R3 are independently selected from hydrogen or C 1-6 alkyl;

[0034] Ar1 and Ar 11 are each independently phenyl or pyridine which is unsubstituted or optionally substituted with one to four Ra;

[0035] Each Ra is independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl) 2-phosphoryl or 3-8 membered cycloalkyl;

[0036] Ar2 and Ar 22Each is independently selected from a 5-6 membered heterocyclyl which is unsubstituted or optionally substituted with one to four Rb, a phenyl which is unsubstituted or optionally substituted with one to four Rb, a 6-13 membered bicyclic aryl which is unsubstituted or optionally substituted with one to four Rb, a 5-6 membered heteroaryl which is unsubstituted or optionally substituted with one to four Rb, a 6-13 membered bicyclic heterocyclyl which is unsubstituted or optionally substituted with one to four Rb, a 6-13 membered bicyclic heterocyclyl which is unsubstituted or optionally substituted with one to four Rb, an 8-21 membered tricyclic heterocyclyl which is unsubstituted or optionally substituted with one to four Rb, and an 8-21 membered tricyclic spiroheterocyclyl which is unsubstituted or optionally substituted with one to four Rb, and the heteroatoms of the heterocyclyl and heteroaryl are selected from one or more combinations of N, O and S;

[0037] Each Rb is independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, 3-8 membered cycloalkyl or deuterated C 1-6 Alkoxy.

[0038] In one embodiment, in the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof,

[0039] Ar1 and Ar 11 are independently selected from phenyl which is unsubstituted or optionally substituted by one to four Ra ​​or

[0040] Ar2 and Ar 22 are independently selected from the following groups which are unsubstituted or optionally substituted with one to four Rb, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,

[0041] In one embodiment, in the compound represented by formula (I), its isomers, or pharmaceutically acceptable salts thereof, each substituent is independently selected from the following structures, or there may be two or more substituents. When there are two or more substituents, a combination of different groups may be selected:

[0042] R1 is selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, halogenated C 1-3 Alkylamino, halogenated C 1-3 Alkyl, C2-4 Alkenyl, C 1-3 Alkylthio, 3-6 membered cycloalkyl or amino substituted by 3-6 membered cycloalkyl;

[0043] R2 and R3 are independently selected from hydrogen or C 1-3 alkyl;

[0044] Ar1 and Ar 11 are each independently phenyl which is unsubstituted or optionally substituted with one to four Ra;

[0045] Each Ra is independently selected from hydrogen, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Alkylthio, (C 1-3 alkyl) 2-phosphoryl or 3-6-membered cycloalkyl;

[0046] Ar2 and Ar 22 Each of the following groups is independently selected from phenyl or naphthyl, which is unsubstituted or optionally substituted with one to four Rb; 5-6 membered heteroaryl, which is unsubstituted or optionally substituted with one to four Rb; 5-6 membered benzo monocyclic heterocyclyl, which is unsubstituted or optionally substituted with one to four Rb; 8-10 membered bicyclic fused heteroaryl, which is unsubstituted or optionally substituted with one to four Rb; 8-21 membered tricyclic heterocyclyl, which is unsubstituted or optionally substituted with one to four Rb; the 8-10 membered bicyclic fused heteroaryl refers to a group having 8-10 ring atoms formed by a monocyclic heteroaryl ring fused to a phenyl or monoheteroaryl group; the heteroatoms of the heterocyclyl and heteroaryl groups are selected from one or more combinations of N, O and S;

[0047] Each Rb is independently selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, (C 1-3 alkyl)2phosphoryl, C 1-3 Alkylsulfonyl imide, 3-6 membered cycloalkyl or deuterated C 1-3 Alkoxy.

[0048] In one embodiment, in the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof,

[0049] Ar1 and Ar 11 are each independently phenyl which is unsubstituted or optionally substituted with one to four Ra;

[0050] Ra is selected from fluorine, chlorine, bromine, methyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, cyclopropyl, dimethylphosphoryl;

[0051] Ar2 and Ar 22 Each independently selected from the following groups which are unsubstituted or optionally substituted by one to four Rb, phenyl, pyridyl, pyrrolyl, thienyl, furyl, pyrazolyl,

[0052] Rb is selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, methoxy, deuterated methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylthio, cyclopropyl, dimethylphosphoryl, methylsulfonimide.

[0053] In one embodiment, in the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof, Ar1 and Ar 11 are independently selected from

[0054] In one embodiment, in the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof, Ar2 and Ar 22 are independently selected from benzene,

[0055] In one embodiment, the compound represented by formula (I), its isomer or pharmaceutically acceptable salt thereof, specifically the structure represented by general formula (II):

[0056] R1 is selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl is unsubstituted or optionally substituted by one to four independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the heteroatoms of the heterocyclic group and heteroaryl group are selected from one or more combinations of N, O or S;

[0057] R2 and R3 are independently selected from hydrogen, C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, the C 1-6 Alkyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclyl is unsubstituted or optionally substituted by one to four independently selected from deuterium, hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl or C 2-8 The heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S;

[0058] or R2 and R3 form a ring with the connected N atom to form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is unsubstituted or optionally substituted by one to four independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl or C 2-8 The 3-8 membered N-containing heterocyclic group may further contain one or more combinations of heteroatoms N, O or S;

[0059] Ar1 is selected from phenyl which is unsubstituted or optionally substituted by one to four Ra, or a 5-6 membered heteroaryl which is unsubstituted or optionally substituted by one to four Ra, wherein the heteroatoms of the heteroaryl are selected from one or more combinations of N, O or S;

[0060] Each Ra is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl or C 2-8 The heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S;

[0061] Ar2 is selected from 5-6 membered heterocyclyl which is unsubstituted or optionally substituted by one to four Rb, phenyl which is unsubstituted or optionally substituted by one to four Rb, 5-6 membered heteroaryl which is unsubstituted or optionally substituted by one to four Rb, 6-13 membered bicyclic heterocyclyl which is unsubstituted or optionally substituted by one to four Rb, 6-13 membered bicyclic heteroaryl which is unsubstituted or optionally substituted by one to four Rb, 8-21 membered tricyclic heterocyclyl which is unsubstituted or optionally substituted by one to four Rb, 8-21 membered tricyclic spiro heterocyclyl which is unsubstituted or optionally substituted by one to four Rb, and the heteroatoms of the heterocyclyl and heteroaryl are selected from one or more combinations of N, O or S; the C atom on the ring may be oxidized to C(O);

[0062] Each Rb is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl is unsubstituted or optionally substituted by one to four independently selected radicals selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkynyl, C 2-8 Alkenyl or C 1-6The heterocyclic group is substituted with an alkylsulfonyl group, and the heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S.

[0063] In one embodiment, the compound represented by formula (I), its isomer or pharmaceutically acceptable salt thereof, specifically the structure represented by general formula (III):

[0064] R1 is selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, halogenated C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, C 1-6 Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl is unsubstituted or optionally substituted by one to four independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the heteroatoms of the heterocyclic group and heteroaryl group are selected from one or more combinations of N, O or S;

[0065] Ar 11 phenyl, which is unsubstituted or optionally substituted by one to four Ra, or a 5-6 membered heteroaryl, which is unsubstituted or optionally substituted by one to four Ra, wherein the heteroatoms of the heteroaryl are selected from one or more combinations of N, O or S;

[0066] Each Ra is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl or C 2-8 The heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S;

[0067] Ar 22substituted or optionally substituted by one to four Rb 5-6 membered heterocyclic group, phenyl group, 5-6 membered heteroaryl group, 6-13 membered bicyclic heterocyclic group, 6-13 membered bicyclic heteroaryl group, 8-21 membered tricyclic heterocyclic group, 8-21 membered tricyclic heterocyclic group, spiro heterocyclic group, wherein the heteroatoms of the heterocyclic group and the heteroaryl group are selected from one or more combinations of N, O and S; the C atoms on the ring may be oxidized to C(O);

[0068] Each Rb is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 1-6 Alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 Alkylsulfonyl imide, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl is unsubstituted or optionally substituted by one to four independently selected radicals selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkynyl, C 2-8 Alkenyl or C 1-6The heterocyclic group is substituted with an alkylsulfonyl group, and the heteroatom of the heterocyclic group is selected from one or more combinations of N, O or S.

[0069] In one embodiment, the compound represented by formula (I), its isomer or pharmaceutically acceptable salt thereof, specifically the structure represented by general formula (IV):

[0070] in,

[0071] R1 is selected from CF3, F, Cl, -CH3, -OCH3, -OCH2CH3, -NHCH2CH3, cyclopropyl, -NHcyclopropyl;

[0072] Ar2 is selected from benzene,

[0073] In one embodiment, in the compound represented by formula (IV), its isomers or pharmaceutically acceptable salts thereof,

[0074] R1 is selected from CF3, Cl, -OCH3, -NHCH2CH3, cyclopropyl;

[0075] Ar2 is selected from

[0076] In one embodiment, the compound represented by formula (I), (II), (III), (IV), its isomers or pharmaceutically acceptable salts thereof are selected from the following structures:

[0077] Another embodiment of the present invention provides a pharmaceutical composition comprising the compound of the present invention, its isomer or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable excipient.

[0078] Another embodiment of the present invention protects a pharmaceutical composition comprising the compound of the present invention, its isomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents and excipients.

[0079] Another embodiment of the present invention protects the use of the compound of the present invention, its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a disease related to the expression or activity of MAT2A.

[0080] In another embodiment of the present invention, the disease or disorder is selected from tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably tumors.

[0081] In another embodiment of the present invention, the tumor is a cancer selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumor, glioma, astrocytoma, ependymoma, glioblastoma, glioblastoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, neurilemoma, thyroid cancer, Wilms' tumor and teratoma; more preferably selected from non-small cell lung cancer, pancreatic cancer, melanoma, bladder cancer, head and neck squamous cell carcinoma, esophageal cancer and glioblastoma.

[0082] Another embodiment of the present invention provides a method for preventing or treating a disease associated with the expression or activity of MAT2A, comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of the present invention, its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention. Beneficial effects

[0083] The present invention provides a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof. The compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof exhibits potent MAT2A inhibitory activity and in vivo pharmacokinetic properties, and shows good in vivo pharmacodynamic response in animal models.

[0084] Definitions and Explanations of Terms

[0085] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0086] The "halogen" described in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.

[0087] The term "halo" as used herein means that any hydrogen atom in a substituent group may be replaced by one or more halogen atoms, which may be the same or different. "Halogen" is as defined above.

[0088] The "C 1-6 “Alkyl” refers to a straight or branched chain alkyl derived from a hydrocarbon moiety containing 1 to 6 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl-2-methylpropyl. The “C 1-6 "Alkyl" is preferably C 1-4 Alkyl, C 1-3 alkyl.

[0089] The "C 2-8 The term "alkenyl" refers to a straight chain, branched chain or cyclic olefin group derived from an olefin moiety of 2 to 8 carbon atoms containing a carbon-carbon double bond by removing one hydrogen atom, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl and 1,4-hexadienyl.

[0090] The "C 2-8 "Alkynyl" refers to a straight-chain or branched alkyne group derived from an alkyne portion of 2 to 8 carbon atoms containing a carbon-carbon triple bond by removing a hydrogen atom, such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, etc. The "C 2-8 "Alkynyl" is preferably C 2-4 Alkynyl, C 2-3 Alkynyl.

[0091] The "C 1-6 "Alkoxy" refers to the "C 1-6 Alkyl" is a group connected to the parent molecule through an oxygen atom, that is, "C 1-6 Alkyl-O-" groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy, etc. The "C 1-6 "Alkoxy" is preferably C 1-4 Alkoxy, C 1-3 Alkoxy,

[0092] The invention's "C 1-6 Alkylamino", "(C 1-6 Alkyl)2amino", "C 1-6 Alkylcarbonylamino", "C 1-6 Alkylsulfonylamino", "C 1-6 Alkylaminocarbonyl", "(C 1-6 Alkyl)2amino-carbonyl", "C 1-6 Alkoxy-carbonyl", "C 1-6 Alkylsulfonyl", "C 1-6 Alkylthio", "C 1-6 Alkylcarbonyl", "aminocarbonyl", "hydroxyl C 1-6 Alkyl", "(C 1-6 alkyl)2phosphoryl","C 1-6 "Alkylsulfonyl imide" refers to C 1-6 Alkyl-NH-, (C 1-6 Alkyl)(C 1-6 Alkyl) N-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Alkyl-S(O)2-NH-, C 1-6 Alkyl-NH-C(O)-, (C 1-6 Alkyl)(C 1-6 Alkyl)NC(O)-, C 1-6 Alkyl-OC(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-S-, C 1-6 Alkyl-C(O)-, NH 2- C(O)-、OH-C 1-6 Alkyl-, (C 1-6 Alkyl)(C 1-6 Alkyl)P(O)-, C 1-6 Alkyl-S(O)NH-; the "C 1-6 "Alkyl" is as defined above, preferably "C 1-4 Alkyl, C 1-3 alkyl".

[0093] The "condensed ring" described in the present invention refers to a polycyclic structure formed by two or more cyclic structures connected in a parallel or bridge manner. Each cyclic structure refers to any monocyclic alkyl, monoheterocyclic, monocycloalkenyl, phenyl, or monoheteroaryl group. The parallel ring refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond). The bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. Multiple cyclic structures are optionally connected in a parallel or bridge manner.

[0094] The spiro ring described in the present invention refers to a condensed ring structure formed by two or more cyclic structures sharing a ring atom.

[0095] A bicyclic fused ring group is one in which two cyclic structures are connected by a parallel and bridge connection, such as a 6-13-membered bicyclic fused ring group. A 6-13-membered bicyclic fused ring group further includes a 6-13-membered bicyclic fused cycloalkyl group, a 6-13-membered bicyclic fused cycloalkenyl group, a 6-13-membered bicyclic fused heterocyclic group, an 8-13-membered bicyclic fused heteroaryl group, and an 8-13-membered bicyclic fused aryl group. A bicyclic fused ring group is one in which two cyclic structures are connected by a parallel and bridge connection, including a bicyclic cycloalkyl group, a bicyclic cycloheterocyclic group, a bicyclic cycloaryl group, and a bicyclic cycloheteroaryl group.

[0096] A bicyclic spirocyclyl is a group in which two cyclic structures are connected in a spiral manner, such as a 6-13-membered bicyclic spirocyclyl. A 6-13-membered bicyclic spirocyclyl further includes a 6-13-membered bicyclic spiroalkyl, a 6-13-membered bicyclic spiroalkenyl, and a 6-13-membered bicyclic spiroheterocyclyl.

[0097] A polycyclic fused ring group is one in which two or more cyclic structures are connected by a combination of a ring and a bridge, including tricyclic cycloalkyl, tricyclic cycloalkenyl, tricyclic heterocyclyl, tricyclic cycloaryl, and tricyclic heteroaryl. For example, a monocyclic ring structure is connected by a combination of a ring and a bridge to a 6-13 membered bicyclic fused ring group, such as an 8-21 membered polycyclic fused ring group. The 8-21 membered polycyclic fused ring group further includes an 8-21 membered polycyclic fused cycloalkyl, an 8-21 membered polycyclic fused cycloalkenyl, an 8-21 membered polycyclic fused heterocyclyl, an 8-21 membered polycyclic fused heteroaryl, and an 8-21 membered polycyclic fused aryl.

[0098] A polycyclic spirocyclic group is one in which two or more cyclic structures are connected in a spiro connection, such as an 8-21-membered polycyclic spirocyclic group. An 8-21-membered polycyclic fused ring group further includes an 8-21-membered bicyclic spiroalkyl group, an 8-21-membered bicyclic spiroalkenyl group, and an 8-21-membered bicyclic spiroheterocyclic group.

[0099] A polycyclic spirocyclic group is one in which two or more cyclic structures are connected in a para- and spiro-connected manner, such as an 8-21-membered polycyclic spirocyclic group. An 8-21-membered polycyclic spirocyclic group further includes an 8-21-membered polycyclic spirocycloalkyl group, an 8-21-membered polycyclic spirocycloalkenyl group, and an 8-21-membered polycyclic spiroheterocyclic group.

[0100] Examples of 8-21 membered polycyclic spiro heterocyclic groups include, but are not limited to

[0101] The 8-21 membered polycyclic fused heterocyclic group includes an 8-21 membered polycyclic bridged heterocyclic group and an 8-21 membered polycyclic fused heterocyclic group.

[0102] Examples of 8-21 membered polycyclic heterocyclic groups include, but are not limited to

[0103] The 3-8 membered monocyclic group of the present invention includes monocyclic alkyl, monoheterocyclic, monocyclic alkenyl, monoheteroaryl and phenyl. Monocyclic alkyl is a cyclic hydrocarbon group containing 3-8 carbon atoms, including 3-8 membered cycloalkyl, 4-7 membered cycloalkyl, 4-6 membered cycloalkyl, 5-6 membered cycloalkyl or C 3-6 Cycloalkyl: 3-8 membered cycloalkyl, examples of which include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0104] A monoheterocyclic group refers to a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms. A monoheterocyclic group may be saturated or partially saturated, and includes 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-6 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 4-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 3-8 membered nitrogen-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, and 5-6 membered saturated heterocyclic groups. "3-8" membered saturated heterocyclic group", examples of which include but are not limited to aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathianyl; "3-8 membered partially saturated heterocyclic group", examples of which include but are not limited to 4,5-dioxanyl 1,2-isoxazolyl, 1,4-isoxazinyl, or 6H-1,3-oxazinyl.

[0105] Monocycloalkenyl refers to a partially saturated carbocyclic group, including 3-8 membered cycloalkenyl, 4-7 membered cycloalkenyl, and 5-6 membered cycloalkenyl.

[0106] The heteroaryl group described in the present invention refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N. The monoheteroaryl group may be a 5-7 membered heteroaryl group or a 5-6 membered heteroaryl group, and examples thereof include but are not limited to furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, and triazinyl.

[0107] 6-13 membered bicyclic condensed cycloalkyl groups include 6-13 membered bicyclic cycloalkyl groups and 6-13 membered bicyclic bridged cycloalkyl groups. They may be saturated, partially saturated or unsaturated, but not aromatic. Bicyclic cycloalkyl groups may be 6-13 membered bicyclic cycloalkyl groups, 6-11 membered bicyclic cycloalkyl groups, or 7-10 membered bicyclic cycloalkyl groups, representative examples of which include but are not limited to bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. The bicyclic bridged cyclic group may be a 6-13 membered bicyclic bridged cyclic group, a 6-11 membered bicyclic bridged cyclic group, or a 7-10 membered bicyclic bridged cyclic group, examples of which include but are not limited to:

[0108] 6-13 membered bicyclic fused cycloalkenyl means that at least one ring is saturated, partially saturated or unsaturated, including 6-13 membered bicyclic cycloalkenyl and 6-13 membered bicyclic bridged cycloalkenyl. Representative examples of 6-13 membered bicyclic cycloalkenyl include but are not limited to

[0109] The 6-13 membered bicyclic fused heterocyclic group includes a 6-13 membered bicyclic fused heterocyclic group and a 6-13 membered bicyclic bridged heterocyclic group, which may be saturated, partially saturated or unsaturated, but not aromatic. The fused heterocyclic group is a 5-6 membered monocyclic heterocyclic group fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group, or a 5-6 membered monocyclic heteroaryl group. The heterocyclic group can be a 6-12 membered heterocyclic group, a 7-10 membered heterocyclic group, a 6-10 membered heterocyclic group, an 8-10 membered bicyclic heterocyclic group, or a 6-12 membered saturated heterocyclic group. Representative examples include, but are not limited to, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[ 3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindole-1-yl, dihydroindole-2-yl, dihydroindole-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl,

[0110] The bridged heterocyclic group may be a 6-12 membered bridged heterocyclic group, a 7-11 membered bridged heterocyclic group, or a 6-12 membered saturated bridged heterocyclic group, examples of which include but are not limited to:

[0111] An 8-13 membered bicyclic fused heteroaryl group refers to a group formed by a monocyclic heteroaryl ring fused to a phenyl group or a monoheteroaryl group. The fused heteroaryl group may be an 8-13 membered heteroaryl group, a 9-10 membered heteroaryl group, or an 8-10 membered bicyclic heteroaryl group. Examples thereof include but are not limited to

[0112] The 8-13 membered bicyclic fused aryl group refers to a group formed by condensing a single aromatic ring to a single aromatic group, including naphthalene, phenanthrene and the like.

[0113] The ring C atoms of the present invention can be oxidized to C(O).

[0114] The "isomers" mentioned in the present invention refer to stereoisomers and tautomers.

[0115] Stereoisomers refer to enantiomers produced when asymmetric atoms exist in a compound; cis-trans isomers are produced when a double bond or a cyclic structure exists in a compound; all enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers and mixtures thereof of the compounds of formula (I) are included in the scope of the present invention.

[0116] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions. Tautomers are a special type of functional group isomers. For example, the tautomerism of carbonyl compounds containing α-H is more specific. Such as other proton migration tautomerism, specifically phenol-keto tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.

[0117] T, T1, and T2 are each independently any group that conforms to the bonding rules of the compound.

[0118] The term "optionally substituted by one to four groups independently selected from..." used in the present invention means substituted by one group selected from..., substituted by two groups independently selected from..., substituted by three groups independently selected from... or substituted by four groups independently selected from...

[0119] The "pharmaceutically acceptable salts" of the present invention refer to pharmaceutically acceptable acid and base addition salts or solvates thereof. For example, acid addition salts of compounds of the present invention having nitrogen atoms in the chain or ring with sufficient basicity, such as acid addition salts formed with the following inorganic acids: such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate, or acid addition salts formed with the following organic acids: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxybenzoic acid benzoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

[0120] In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., calcium salt or magnesium salt), an ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with the following substances: sodium ion, potassium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. As an example, the pharmaceutically acceptable salts include salts of -COOH group formed with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol.

[0121] In addition, basic nitrogen-containing groups can be quaternized using reagents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl and phenethyl bromides, etc. As examples, pharmaceutically acceptable salts include hydrochlorides, sulfates, nitrates, bisulfates, hydrobromides, acetates, oxalates, citrates, methanesulfonates, formates or meglumine salts, etc.

[0122] Preferably, the pharmaceutically acceptable salt is selected from the following acid addition salts: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, p-toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH2)n-COOH (wherein n is 0 to 4)), etc. The base addition salt is selected from the following: sodium salt, potassium salt, calcium salt, ammonium salt, etc. A variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.

[0123] The pharmaceutically acceptable excipients described herein can be those widely used in the field of pharmaceutical production. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after administration to a subject, or to promote effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients described herein can be inert fillers, or can provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients described herein can include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0124] Examples of pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0125] The dosage form of the medicine of the present invention can be selected according to specific circumstances. Pharmaceutical dosage forms are usually composed of medicine, excipients and container / sealing system. One or more excipients (also known as inactive ingredients) can be added to the compound of the present invention to improve or promote the manufacture, stability, administration and safety of the medicine, and the method for obtaining the required drug release curve can be provided. Therefore, the excipient type added to the medicine can be determined according to various factors, such as the physical and chemical properties, route of administration and preparation steps of the medicine. In this field, there are pharmaceutical excipients and include those listed in various pharmacopoeias.

[0126] The appropriate formulation depends on the desired route of administration. Routes of administration include intravenous injection, transmucosal or nasal administration, oral administration, and the like. For oral administration, the compound can be formulated into liquid or solid dosage forms and as immediate release or controlled / slow release formulations. Suitable dosage forms for oral ingestion by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions, and emulsions.

[0127] Solid oral dosage forms can be obtained using excipients including fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadherents, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants, and flavorings. These excipients can be synthetic or natural origin. Examples of the excipient include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salt, sugar (i.e., dextrose, sucrose, lactose, etc.), talc, mucilage of tragacanth, vegetable oil (hydrogenated), and wax. Ethanol and water can be used as granulation aids. In some cases, tablets may need to be coated with, for example, a taste masking film, a gastric acid resistant film, or a delayed-release film. Natural and synthetic polymers are often used to coat tablets in combination with colorants, sugars, and organic solvents or water to produce dragees. When capsules are preferred over tablets, drug powders, suspensions, or solutions thereof can be delivered in compatible hard or soft shell capsules. DETAILED DESCRIPTION

[0128] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0129] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0130] Example 1. Synthesis of 4-amino-1-(4-chlorophenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0131] Step 1: Synthesis of 3-((4-chlorophenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 1-3)

[0132] At room temperature, 4-chloroaniline (0.74 g, 5.81 mmol), 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (1.00 g, 4.84 mmol), cesium carbonate (3.16 g, 9.68 mmol), palladium acetate (0.08 g, 0.48 mmol), and dppf (0.27 g, 0.48 mmol) were added sequentially to a single-necked flask. The mixture was dissolved in 1,4-dioxane (30 mL). Under nitrogen protection, the reaction was terminated by heating to 100°C for 2 h. The mixture was cooled, filtered, and concentrated to obtain a brown oil, which was purified by column chromatography (EA / PE system) to afford 1.21 g of a yellow solid (84% yield).

[0133] Step 2: Synthesis of N-(4-chlorophenyl)-N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-methoxyphenyl)acetamide (Intermediate 1-4)

[0134] At room temperature, intermediate 1-3 (0.30 g, 1.00 mmol), 4-methoxyphenylacetic acid (0.33 g, 2.00 mmol), TEA (0.20 g, 2.00 mmol), and HATU (0.76 g, 2.00 mmol) were added sequentially to a single-necked flask. The mixture was dissolved in DMF (30 mL) and, under N protection, heated to 60°C for 24 h to terminate the reaction. The mixture was cooled, poured into water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oil. Purification by column chromatography (EA / PE system) afforded 0.05 g of a brown solid (yield 11%).

[0135] Step 3: Synthesis of 4-amino-1-(4-chlorophenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 1)

[0136] At room temperature, intermediate 1-4 (0.05 g, 0.11 mmol) was added sequentially to a single-necked flask and dissolved in DMF (3 mL). NaH (0.01 g, 0.15 mmol) was added at room temperature for N protection, and the reaction was terminated at room temperature for 2 h. The mixture was cooled, quenched with saturated ammonium chloride, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oil. Purification on a thick silica gel preparative plate (EA / PE system) afforded 0.01 g of an off-white solid in a 20% yield. MS (ESI) m / z: 446.4 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),7.68(d,J=8.5Hz,2H),7.46(d,J=8.5Hz,2H),7 .33(d,J=8.6Hz,2H),7.09(s,1H),7.03(d,J=8.7Hz,2H),6.35(s,2H),3.80(s,3H).

[0137] Example 2. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0138] Step 1: Synthesis of 3-((4-(difluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 2-2)

[0139] To a single-necked flask at room temperature were added 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.30 g, 1.46 mmol), p-difluoromethoxyaniline (0.27 g, 2.18 mmol), palladium acetate (0.03 g, 0.15 mmol), dppf (0.09 g, 0.15 mmol), and cesium carbonate (0.95 g, 2.92 mmol), followed by dissolution with 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times, and the temperature was raised to 80°C for 1.5 h before termination. The residue was cooled and concentrated to afford a yellow solid, which was purified by column chromatography (EA / PE) to afford 0.22 g of a yellow solid (50% yield).

[0140] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-methoxyphenyl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 2-3)

[0141] Intermediate 2-2 (0.15 g, 0.46 mmol) was added to a single-necked flask at room temperature and dissolved in DCM (10 mL). DIPEA (0.12 g, 0.91 mmol) and p-methoxyphenylacetyl chloride (0.12 g, 0.68 mmol) were then slowly added at 0°C. The reaction was allowed to proceed for 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE) to afford 0.08 g of a yellow solid (40% yield).

[0142] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 2)

[0143] Intermediate 2-3 (0.08 g, 0.24 mmol) was dissolved in DMF at room temperature and NaH (0.01 g, 0.36 mmol) was added at 0°C for 1 h. The reaction was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.008 g of a pale yellow solid (10% yield). MS (ESI) m / z: 478.4 [M+H] +1H NMR (400MHz, DMSO-d6) δ8.83(s,1H),7.49(d,J=8.5Hz,2H),7.43–7.39(m,3H),7.33(d,J=8.3Hz,2H),7.08–7.00(m,3H),6.35(s,2H),3.80(s,3H).

[0144] Example 3. Synthesis of 4-amino-1-(2-chlorophenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0145] Step 1: Synthesis of 3-((2-chlorophenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 3-2)

[0146] To a single-necked flask at room temperature were added 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.20 g, 0.97 mmol), o-chloroaniline (0.15 g, 1.47 mmol), palladium acetate (0.02 g, 0.10 mmol), dppf (0.06 g, 0.10 mmol), and cesium carbonate (0.60 g, 1.94 mmol), followed by dissolution with 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times, and the temperature was raised to 80°C for 1.5 h before termination. The residue was cooled and concentrated to afford a yellow solid, which was purified by column chromatography (EA / PE system) to afford 0.14 g of a yellow solid (60% yield).

[0147] Step 2: Synthesis of N-(2-chlorophenyl)-N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-methoxyphenyl)acetamide (Intermediate 3-3)

[0148] Intermediate 3-2 (0.12 g, 0.27 mmol) was added to a single-necked flask at room temperature. DIPEA (0.06 g, 0.54 mmol) and p-methoxyphenylacetyl chloride (0.07 g, 0.40 mmol) were then slowly added at 0°C. The reaction was terminated at room temperature for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.07 g of a yellow solid (45% yield).

[0149] Step 3: Synthesis of 4-amino-1-(2-chlorophenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 3)

[0150] Intermediate 3-3 (0.07 g, 0.16 mmol) was dissolved in DMF at room temperature and NaH (0.01 g, 0.24 mmol) was added at 0°C for 1 h. The reaction was terminated by quenching with ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.009 g of a light yellow solid. Yield: 13%. MS (ESI) m / z: 446.4 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.88(s,1H),7.83–7.75(m,1H),7.66–7.57(m,3H),7 .38–7.30(m,2H),7.08–7.01(m,2H),6.92(s,1H),6.45(s,2H),3.81(s,3H).

[0151] Example 4. Synthesis of 4-amino-1-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0152] Step 1: Synthesis of N-(2-chlorophenyl)-2-(4-chlorophenyl)-N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)acetamide (Intermediate 4-2)

[0153] Intermediate 3-2 (0.12 g, 0.27 mmol) was added to a single-necked flask at room temperature. DIPEA (0.06 g, 0.54 mmol) and p-chlorophenylacetyl chloride (0.08 g, 0.40 mmol) were then slowly added at 0°C. The reaction was allowed to proceed for 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.07 g of a yellow solid (48% yield).

[0154] Step 2: Synthesis of 4-amino-1-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 4)

[0155] Intermediate 4-2 was dissolved in DMF at room temperature and NaH (0.01 g, 0.23 mmol) was added at 0°C for 1 h. The reaction was terminated by adding ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.02 g of a pale yellow solid in a 23% yield. MS (ESI) m / z: 450.3 [M+H] +1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),7.82–7.76(m,1H),7.66–7.59(m,3H),7.5 1(dd,J=8.3,3.4Hz,2H),7.42(dd,J=8.7,3.0Hz,2H),6.95(s,1H),6.69(s,2H).

[0156] Example 5. Preparation of 4-amino-1,3-bis(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0157] Step 1: Synthesis of 3-((4-methoxyphenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 5-1)

[0158] To a single-necked flask at room temperature were added 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.20 g, 0.97 mmol), 4-methoxyaniline (0.15 g, 1.47 mmol), palladium acetate (0.02 g, 0.10 mmol), BINAP (0.06 g, 0.10 mmol), and cesium carbonate (0.60 g, 1.94 mmol). The mixture was dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times and the reaction was terminated by heating to 80°C for 1.5 h. The mixture was cooled and concentrated to obtain a residue, which was purified by column chromatography (EA / PE system) to afford 0.16 g of a yellow solid (65% yield).

[0159] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N,2-bis(4-methoxyphenyl)acetamide (Intermediate 5-2)

[0160] Intermediate 5-1 (0.15 g, 0.34 mmol) was added to a single-necked flask at room temperature and dissolved in DCM (10 ml). DIPEA (0.09 g, 0.68 mmol) and p-methoxyphenylacetyl chloride (0.09 g, 0.51 mmol) were slowly added sequentially at 0°C. The reaction was terminated by 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.10 g of a yellow solid (55% yield).

[0161] Step 3: Synthesis of 4-amino-1,3-bis(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 5)

[0162] Intermediate 5-2 (0.10 g, 0.23 mmol) was dissolved in DMF at room temperature. NaH (0.02 g, 0.34 mmol) was added and the reaction was terminated at 0°C for 1 h. The reaction was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.04 g of a light yellow solid in a 43% yield. MS (ESI) m / z: 442.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),7.32(td,J=9.2,1.9Hz,4H),7.17-7.12(m,2H),7.04(m,3H),6.29(s,2H),3.85(s,3H),3.80(s,3H).

[0163] Example 6. Synthesis of 4-amino-3-(4-methoxyphenyl)-1-(4-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0164] Step 1: Synthesis of 3-((4-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 6-1)

[0165] To a single-necked flask at room temperature were added 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.20 g, 0.97 mmol), 4-trifluoromethoxyaniline (0.16 g, 1.47 mmol), palladium acetate (0.02 g, 0.10 mmol), BINAP (0.06 g, 0.10 mmol), and cesium carbonate (0.60 g, 1.94 mmol). The mixture was dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times and the temperature was raised to 80°C for 1.5 h. The mixture was cooled and concentrated to obtain a residue, which was purified by column chromatography (EA / PE system) to afford 0.14 g of a yellow solid (61% yield).

[0166] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-methoxyphenyl)-N-(4-(trifluoromethoxy)phenyl)acetamide (Intermediate 6-2)

[0167] Intermediate 6-1 (0.13 g, 0.26 mmol) was added to a single-necked flask at room temperature and dissolved in DCM (20 ml). DIPEA (0.07 g, 0.53 mmol) and p-methoxyphenylacetyl chloride (0.07 g, 0.39 mmol) were slowly added sequentially at 0°C. The reaction was terminated by 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.07 g of a yellow solid (46% yield).

[0168] Step 3: Synthesis of 4-amino-3-(4-methoxyphenyl)-1-(4-(trifluoromethoxy)phenyl)-7-trifluoromethyl-1,5-naphthyridin-2(1H)-one (Example 6)

[0169] Intermediate 6-2 (0.07 g, 0.14 mmol) was dissolved in DMF at room temperature and reacted at 0°C for 1 h with the addition of NaH (0.01 g, 0.21 mmol). The reaction was terminated by adding ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.02 g of a light yellow solid in a 32% yield. MS (ESI) m / z: 496.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.66–7.56(m,4H),7.34(dd,J=8.7,2.4Hz,2H),7.08–7.00(m,3H),6.38(s,2H),3.80(s,3H).

[0170] Example 7. Synthesis of 4-amino-1-(2-bromophenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0171] Step 1: Synthesis of 3-((2-bromophenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 7-1)

[0172] To a single-necked flask at room temperature were added 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.20 g, 0.97 mmol), o-bromoaniline (0.16 g, 1.47 mmol), palladium acetate (0.02 g, 0.10 mmol), BINAP (0.06 g, 0.10 mmol), and cesium carbonate (0.60 g, 1.94 mmol). The mixture was dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times and the temperature was raised to 80°C for 1.5 h. The mixture was cooled and concentrated to obtain a residue, which was purified by column chromatography (EA / PE system) to afford 0.16 g of a yellow solid (70% yield).

[0173] Step 2: Synthesis of N-(2-bromophenyl)-N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-methoxyphenyl)acetamide (Intermediate 7-2)

[0174] Intermediate 7-1 (0.15 g, 0.31 mmol) was added to a single-necked flask at room temperature and dissolved in DCM (10 mL). DIPEA (0.07 g, 0.62 mmol) and p-methoxyphenylacetyl chloride (0.08 g, 0.46 mmol) were slowly added sequentially at 0°C. The reaction was terminated at room temperature for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.07 g of a yellow solid (39% yield).

[0175] Step 3: Synthesis of 4-amino-1-(2-bromophenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 7)

[0176] Intermediate 7-2 (0.07 g, 0.14 mmol) was dissolved in DMF at room temperature and reacted at 0°C for 1 h with the addition of NaH (0.01 g, 0.21 mmol). The reaction was terminated by adding ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.01 g of a light yellow solid. Yield: 19%. MS (ESI) m / z: 490.3 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.88(s,1H),7.93(d,J=7.9Hz,1H),7.68–7.58(m,2H),7.53(td,J=7.6, 2.0Hz,1H),7.34(d,J=8.8Hz,2H),7.04(d,J=8.8Hz,2H),6.89(s,1H),6.44(s,2H),3.80(s,3H).

[0177] Example 8. Synthesis of 4-amino-1-(4-cyclopropylphenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0178] Step 1: Synthesis of 3-((4-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 8-1)

[0179] To a single-necked flask at room temperature were added 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.20 g, 0.97 mmol), 4-cyclopropylaniline (0.15 g, 1.47 mmol), palladium acetate (0.02 g, 0.10 mmol), BINAP (0.06 g, 0.10 mmol), and cesium carbonate (0.60 g, 1.94 mmol). The mixture was dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times and the reaction was terminated by heating to 80°C for 1.5 h. The mixture was cooled and concentrated to obtain a residue, which was purified by column chromatography (EA / PE system) to afford 0.10 g of a yellow solid (55% yield).

[0180] Step 2: Synthesis of N-(2-cyano-5-trifluoromethyl)pyridin-3-yl)-N-(4-cyclopropylphenyl)-2-(4-methoxyphenyl)acetamide (Intermediate 8-2)

[0181] At room temperature, intermediate 8-1 (0.10 g, 0.22 mmol) was added to a single-necked flask and dissolved in DCM (10 mL). DIPEA (0.06 g, 0.44 mmol) and p-methoxyphenylacetyl chloride (0.06 g, 0.33 mmol) were slowly added sequentially at 0°C. The reaction was terminated at room temperature for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.07 g of a yellow solid (50% yield).

[0182] Step 3: Synthesis of 4-amino-1-(4-cyclopropylphenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0183] Intermediate 8-2 (0.07 g, 0.14 mmol) was dissolved in DMF at room temperature and reacted at 0°C for 1 h with the addition of NaH (0.01 g, 0.21 mmol). The reaction was terminated by adding ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.02 g of a light yellow solid. Yield: 33%. MS (ESI) m / z: 452.5 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.37–7.22(m,6H),7.02(m,3H),6.30(s ,2H),3.80(s,3H),1.41–1.16(m,1H),1.08–1.01(m,2H),0.81-0.76(m,2H).

[0184] Example 9. Synthesis of 4-amino-1-(4-bromophenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0185] Step 1: Synthesis of 3-((4-bromophenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 9-1)

[0186] To a single-necked flask at room temperature were added 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.20 g, 0.97 mmol), 4-bromoaniline (0.16 g, 1.47 mmol), palladium acetate (0.02 g, 0.10 mmol), BINAP (0.06 g, 0.10 mmol), and cesium carbonate (0.60 g, 1.94 mmol). The mixture was dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times and the reaction was terminated by heating to 80°C for 1.5 h. The residue was cooled and concentrated to obtain a yellow solid, which was purified by column chromatography (EA / PE system) to afford 0.16 g of a yellow solid (70% yield).

[0187] Step 2: Synthesis of N-(4-bromophenyl)-N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-methoxyphenyl)acetamide (Intermediate 9-2)

[0188] Intermediate 9-1 (0.15 g, 0.31 mmol) was added to a single-necked flask at room temperature and dissolved in DCM (10 mL). DIPEA (0.07 g, 0.62 mmol) and p-methoxyphenylacetyl chloride (0.08 g, 0.46 mmol) were slowly added sequentially at 0°C. The reaction was terminated by 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.07 g of a yellow solid (39% yield).

[0189] Step 3: Synthesis of 4-amino-1-(4-bromophenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 9)

[0190] Intermediate 9-2 (0.07 g, 0.14 mmol) was dissolved in DMF at room temperature. NaH (0.01 g, 0.21 mmol) was added at 0°C and the reaction was terminated at room temperature for 1 h. The reaction was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.008 g of a light yellow solid. Yield: 12%. MS (ESI) m / z: 490.3 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),7.82(d,J=8.2Hz,1H),7.39(d,J=8.5Hz,1H),7.33(d,J=8.5Hz,1H),7.12–7.00(m,3H),6.36(s,2H),3.80(s,3H).

[0191] Example 10. Synthesis of 4-amino-3-(4-methoxyphenyl)-1-(p-tolyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0192] Step 1: Synthesis of 3-(p-tolylamino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 10-1)

[0193] To a single-necked flask at room temperature were added 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.20 g, 0.97 mmol), p-methylaniline (0.14 g, 1.47 mmol), palladium acetate (0.02 g, 0.10 mmol), BINAP (0.06 g, 0.10 mmol), and cesium carbonate (0.60 g, 1.94 mmol). The mixture was dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times and the temperature was raised to 80°C for 1.5 h. The mixture was cooled and concentrated to obtain a residue, which was purified by column chromatography (EA / PE system) to afford 0.10 g of a yellow solid (55% yield).

[0194] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-methoxyphenyl)-N-(p-tolyl)acetamide (Intermediate 10-2)

[0195] Intermediate 10-1 (0.10 g, 0.22 mmol) was added to a single-necked flask at room temperature and dissolved in DCM (20 mL). DIPEA (0.06 g, 0.44 mmol) and p-methoxyphenylacetyl chloride (0.06 g, 0.33 mmol) were slowly added sequentially at 0°C. The reaction was terminated at room temperature for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.06 g of a yellow solid (48% yield).

[0196] Step 3: Synthesis of 4-amino-3-(4-methoxyphenyl)-1-(p-tolyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 10)

[0197] Intermediate 10-2 (0.06 g, 0.14 mmol) was dissolved in DMF at room temperature and reacted at 0°C for 1 h with the addition of NaH (0.01 g, 0.21 mmol). The reaction was terminated by adding ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Column chromatography (EA / PE system) afforded 0.01 g of a light yellow solid. MS (ESI) m / z: 426.5 [M+H] +1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.42(d,J=7.8Hz,2H),7.33(dd,J=8.5,1.8Hz,2 H),7.26(d,J=7.8Hz,2H),7.10–6.98(m,3H),6.30(s,2H),3.80(s,3H),2.43(s,3H).

[0198] Example 11. Synthesis of 4-amino-3-(4-methoxyphenyl)-1-(4-(methylthio)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0199] Step 1: Synthesis of 3-((4-(methylthio)phenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 11-1)

[0200] At room temperature, 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (0.30 g, 1.45 mmol), 4-(methylthio)aniline (0.30 g, 2.17 mmol), palladium acetate (0.07 g, 0.29 mmol), BINAP (0.18 g, 0.29 mmol), and cesium carbonate (0.95 g, 2.90 mmol) were added to a single-necked flask in sequence and dissolved in 1,4-dioxane (10 mL). The atmosphere was replaced with N2 three times, and the temperature was raised to 80°C for 2 h to terminate the reaction. The residue was cooled and concentrated to obtain a yellow solid, which was purified by column chromatography (EA / PE system) to afford 0.25 g of a yellow solid in a 56% yield. MS (ESI) m / z: 310.3 [M+H] + .

[0201] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-methoxyphenyl)-N-(4-(methylthio)phenyl)acetamide (Intermediate 11-2)

[0202] At room temperature, intermediate 11-1 (0.25 g, 0.81 mmol) was added to a single-necked flask. The temperature was lowered to 0°C, and DIPEA (0.21 g, 1.62 mmol) and p-methoxyphenylacetyl chloride (0.22 g, 1.21 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 24 h. Concentration afforded a residue, which was purified by column chromatography (EA / PE system) to afford 0.10 g of a yellow oil in a 27% yield. MS (ESI) m / z: 458.3 [M+H] + .

[0203] Step 3: Synthesis of 4-amino-3-(4-methoxyphenyl)-1-(4-(methylthio)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 11)

[0204] Intermediate 11-2 (0.10 g, 0.22 mmol) was dissolved in DMF (2 mL) at room temperature. NaH (0.014 g, 0.33 mmol) was added at 0°C and the reaction was terminated at room temperature for 1 h. The mixture was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.026 g of a light yellow solid (26% yield). MS (ESI) m / z: 458.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.82 (s, 1H), 7.48 (s, 1H), 7.46 (d, J = 2.4Hz, 1H), 7.35 (s, 2H) ,7.33(s,2H),7.07(s,1H),7.04–7.01(m,2H),6.32(s,2H),3.80(s,3H),2.56(s,3H).

[0205] Example 12. Synthesis of 4-amino-3-(benzo[d][1,3]dioxolan-5-yl)-1-(4-(difluoromethoxy)phenyl)-7-trifluoromethyl-1,5-naphthyridin-2(1H)-one

[0206] Step 1: Synthesis of 2-(Benzo[d][1,3]dioxolan-5-yl)-N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 12-2)

[0207] At room temperature, intermediate 2-2 (0.15 g, 0.46 mmol) was added to a single-necked flask. The temperature was lowered to 0°C, and DIPEA (0.20 g, 0.92 mmol) and 2-(benzo[d][1,3]dioxolan-5-yl)acetyl chloride (0.14 g, 0.68 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 24 h. Concentration afforded a residue, which was purified by column chromatography (EA / PE system) to afford 0.04 g of a yellow oily liquid (18% yield). MS (ESI) m / z: 492.3 [M+H]. + .

[0208] Step 2: Synthesis of 4-amino-3-(benzo[d][1,3]dioxolan-5-yl)-1-(4-(difluoromethoxy)phenyl)-7-trifluoromethyl-1,5-naphthyridin-2(1H)-one (Example 12)

[0209] Intermediate 12-2 (0.04 g, 0.08 mmol) was dissolved in DMF (2 mL) at room temperature. NaH (0.005 g, 0.12 mmol) was added at 0°C and the reaction was terminated at room temperature for 1 h. The mixture was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.005 g of a light yellow solid in a 12% yield. MS (ESI) m / z: 492.4 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.83(d,J=1.8Hz,1H),7.59–7.46(m,3H),7.42–7.39(m,2H),7.06(s,1H),7.00(dd ,J=7.9,1.3Hz,1H),6.90(d,J=1.5Hz,1H),6.86(dt,J=7.9,1.5Hz,1H),6.44(s,2H),6.06(d,J=1.3Hz,2H).

[0210] Example 13. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(quinolin-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0211] Step 1: Synthesis of 2-(quinolin-6-yl)acetyl chloride (Intermediate 13-2)

[0212] Dissolve 2-(quinolin-6-yl)acetic acid (0.10 g, 0.60 mmol) in DCM (2 mL) at room temperature. Lower the temperature to 0°C and slowly add oxalyl chloride (0.09 g, 0.72 mmol) and a catalytic amount of DMF. The reaction is terminated at room temperature for 1 h. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0213] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)-2-(quinolin-6-yl)acetamide (Intermediate 13-3)

[0214] At room temperature, intermediate 2-2 (0.11 g, 0.33 mmol) was added to a single-necked flask and dissolved in DCM (10 mL). DIPEA (0.09 g, 0.67 mmol) and intermediate 13-2 (0.10 g, 0.50 mmol) were then slowly added at 0°C. The reaction was allowed to proceed for 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.04 g of a yellow solid (40% yield).

[0215] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(quinolin-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0216] Intermediate 13-3 (0.04 g, 0.12 mmol) was dissolved in DMF at room temperature and NaH (0.01 g, 0.20 mmol) was added at 0°C. The reaction was terminated at room temperature for 1 h. The mixture was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.011 g of a light yellow solid in a 27% yield. MS (ESI) m / z: 499.4 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.92(dd,J=4.3,1.7Hz,1H),8.87(d,J=1.9Hz,1H),8.42–8.39(m,1H),8.07(d,J=8.7Hz,1H),8 .03(d,J=1.9Hz,1H),7.78(d,J=1.9Hz,1H),7.59–7.50(m,4H),7.43–7.40(m,2H),7.12(d,J=1.9Hz,1H),6.70(s,2H).

[0217] Example 14. Synthesis of 4-amino-1-(4-(dimethylphosphoryl)phenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0218] Step 1: Synthesis of (4-aminophenyl)dimethylphosphine oxide (Intermediate 14-2)

[0219] 4-Bromoaniline (1.00 g, 5.81 mmol) was dissolved in anhydrous DMF (10 mL) at room temperature. Dimethylphosphine oxide (0.38 g, 4.82 mmol), palladium acetate (0.07 g, 0.29 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (1.20 g, 2.09 mmol), and potassium phosphate (1.36 g, 6.39 mmol) were added. The reaction was terminated by microwave heating at 150°C for 1 h. Purification by column chromatography (DCM / MeOH) afforded 0.10 g of a white solid in a 10% yield. MS (ESI) m / z: 170.1 [M+H] + .

[0220] Step 2: Synthesis of 3-((4-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyridinecarbonitrile (Intermediate 14-3)

[0221] At room temperature, intermediate 1-2 (0.10 g, 0.49 mmol), intermediate 14-2 (0.10 g, 0.59 mmol), palladium acetate (0.022 g, 0.098 mmol), BINAP (0.061 g, 0.098 mmol), and cesium carbonate (0.32 g, 0.98 mmol) were added to a single-necked flask in sequence and dissolved in 1,4-dioxane (5 mL). The atmosphere was replaced with N2 three times, and the temperature was raised to 80°C for 2 h to terminate the reaction. The residue was cooled and concentrated to obtain a residue, which was purified by column chromatography (DCM / MeOH system) to obtain 0.07 g of a yellow oily liquid in a 42% yield. MS (ESI) m / z: 340.3 [M+H] + .

[0222] Step 3: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(dimethylphosphoryl)phenyl)-2-(4-methoxyphenyl)acetamide (Intermediate 14-4)

[0223] At room temperature, intermediate 14-3 (0.07 g, 0.22 mmol) was dissolved in DCM (6 mL). The temperature was lowered to 0°C, and DIPEA (0.06 g, 0.44 mmol) and 2-(4-methoxyphenyl)acetyl chloride (0.06 g, 0.33 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 12 h. The residue was concentrated and purified by column chromatography (DCM / MeOH) to afford 0.05 g of a yellow oily liquid in a 50% yield. MS (ESI) m / z: 488.4 [M+H] + Step 4: Synthesis of 4-amino-1-(4-(dimethylphosphoryl)phenyl)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 14)

[0224] Intermediate 14-4 (0.05 g, 0.11 mmol) was dissolved in DMF (2 mL) at room temperature and NaH (0.01 g, 0.15 mmol) was added at 0°C for 1 h. The reaction was quenched with ice water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (DCM / MeOH) afforded 0.003 g of a pale yellow solid (6% yield). MS (ESI) m / z: 488.4 [M+H] + .

[0225] Example 15. Synthesis of 4-amino-1,3-bis(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0226] Step 1: Synthesis of 2-(4-(difluoromethoxy)phenyl)acetyl chloride (Intermediate 15-2)

[0227] Dissolve 2-(4-(difluoromethoxy)phenyl)acetic acid (0.20 g, 0.99 mmol) in DCM (4 mL) at room temperature. Lower the temperature to 0°C and slowly add oxalyl chloride (0.15 g, 1.19 mmol). Terminate the reaction at room temperature for 1 h. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0228] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N,2-bis(4-(difluoromethoxy)phenyl)acetamide (Intermediate 15-3): At room temperature, Intermediate 2-2 (0.20 g, 0.61 mmol) was dissolved in DCM (6 mL). The temperature was lowered to 0°C, and DIPEA (0.32 g, 2.44 mmol) and Intermediate 15-2 (0.20 g, 0.91 mmol) were slowly added. The reaction was allowed to proceed at room temperature for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to give 0.08 g of a yellow oily liquid in a 26% yield. MS (ESI) m / z: 514.4 [M+H] + .

[0229] Step 3: Synthesis of 4-amino-1,3-bis(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 15)

[0230] Intermediate 15-3 (0.08 g, 0.16 mmol) was dissolved in DMF (2 mL) at room temperature and NaH (0.01 g, 0.23 mmol) was added at 0°C for 1 h. The reaction was terminated by quenching with ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.02 g of a light yellow solid in a 25% yield. MS (ESI) m / z: 514.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.50–7.38(m,7H),7.31–7.21(m,3H),7.12–7.06(m,1H),6.51(s,2H).

[0231] Example 16. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0232] Step 1: Synthesis of 2-(4-(trifluoromethoxy)phenyl)acetyl chloride (Intermediate 16-2)

[0233] Dissolve 2-(4-(trifluoromethoxy)phenyl)acetic acid (0.20 g, 0.99 mmol) in DCM (4 mL) at room temperature. Lower the temperature to 0°C and slowly add oxalyl chloride (0.14 g, 1.09 mmol). Terminate the reaction at room temperature for 1 h. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0234] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)-2-(4-trifluoromethoxyphenyl)acetamide (Intermediate 16-3)

[0235] At room temperature, intermediate 2-2 (0.20 g, 0.61 mmol) was dissolved in DCM (6 mL). The temperature was lowered to 0°C, and DIPEA (0.32 g, 2.44 mmol) and intermediate 16-2 (0.20 g, 0.91 mmol) were slowly added. The reaction was allowed to proceed at room temperature for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.10 g of a yellow oily liquid in a 31% yield. MS (ESI) m / z: 532.4 [M+H] + .

[0236] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-(trifluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 16)

[0237] Intermediate 16-3 (0.10 g, 0.19 mmol) was dissolved in DMF (2 mL) at room temperature and NaH (0.012 g, 0.28 mmol) was added at 0°C for 1 h. The reaction was terminated by adding ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.02 g of a light yellow solid (20% yield). MS (ESI) m / z: 532.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.85(d,J=1.8Hz,1H),7.60–7.47(m,4H),7.45–7.38(m,5H),7.09(d,J=1.9Hz,1H),6.63(s,2H).

[0238] Example 17. Synthesis of 4-(4-amino-1-(4-(difluoromethoxy)phenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,5-naphthyridin-3-yl)benzonitrile

[0239] Step 1: Synthesis of 2-(4-cyanophenyl)acetyl chloride (Intermediate 17-2)

[0240] At room temperature, dissolve 2-(4-cyanophenyl)acetic acid (0.20 g, 1.24 mmol) in DCM (4 mL). Lower the temperature to 0°C and slowly add oxalyl chloride (0.19 g, 1.49 mmol). The reaction is terminated at room temperature for 1 h. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0241] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-cyanophenyl)-N-(4-difluoromethoxyphenyl)acetamide (Intermediate 17-3)

[0242] At room temperature, intermediate 2-2 (0.20 g, 0.83 mmol) was dissolved in DCM (6 mL). The temperature was lowered to 0°C, and DIPEA (0.43 g, 3.32 mmol) and intermediate 17-2 (0.22 g, 1.24 mmol) were slowly added in sequence. The reaction was allowed to proceed at room temperature for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.05 g of a yellow oily liquid in a 15% yield. MS (ESI) m / z: 473.4 [M+H] + .

[0243] Step 3: Synthesis of 4-(4-amino-1-(4-(difluoromethoxy)phenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,5-naphthyridin-3-yl)benzonitrile (Example 17)

[0244] Intermediate 17-3 (0.05 g, 0.11 mmol) was dissolved in DMF (2 mL) at room temperature and NaH (0.008 g, 0.16 mmol) was added at 0°C for 1 h. The reaction was terminated by quenching with ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.006 g of a light yellow solid (12% yield). MS (ESI) m / z: 473.4 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.85(d,J=1.9Hz,1H),7.91(d,J=8.3Hz,2H),7.64–7.59(m ,2H),7.49(d,J=8.8Hz,2H),7.43–7.36(m,3H),7.09(d,J=1.9Hz,1H),6.77(s,2H).

[0245] Example 18. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(thiophen-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0246] Step 1: Synthesis of 2-(thiophen-3-yl)acetyl chloride (Intermediate 18-2)

[0247] Dissolve 2-(Thiophen-3-yl)acetic acid (0.10 g, 0.60 mmol) in DCM (2 mL) at room temperature. Slowly add oxalyl chloride (0.09 g, 0.72 mmol) and a catalytic amount of DMF at 0°C. The reaction is terminated at room temperature for 1 h. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0248] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl-2-(thiophen-3-yl)acetamide (Intermediate 18-3)

[0249] At room temperature, intermediate 2-2 (0.11 g, 0.33 mmol) dissolved in DCM (10 mL) was added to a single-necked flask. DIPEA (0.09 g, 0.67 mmol) and intermediate 18-2 (0.10 g, 0.50 mmol) were slowly added sequentially at 0°C. The reaction was terminated by 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.06 g of a yellow solid (60% yield).

[0250] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(thiophen-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 18)

[0251] Intermediate 18-3 (0.06 g, 0.18 mmol) was dissolved in DMF (5 mL) at room temperature and NaH (0.02 g, 0.27 mmol) was added at 0°C. The reaction was terminated at room temperature for 1 h. The mixture was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.028 g of a light yellow solid in a 47% yield. MS (ESI) m / z: 454.4 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.84(s,1H),7.69–7.66(m,1H),7.64–7.58(m,1H),7.49(d ,J=8.7Hz,2H),7.44–7.38(m,3H),7.29(d,J=4.9Hz,1H),7.06(s,1H),6.60(s,2H).

[0252] Example 19. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0253] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 19)

[0254] Intermediate 2-2 (0.20 g, 0.83 mmol) was dissolved in DCM (4 mL) at room temperature. The temperature was lowered to 0°C, and DIPEA (0.43 g, 3.32 mmol) and p-fluorophenylacetyl chloride (0.22 g, 1.24 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 24 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.045 g of a yellow solid, in a 16% yield. MS (ESI) m / z: 466.3 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.84(dd,J=1.9,0.8Hz,1H),7.59–7.45(m,3H),7.45–7.41( m,3H),7.40(d,J=1.6Hz,1H),7.29(d,J=9.0Hz,2H),7.09–7.07(m,1H),6.50(s,2H).

[0255] Example 20. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(6-methoxypyridin-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0256] Step 1: Synthesis of 2-(6-methoxypyridin-2-yl)acetyl chloride (Intermediate 20-2)

[0257] Dissolve 2-(6-methoxypyridin-2-yl)acetic acid (0.10 g, 0.60 mmol) in DCM (2 mL) at room temperature. Lower the temperature to 0°C and slowly add oxalyl chloride (0.09 g, 0.72 mmol) and a catalytic amount of DMF. Allow to react for 1 h at room temperature. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0258] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)-2-(6-methoxypyridin-3-yl)acetamide (Intermediate 20-3)

[0259] Intermediate 2-2 (0.11 g, 0.33 mmol) was added to a single-necked flask at room temperature and dissolved in DCM (10 mL). DIPEA (0.09 g, 0.67 mmol) and Intermediate 20-2 (0.10 g, 0.50 mmol) were then slowly added at 0°C. The reaction was terminated by 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.04 g of a yellow solid (40% yield).

[0260] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(6-methoxypyridin-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 20)

[0261] Intermediate 20-3 (0.04 g, 0.12 mmol) was dissolved in DMF (5 mL) at room temperature and NaH (0.01 g, 0.20 mmol) was added at 0°C for 1 h. The reaction was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.005 g of a light yellow solid (12% yield). MS (ESI) m / z: 479.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=1.9Hz,1H),8.17(d,J=2.4Hz,1H),7.69(dd,J=8.5,2.4Hz,1H),7.50(d ,J=2.3Hz,2H),7.44–7.37(m,3H),7.08(d,J=1.9Hz,1H),6.91(d,J=8.5Hz,1H),6.67(s,2H),3.90(s,3H).

[0262] Example 21. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0263] Step 1: Synthesis of 2-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)acetyl chloride (Intermediate 21-2)

[0264] Dissolve 2-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)acetic acid (0.10 g, 0.60 mmol) in DCM (2 mL) at room temperature. Lower the temperature to 0°C and slowly add oxalyl chloride (0.09 g, 0.72 mmol) followed by a catalytic amount of DMF. The reaction is terminated at room temperature for 1 h. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0265] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)-2-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)acetamide (Intermediate 21-3)

[0266] Intermediate 2-2 (0.11 g, 0.33 mmol) was added to a single-necked flask at room temperature and dissolved in DCM (10 mL). DIPEA (0.09 g, 0.67 mmol) and intermediate 21-2 (0.10 g, 0.50 mmol) were then slowly added at 0°C. The reaction was terminated by 12 h at room temperature. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.04 g of a yellow solid (40% yield).

[0267] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxan-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 21)

[0268] Intermediate 21-3 (0.04 g, 0.12 mmol) was dissolved in DMF (5 mL) at room temperature and NaH (0.01 g, 0.20 mmol) was added at 0°C for 1 h. The reaction was terminated by quenching with ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.011 g of a light yellow solid in a 27% yield. MS (ESI) m / z: 506.4 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),7.53–7.44(m,2H),7.44–7.37(m,3H),7. 05(s,1H),6.93(d,J=7.9Hz,1H),6.87–6.84(m,2H),6.38(s,2H),4.28(s,4H).

[0269] Example 22. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0270] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0271] At room temperature, intermediate 2-2 (0.20 g, 0.83 mmol) was dissolved in DCM (4 mL). The temperature was lowered to 0°C, and DIPEA (0.43 g, 3.32 mmol) and 2-(3,4-dimethoxyphenyl)acetyl chloride (0.27 g, 1.24 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 24 h. Concentration afforded a residue, which was purified by column chromatography (EA / PE system) to afford 0.045 g of a yellow solid, in a 16% yield. MS (ESI) m / z: 508.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84–8.83(m,1H),7.62–7.21(m,5H),7.08–7.03(m,2H),6.96–6.92(m,2H),6.40(s,2H),3.80(s,3H),3.75(s,3H).

[0272] Example 23. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0273] Step 1: Synthesis of dimethyl 2-(2-methyl-2H-indazol-5-yl)malonate (Intermediate 23-2)

[0274] At room temperature, 5-bromo-2-methyl-2H-indazole (1.00 g, 4.88 mmol) was dissolved in toluene (10 mL), and dimethyl malonate (0.65 g, 4.88 mmol), Pd2(dba)3 (0.40 g, 0.49 mmol), X-phos (0.42 g, 0.98 mmol), and cesium carbonate (1.87 g, 5.74 mmol) were added. The reaction was terminated at 108°C for 16 h. Filtered through celite and concentrated to obtain 1.30 g of a yellow oil. The product did not need to be purified and could be used directly in the next reaction. Step 2: Synthesis of 2-(2-methyl-2H-indazol-5-yl)malonic acid (Intermediate 23-3)

[0275] Intermediate 23-2 (1.30 g, 4.88 mmol) was dissolved in EtOH (16 mL) and H₂O (4 mL) at room temperature. Sodium hydroxide (0.65 g, 16.29 mmol) was added and the reaction was terminated at 100°C for 16 h. The pH was adjusted to 5-6 with dilute hydrochloric acid, extracted with EA, and the organic phase was concentrated to obtain 1.0 g of a yellow solid. The product was used directly in the next reaction without purification.

[0276] Step 3: Synthesis of 2-(2-methyl-2H-indazol-5-yl)acetic acid (Intermediate 23-4)

[0277] Intermediate 23-3 (1.0 g, 4.25 mmol) was dissolved in HCl / 1,4-dioxane (10 mL) at room temperature and reacted at 100°C for 16 h. The residue was concentrated and purified by column chromatography (ACN / H2O) to give 0.30 g of a white solid (33% yield).

[0278] Step 4: Synthesis of 2-(2-methyl-2H-indazol-5-yl)acetyl chloride (Intermediate 23-5)

[0279] Intermediate 23-4 (0.15 g, 0.90 mmol) was dissolved in DCM (3 mL) at room temperature. Oxalyl chloride (0.14 g, 1.08 mmol) and a catalytic amount of DMF were slowly added sequentially at 0°C. The reaction was terminated at room temperature for 1 h. The residue was concentrated to obtain the product, which was used directly in the next reaction without purification.

[0280] Step 5: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)acetamide (Intermediate 23-6)

[0281] Intermediate 2-2 (0.20 g, 0.61 mmol) was dissolved in ACN (6 mL) at room temperature. DIPEA (0.32 g, 2.44 mmol), Intermediate 23-5 (0.17 g, 0.91 mmol), and DMAP (0.01 g, 0.06 mmol) were slowly added sequentially at 0°C. The reaction was terminated at 60°C for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.02 g of a yellow oily liquid (7% yield).

[0282] Step 6: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 23)

[0283] Intermediate 23-6 (0.02 g, 0.04 mmol) was dissolved in DMF at room temperature and NaH (0.01 g, 0.06 mmol) was added at 0°C for 1 h. The reaction was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.005 g of a light yellow solid (yield 25%). MS (ESI) m / z: 502.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.35(s,1H),7.72(s,1H),7.62(d,J=8.1Hz 1H),7.50(d,J=8.5Hz,2H),7.41(d,J=8.9Hz,2H),7.27–7.17(m,2H),7.08(d,J=1.9Hz,1H),6.40(s,2H),4.19(s,3H).

[0284] Example 24. Synthesis of 4-amino-3-(4-bromophenyl)-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0285] Step 1: Synthesis of 4-amino-3-(4-bromophenyl)-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 24)

[0286] At room temperature, intermediate 2-2 (0.60 g, 1.82 mmol) was dissolved in DCM (6 mL). The temperature was lowered to 0°C, and DIPEA (0.94 g, 7.28 mmol) and p-fluorophenylacetyl chloride (0.64 g, 2.73 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 24 h. Concentration afforded a residue, which was purified by column chromatography (EA / PE system) to afford 0.035 g of a yellow solid (5% yield). MS (ESI) m / z: 527.4 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.84(d,J=1.9Hz,1H),7.66–7.63(m,2H),7.59–7.46(m,3H) ,7.41(d,J=4.6Hz,2H),7.37–7.34(m,2H),7.07(d,J=1.9Hz,1H),6.64–6.55(m,2H).

[0287] Example 25. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0288] Step 1: Synthesis of 2-(5-methoxypyridin-2-yl)acetyl chloride (Intermediate 25-2)

[0289] Dissolve 2-(5-methoxypyridin-2-yl)acetic acid (0.20 g, 1.20 mmol) in DCM (2 mL) at room temperature. Lower the temperature to 0°C and slowly add oxalyl chloride (0.18 g, 1.44 mmol). Terminate the reaction at room temperature for 1 h. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0290] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 25)

[0291] At room temperature, intermediate 2-2 (0.20 g, 0.83 mmol) was dissolved in DCM (4 mL). The temperature was lowered to 0°C, and DIPEA (0.43 g, 3.32 mmol) and intermediate 25-2 (0.20 g, 1.24 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 24 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.003 g of a yellow solid (yield 2%). MS (ESI) m / z: 479.4 [M+H] + .

[0292] Example 26. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(5-(dimethylphosphoryl)pyridin-2-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0293] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(5-(dimethylphosphoryl)pyridin-2-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 26)

[0294] Example 24 (0.35 g, 0.07 mmol) was dissolved in anhydrous DMF (4 mL) at room temperature. Dimethylphosphine oxide (0.006 g, 0.07 mmol), palladium acetate (0.002 g, 0.007 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.015 g, 0.026 mmol), and potassium phosphate (0.017 g, 0.077 mmol) were added. The reaction was terminated by microwave heating at 150°C for 1 h. Purification by column chromatography (ACN / H2O system) afforded 0.032 g of a white solid in a 92% yield. MS (ESI) m / z: 524.4 [M+H]+1 H NMR (400MHz, DMSO-d6) δ8.85(d,J=1.9Hz,1H),7.85(dd,J=11.3,7.9Hz,2H),7.56(dd,J=8.2,2.4Hz,2H ),7.51–7.48(m,2H),7.42–7.22(m,3H),7.08(d,J=1.9Hz,1H),6.59(s,2H),1.70(s,3H),1.67(s,3H).

[0295] Example 27. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(5-(methoxy-d3)phenyl-2-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0296] Step 1: Synthesis of ethyl 2-(4-(methoxy-d3)phenyl)acetate (Intermediate 27-2)

[0297] At room temperature, ethyl 2-(4-hydroxyphenyl)acetate (1.50 g, 8.32 mmol) was dissolved in anhydrous THF (10 mL). The temperature was lowered to 0°C, and NaH (0.50 g, 9.98 mmol) was slowly added. The mixture was stirred for 0.5 h, followed by the addition of deuterated iodomethane (1.20 g, 8.32 mmol). The reaction was allowed to return to room temperature for 16 h. The reaction was quenched with saturated ammonium chloride solution in an ice-water bath, extracted with PE, dried, concentrated, and filtered to obtain 1.25 g of a yellow oily liquid. MS (ESI) m / z: 198.2 [M+H] + .

[0298] Step 2: Synthesis of 2-(4-(methoxy-d3)phenyl)acetic acid (Intermediate 27-3)

[0299] Intermediate 27-2 (1.25 g, 6.34 mmol) was dissolved in MeOH (10 mL) and H₂O (2 mL) at room temperature. LiOH·H₂O (0.53 g, 12.68 mmol) was added and the reaction was terminated at room temperature for 3 h. The residue was concentrated and extracted with DCM. The aqueous phase was adjusted to pH 3-4, washed with DCM, and concentrated to give 0.78 g of a white solid, in a 73% yield. MS (ESI) m / z: 170.2 [M+H] + .

[0300] Step 3: Synthesis of 2-(4-(methoxy-d3)phenyl)acetyl chloride (Intermediate 27-4)

[0301] At room temperature, intermediate 27-3 (0.30 g, 1.77 mmol) was dissolved in DCM (3 mL). The temperature was lowered to 0°C, and oxalyl chloride (0.27 g, 2.12 mmol) was slowly added. The reaction was terminated at room temperature for 1 h. The residue was concentrated to obtain the product, which was used directly in the next reaction without purification.

[0302] Step 4: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(5-(methoxy-d3)pyridin-2-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 27)

[0303] At room temperature, intermediate 2-2 (0.40 g, 1.21 mmol) was dissolved in DCM (4 mL). The temperature was lowered to 0°C, and DIPEA (0.63 g, 4.84 mmol) and intermediate 27-4 (0.33 g, 1.82 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 24 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.032 g of a yellow solid (yield 6%). MS (ESI) m / z: 481.2 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.83(d,J=1.9Hz,1H),7.49(d,J=8.9Hz,2H),7.44–7.36(m ,3H),7.34(d,J=8.7Hz,2H),7.06(d,J=1.9Hz,1H),7.04–7.01(m,2H),6.35(s,2H).

[0304] Example 28. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0305] Step 1: Synthesis of dimethyl 2-(1-methyl-1H-benzo[d]imidazol-6-yl)malonate (Intermediate 28-2)

[0306] At room temperature, 6-bromo-1-methyl-1H-benzo[d]imidazole (1.00 g, 4.88 mmol) was dissolved in toluene (10 mL). Dimethyl malonate (0.65 g, 4.88 mmol), Pd(dba) (0.40 g, 0.49 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos) (0.42 g, 0.98 mmol), and cesium carbonate (1.87 g, 5.74 mmol) were added. The reaction was terminated at 108°C for 16 h. Filtration through celite and concentration afforded 1.30 g of the crude product as a yellow oil. The product was used directly in the next reaction without purification.

[0307] Step 2: Synthesis of 2-(1-methyl-1H-benzo[d]imidazol-6-yl)malonic acid (Intermediate 28-3)

[0308] Intermediate 28-2 (1.30 g, 4.88 mmol) was dissolved in EtOH (16 mL) and H₂O (4 mL) at room temperature. Sodium hydroxide (0.65 g, 16.29 mmol) was added and the reaction was terminated at 100°C for 16 h. The pH was adjusted to 3-4 with dilute hydrochloric acid, extracted with EA, and the organic phase was concentrated to obtain 1.0 g of a yellow oily liquid. The product was used directly in the next reaction without purification.

[0309] Step 3: Synthesis of 2-(1-methyl-1H-benzo[d]imidazol-6-yl)acetic acid (Intermediate 28-4)

[0310] Intermediate 28-3 (1.0 g, 4.25 mmol) was dissolved in HCl / 1,4-dioxane (10 mL) at room temperature and reacted at 100°C for 16 h. The residue was concentrated and purified by column chromatography (ACN / H2O) to give 0.30 g of a white solid (33% yield).

[0311] Step 4: Synthesis of 2-(1-methyl-1H-benzo[d]imidazol-6-yl)acetyl chloride (Intermediate 28-5)

[0312] Intermediate 28-4 (0.15 g, 0.90 mmol) was dissolved in DCM (3 mL) at room temperature. Oxalyl chloride (0.14 g, 1.08 mmol) and a catalytic amount of DMF were slowly added sequentially at 0°C. The reaction was terminated at room temperature for 1 h. The residue was concentrated to obtain the product, which was used directly in the next reaction without purification.

[0313] Step 5: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)acetamide (Intermediate 28-6)

[0314] Intermediate 2-2 (0.20 g, 0.61 mmol) was dissolved in ACN (6 mL) at room temperature. DIPEA (0.32 g, 2.44 mmol), Intermediate 28-5 (0.17 g, 0.91 mmol), and DMAP (0.01 g, 0.06 mmol) were slowly added sequentially at 0°C. The reaction was terminated at 60°C for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.02 g of a yellow oily liquid (7% yield).

[0315] Step 6: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 28)

[0316] Intermediate 28-6 (0.02 g, 0.04 mmol) was dissolved in DMF at room temperature and NaH (0.01 g, 0.06 mmol) was added at 0°C for 1 h. The reaction was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.006 g of a light yellow solid (30% yield). MS (ESI) m / z: 502.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.22(s,1H),7.71(d,J=8.4Hz,1H),7.58(d,J=8.4Hz,1H),7. 51(d,J=8.2Hz,2H),7.46–7.38(m,3H),7.24–7.20(m,1H),7.10(s,1H),6.44(s,2H),3.86(s,3H).

[0317] Example 29. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0318] Step 1: Synthesis of 2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)alanine dimethyl ester (Intermediate 29-2)

[0319] At room temperature, 5-bromo-1-methylpyridin-2(1H)-one (1.00 g, 5.32 mmol) was dissolved in toluene (10 mL). Dimethyl malonate (0.73 g, 5.32 mmol), Pd2(dba)3 (0.49 g, 0.53 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-phos) (0.51 g, 1.06 mmol), and cesium carbonate (2.10 g, 6.38 mmol) were added. The reaction was terminated at 108°C for 16 h. Filtration through celite and concentration afforded 1.30 g of a yellow oily liquid. The product was used directly in the next step without purification. MS (ESI) m / z: 240.2 [M+H] + .

[0320] Step 2: Synthesis of 2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)alanine (Intermediate 29-3)

[0321] Intermediate 29-2 (1.30 g, 5.43 mmol) was dissolved in EtOH (16 mL) and H₂O (4 mL) at room temperature. NaOH (0.65 g, 16.29 mmol) was added and the reaction was terminated at 100°C for 16 h. The residue was concentrated and purified by column chromatography (DCM / MeOH) to afford 0.64 g of a yellow solid in a 56% yield. MS (ESI) m / z: 212.2 [M+H] + .

[0322] Step 3: Synthesis of 2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetic acid (Intermediate 29-4)

[0323] Intermediate 29-3 (0.64 g, 3.03 mmol) was dissolved in HCl / 1,4-dioxane (10 mL) at room temperature and the reaction was terminated at 100°C for 16 h. The residue was concentrated and purified by column chromatography (ACN / H2O) to afford 0.15 g of a white solid in a 30% yield. MS (ESI) m / z: 168.2 [M+H] + Step 4: Synthesis of 2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetyl chloride (Intermediate 29-5)

[0324] At room temperature, intermediate 29-4 (0.15 g, 0.90 mmol) was dissolved in DCM (3 mL). The temperature was lowered to 0°C, and oxalyl chloride (0.14 g, 1.08 mmol) was slowly added. The reaction was terminated at room temperature for 1 h. The residue was concentrated to obtain the product, which was used directly in the next reaction without purification.

[0325] Step 5: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)acetamide (Intermediate 29-6)

[0326] At room temperature, intermediate 2-2 (0.20 g, 0.61 mmol) was dissolved in DCM (6 mL). The temperature was lowered to 0°C, and DIPEA (0.32 g, 2.44 mmol) and intermediate 29-5 (0.17 g, 0.91 mmol) were slowly added sequentially. The reaction was allowed to proceed at room temperature for 24 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.02 g of a yellow oily liquid, a 7% yield. MS (ESI) m / z: 479.4 [M+H] + .

[0327] Step 6: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 29)

[0328] Intermediate 29-6 (0.02 g, 0.04 mmol) was dissolved in DMF (1 mL) at room temperature and NaH (0.005 g, 0.06 mmol) was added at 0°C for 1 h. The reaction was terminated by quenching with ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.08 g of a light yellow solid in a 40% yield. MS (ESI) m / z: 479.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=1.9Hz,1H),7.69(d,J=2.5Hz,1H),7.46(d,J=8.9Hz,2H),7.42–7. 38(m,3H),7.36–7.21(m,1H),7.07(d,J=2.0Hz,1H),6.89(s,2H),6.44(d,J=9.3Hz,1H),3.45(s,3H).

[0329] Example 30. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-(S-methylsulfonylimino)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0330] Step 1: Synthesis of 2-(4-(methylthio)phenylacetyl chloride (Intermediate 30-2)

[0331] Dissolve 2-(4-methylthio)phenylacetic acid (0.05 g, 0.30 mmol) in DCM (2 mL) at room temperature. Slowly add oxalyl chloride (0.05 g, 0.36 mmol) and a catalytic amount of DMF at 0°C. The reaction is terminated at room temperature for 1 h. Concentrate the residue to obtain the product, which can be used directly in the next reaction without purification.

[0332] Step 2: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)-2-(4-(methylthio)phenyl)acetamide (Intermediate 30-3)

[0333] At room temperature, intermediate 2-2 (0.06 g, 0.33 mmol) was added to a single-necked flask and dissolved in DCM (10 mL). DIPEA (0.05 g, 0.67 mmol) and intermediate 30-2 (0.05 g, 0.50 mmol) were slowly added sequentially at 0°C. The reaction was terminated at room temperature for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.04 g of a yellow solid (50% yield).

[0334] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-(methylthio)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Intermediate 30-4)

[0335] Intermediate 30-3 (0.04 g, 0.10 mmol) was dissolved in 1,4-dioxane at room temperature. NaH (0.01 g, 0.20 mmol) was added at 0°C and the reaction was terminated at room temperature for 1 h. The reaction was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.03 g of a pale yellow solid (75% yield).

[0336] Step 4: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(4-(S-methylsulfonylimino)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 30)

[0337] Intermediate 30-4 (0.03 g, 0.06 mmol) was dissolved in methanol at room temperature. Ammonium carbonate (0.01 g, 0.12 mmol) and iodobenzene acetate (0.03 g, 0.09 mmol) were added sequentially. The reaction was terminated at room temperature for 2 h. Water was added, extracted with EA, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.02 g of a pale yellow solid in a 72% yield. MS (ESI) m / z: 525.4 [M+H] +1H NMR (400MHz, DMSO-d6) δ8.86(s,1H),8.00(d,J=8.2Hz,2H),7.63(d,J=8.1Hz,2H),7.50(d ,J=4.0Hz,2H),7.41(d,J=7.8Hz,3H),7.09(s,1H),6.68(s,2H),4.24(s,1H),3.11(s,3H).

[0338] Example 31. Synthesis of 1-(4-(difluoromethoxy)phenyl)-4-(dimethylamino)-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0339] Step 1: Synthesis of 1-(4-(difluoromethoxy)phenyl)-4-dimethylamino-3-(4-methoxyphenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 31)

[0340] Example 2 (0.02 g, 0.04 mmol) was dissolved in DMF at room temperature. NaH (0.01 g, 0.08 mmol) was added at 0°C and stirred at room temperature for 20 min. Methyl iodide (0.02 g, 0.08 mmol) was then added and the reaction was terminated at room temperature for 1 h. The mixture was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.009 g of a light yellow solid (41% yield). MS (ESI) m / z: 506.5 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),7.51–7.46(m,2H),7.45–7.38(m,3H),7.28–7 .24(m,2H),7.06(d,J=2.1Hz,1H),6.99(d,J=6.8Hz,2H),3.80(s,3H),2.75(s,6H).

[0341] Example 32. Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-(4-methoxyphenyl)-4-(methylamino)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0342] Step 1: Synthesis of 1-(4-(difluoromethoxy)phenyl)-3-(4-methoxyphenyl)-4-(methylamino)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 32)

[0343] Example 2 (0.03 g, 0.06 mmol) was dissolved in DMF at room temperature. NaH (0.01 g, 0.06 mmol) was added at 0°C and stirred at room temperature for 20 min. Methyl iodide (0.01 g, 0.06 mmol) was then added and the reaction was terminated at room temperature for 1 h. The mixture was quenched with ice water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.025 g of a light yellow solid in a 78% yield. MS (ESI) m / z: 492.5 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.80(s,1H),7.47(d,J=8.8Hz,2H),7.42–7.35(m,4H),7.26(d,J =8.4Hz,2H),7.06(d,J=1.9Hz,1H),6.93(d,J=8.5Hz,2H),3.78(s,3H),2.41(d,J=5.3Hz 3H).

[0344] Example 33. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0345] Step 1: Synthesis of dimethyl 2-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)malonate (Intermediate 33-2)

[0346] At room temperature, 6-bromo-1-methylbenzo[d][1,2,3]triazole (1.00 g, 4.72 mmol) was dissolved in toluene (10 mL). Dimethyl malonate (0.62 g, 4.72 mmol), Pd2(dba)3 (0.43 g, 0.47 mmol), X-phos (0.45 g, 0.94 mmol), and cesium carbonate (1.85 g, 5.66 mmol) were added. The reaction was terminated at 108°C for 16 h. Filtered through celite and concentrated to obtain 4.50 g of a yellow oily liquid. The product was used directly in the next reaction without purification. MS (ESI) m / z: 264.2 [M+H] + .

[0347] Step 2: Synthesis of 2-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)malonic acid (Intermediate 33-3)

[0348] Intermediate 33-2 (4.50 g, 17.10 mmol) was dissolved in EtOH (32 mL) and H2O (8 mL) at room temperature. NaOH (2.00 g, 51.30 mmol) was added and the reaction was terminated at 100°C for 16 h. Concentration afforded 6.00 g of a yellow solid. The product was used directly in the next reaction without purification. MS (ESI) m / z: 236.2 [M+H] + .

[0349] Step 3: Synthesis of 2-(1-methylbenzo[d][1,2,3]triazol-6-yl)acetic acid (Intermediate 33-4)

[0350] Intermediate 33-3 (6.00 g, 25.50 mmol) was dissolved in HCl / 1,4-dioxane (20 mL) at room temperature and the reaction was terminated at 100°C for 16 h. The residue was concentrated and purified by column chromatography (ACN / H2O) to afford 0.55 g of a white solid in a 60% yield. MS (ESI) m / z: 192.2 [M+H] + .

[0351] Step 4: Synthesis of 2-(1-methylbenzo[d][1,2,3]triazol-6-yl)acetyl chloride (Intermediate 33-5)

[0352] At room temperature, intermediate 33-4 (0.20 g, 1.05 mmol) was dissolved in DCM (3 mL), the temperature was lowered to 0°C, and oxalyl chloride (0.16 g, 1.25 mmol) was slowly added. The reaction was terminated at room temperature for 1 h. The residue was concentrated to obtain the product, which was used directly in the next reaction without purification.

[0353] Step 5: Synthesis of N-(2-cyano-5-trifluoromethylpyridin-3-yl)-N-(4-difluoromethoxy)phenyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)acetamide (Intermediate 33-6)

[0354] At room temperature, intermediate 2-2 (0.18 g, 0.55 mmol) was dissolved in ACN (6 mL). The temperature was lowered to 0°C, and DIPEA (0.28 g, 2.20 mmol) and intermediate 33-5 (0.20 g, 0.82 mmol) were slowly added sequentially. The temperature was then raised to 60°C and the reaction was terminated by 12 h. Concentration afforded a residue, which was purified by column chromatography (EA / PE system) to afford 0.03 g of a yellow oil (7% yield). MS (ESI) m / z: 503.4 [M+H] + .

[0355] Step 6: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d][1,2,3]triazol-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 33)

[0356] Intermediate 33-6 (0.03 g, 0.06 mmol) was dissolved in DMF (2 mL) at room temperature and NaH (0.004 g, 0.09 mmol) was added at 0°C for 1 h. The reaction was terminated by quenching with ice water, extracting with EA, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain a residue. Purification by column chromatography (EA / PE system) afforded 0.023 g of a white solid in a 67% yield. MS (ESI) m / z: 503.4 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.86(d,J=1.9Hz,1H),8.06(d,J=8.6Hz,1H),7.85(s,1H),7.60–7.48(m,3H),7 .43(s,1H),7.40(s,1H),7.38(dd,J=8.6,1.4Hz,1H),7.12(d,J=1.9Hz,1H),6.69(s,2H),4.32(s,3H).

[0357] Example 34. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(quinazolin-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0358] Step 1: Synthesis of N-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 34-1)

[0359] At room temperature, intermediate 2-2 (0.50 g, 1.52 mmol) and KOH (0.30 g, 4.56 mmol) were added to a single-necked flask, dissolved in acetic anhydride (5 mL), and reacted at 120°C for 3 h. The mixture was cooled, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.50 g of a light yellow oily liquid, with a yield of 89%.

[0360] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Intermediate 34-2)

[0361] At room temperature, intermediate 34-1 (0.50 g, 1.35 mmol) was added to a single-necked flask and dissolved in anhydrous THF (5 mL). NaH (0.16 g, 4.04 mmol) was added at 0°C and the reaction was terminated at room temperature for 8 h. The mixture was cooled, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.25 g of an off-white solid, in a 50% yield.

[0362] Step 3: Synthesis of 4-amino-3-bromo-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Intermediate 34-3)

[0363] At room temperature, intermediate 34-2 (0.25 g, 0.67 mmol) was added to a single-necked flask and dissolved in THF (5 mL). NBS (0.13 g, 0.74 mmol) was added at 0°C and the reaction was terminated at room temperature for 0.5 h. The product was extracted with EA, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 0.30 g of a pale yellow solid, which was used directly in the next step without purification.

[0364] Step 4: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (Intermediate 34-4)

[0365] At room temperature, 6-bromoquinazoline (0.50 g, 2.39 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (10 mL). Diboronic acid pinacol ester (0.73 g, 2.87 mmol), potassium acetate (0.47 g, 4.78 mmol), and Pd(dppf)Cl2 (0.18 g, 0.24 mmol) were added sequentially at room temperature. The reaction was terminated under N2 at room temperature for 4 h. The product was filtered through celite, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.020 g of a yellow solid (33% yield).

[0366] Step 5: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(quinazolin-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 34)

[0367] At room temperature, intermediate 34-3 (0.05 g, 0.11 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (2 mL) and H₂O (0.5 mL). Intermediate 34-4 (0.06 g, 0.22 mmol), potassium carbonate (0.03 g, 0.22 mmol), and Pd(dppf)Cl₂ (0.007 g, 0.24 mmol) were added sequentially at room temperature. The reaction was terminated at 100°C under N₂ for 4 h. The mixture was filtered through celite, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.020 g of a yellow solid in 18% yield. MS (ESI) m / z: 500.6 [M+H] +1 H NMR(400MHz,DMSO-d6)δ9.63(s,1H),9.32(s,1H),8.87(s,1H),8.21(s,1H),8.05(q,J=8.7Hz,2H ),7.52(d,J=6.5Hz,2H),7.41(d,J=9.3Hz,2H),7.40(t,J=72.0Hz,1H),7.13(s,1H),6.86(s,2H).

[0368] Example 35. 6-(4-amino-1-(4-(difluoromethoxy)phenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,5-naphthyridin-3-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0369] Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Intermediate 35-2)

[0370] At room temperature, 6-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (0.50 g, 2.19 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (10 mL). Bis(pyraclostrobin) (0.67 g, 2.63 mmol), potassium acetate (0.43 g, 4.38 mmol), and Pd(dppf)Cl2 (0.16 g, 0.22 mmol) were added sequentially at room temperature. The reaction was terminated under N2 at room temperature for 4 h. The product was filtered through celite, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.55 g of an off-white solid in a 91% yield.

[0371] Step 2: Synthesis of 6-(4-amino-1-(4-(difluoromethoxy)phenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,5-naphthyridin-3-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Example 35)

[0372] At room temperature, intermediate 34-3 (0.07 g, 0.16 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (2 mL) and H₂O (0.5 mL). Intermediate 35-2 (0.06 g, 0.24 mmol), potassium carbonate (0.04 g, 0.32 mmol), and Pd(dppf)Cl₂ (0.01 g, 0.016 mmol) were added sequentially at room temperature. The reaction was terminated at 100°C under N₂ for 4 h. The mixture was filtered through celite, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.040 g of a yellow solid in a 50% yield. MS (ESI) m / z: 519.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),8.79(s,1H),7.48(d,J=12.1Hz,2H),7.41(d,J=10.5Hz ,2H),7.40(t,J=72.0Hz,1H),7.08-7.00(m,2H),6.97-6.89(m,2H),6.48(s,2H),4.61(s,2H).

[0373] Example 36. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-phenyl-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0374] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-phenyl-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 36)

[0375] At room temperature, intermediate 34-3 (0.05 g, 0.11 mmol), potassium carbonate (0.03 g, 0.22 mmol), phenylboronic acid (0.03 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (MeOH / DCM system) to obtain 0.015 g of a light yellow solid, with a yield of 30%. MS (ESI) m / z: 448.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84 (s, 1H), 7.52–7.36 (m, 10H), 7.08 (d, J = 1.9Hz, 1H), 6.38 (s, 2H).

[0376] Example 37. Synthesis of 4-amino-3-(benzo[c][1,2,5]oxadiazol-5-yl)-1-(4-difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0377] Step 1: Synthesis of 4-amino-3-(benzo[c][1,2,5]oxadiazol-5-yl)-1-(4-difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0378] At room temperature, intermediate 34-3 (0.07 g, 0.16 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]oxadiazole (0.057 g, 0.23 mmol), Pd(dppf)Cl2 (0.011 g, 0.02 mmol), and anhydrous potassium carbonate (0.042 g, 0.31 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL). H2O (1 mL) was added, and the reaction was terminated at 100°C for 4 h. The reaction mixture was cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by thick silica gel prep plate (PE / EA system) to afford 0.021 g of a yellow solid in a 28% yield. MS (ESI) m / z: 490.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.09–7.98(m,2H),7.55–7.48(m,3H),7.46–7.33(m,3H),7.13(s,1H),7.09(s,2H).

[0379] Example 38. 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(imidazo[1,2-a]pyridin-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0380] Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (Intermediate 38-2)

[0381] At room temperature, 6-bromoimidazo[1,2-a]pyridine (0.50 g, 2.54 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (10 mL). Diboronic acid pinacol ester (0.77 g, 3.04 mmol), potassium acetate (0.50 g, 5.08 mmol), and Pd(dppf)Cl2 (0.19 g, 0.25 mmol) were added sequentially at room temperature. The reaction was terminated under N2 at room temperature for 4 h. Filtered through celite, concentrated, and slurried with methanol to obtain 0.30 g of an off-white solid (48% yield).

[0382] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(imidazo[1,2-a]pyridin-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 38)

[0383] At room temperature, intermediate 34-3 (0.07 g, 0.16 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (2 mL) and H₂O (0.5 mL). Intermediate 38-2 (0.06 g, 0.23 mmol), potassium carbonate (0.04 g, 0.32 mmol), and Pd(dppf)Cl₂ (0.01 g, 0.016 mmol) were added sequentially at room temperature. The reaction was terminated at 100°C under N₂ for 4 h. The mixture was filtered through celite, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.040 g of an earth-colored solid in a 53% yield. MS (ESI) m / z: 488.4 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.55(s,1H),7.96(s,1H),7.60(s,2H),7.51-7. 49(m,2H),7.42-7.40(m,3H),7.18(dd,J=9.3,1.7Hz,1H),7.11(s,1H),6.89(s,2H).

[0384] Example 39. Synthesis of 3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-amino-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0385] Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine (Intermediate 39-2)

[0386] At room temperature, 6-bromo-[1,2,4]triazolo[4,3-a]pyridine (0.50 g, 2.54 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (10 mL). Diboronic acid pinacol ester (0.77 g, 3.02 mmol), potassium acetate (0.50 g, 5.10 mmol), and Pd(dppf)Cl2 (0.18 g, 0.25 mmol) were added in sequence at room temperature. The reaction was terminated under N2 at room temperature for 4 h. Filtered with celite, concentrated, and slurried with methanol to obtain 0.35 g of an off-white solid with a yield of 57%. Step 2: Synthesis of 3-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-amino-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridine-2(1H)-one (Example 39)

[0387] At room temperature, intermediate 34-3 (0.07 g, 0.16 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (2 mL) and H₂O (0.5 mL). Intermediate 39-2 (0.06 g, 0.23 mmol), potassium carbonate (0.04 g, 0.32 mmol), and Pd(dppf)Cl₂ (0.01 g, 0.016 mmol) were then added sequentially at room temperature. The reaction was terminated at 100°C under N₂ for 4 h. The mixture was filtered through celite, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.015 g of an ochre-colored solid (20% yield). MS (ESI) m / z: 489.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.86(s,1H),8.56(s,1H),7.79(d,J=8.1Hz,1H),7.51-7.49( m,2H),7.43-7.40(m,2H),7.40(t,J=76.0Hz,1H),7.29(d,J=9.3Hz,1H),7.12(s,1H),7.06(s,2H).

[0388] Example 40. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0389] Step 1: Synthesis of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrazolo[3,4-b]pyridine (Intermediate 40-2)

[0390] 5-Bromo-2-methyl-2H-pyrazolo[3,4-b]pyridine (0.30 g, 1.41 mmol) was added to a single-necked flask at room temperature and dissolved in 1,4-dioxane (6 mL). Bis(pyraclostrobin) (0.54 g, 2.12 mmol), potassium acetate (0.28 g, 2.82 mmol), and Pd(dppf)Cl2 (0.10 g, 0.14 mmol) were then added sequentially at room temperature. The reaction was terminated under N2 at room temperature for 4 h. The product was filtered through Celite, concentrated, and purified by column chromatography (EA / PE system) to afford 0.20 g of a brown solid in a 55% yield.

[0391] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0392] At room temperature, intermediate 34-3 (0.07 g, 0.16 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (2 mL) and H₂O (0.5 mL). Intermediate 40-2 (0.10 g, 0.40 mmol), potassium carbonate (0.04 g, 0.32 mmol), and Pd(dppf)Cl₂ (0.01 g, 0.016 mmol) were added sequentially at room temperature. The reaction was terminated at 100°C under N₂ for 4 h. The mixture was filtered through celite, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.06 g of a yellow solid in a 74% yield. MS (ESI) m / z: 503.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.86 (s, 1H), 8.50 (d, J = 2.2Hz, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 7.51 (d, J = 8. 9Hz,2H),7.42(s,1H),7.41(s,1H),7.40(t,J=74.0Hz,1H),7.11(s,1H),6.74(s,2H),4.22(s,3H).

[0393] Example 41. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0394] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0395] At room temperature, intermediate 34-3 (0.07 g, 0.17 mmol), potassium carbonate (0.03 g, 0.28 mmol), (1-methyl-1H-benzo[d]imidazol-5-yl)boronic acid (0.03 g, 0.27 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (MeOH / DCM) to give 0.020 g of a light yellow solid, in a 30% yield. MS (ESI) m / z: 502.4 [M+H] + 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=1.9Hz,1H),8.22(s,1H),7.67–7.63(m,2H),7.52(d,J=2.1Hz,1H),7.50(d, J=2.4Hz,1H),7.43–7.39(m,3H),7.28(dd,J=8.3,1.4Hz,1H),7.08(d,J=1.9Hz,1H),6.32(s,2H),3.88(s,3H).

[0396] Example 42. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(quinoxalin-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0397] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(quinoxalin-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0398] Intermediate 34-3 (0.15 g, 0.36 mmol) was dissolved in 1,4-dioxane (8 mL) and H₂O (2 mL) at room temperature. 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (0.18 g, 0.70 mmol), Pd(dppf)Cl₂ (0.026 g, 0.036 mmol), and potassium carbonate (0.15 g, 1.08 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (PE / EA system) to afford 0.028 g of a yellow solid in a 17% yield. MS (ESI) m / z: 500.4 [M+H] +1H NMR (400MHz, DMSO-d6) δ8.97(s,2H),8.87(d,J=1.9Hz,1H),8.15(d,J=8.7Hz,1H),8.12(d,J=1.9Hz,1H) ,7.87(dd,J=8.6,1.9Hz,1H),7.55–7.52(m,2H),7.45–7.39(m,3H),7.13(d,J=1.9Hz,1H),6.83(s,2H).

[0399] Example 43. Synthesis of 4-amino-3-(benzo[d]oxazol-6-yl)-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0400] Step 1: Synthesis of 4-amino-3-(benzo[d]oxazol-6-yl)-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0401] Intermediate 34-3 (0.07 g, 0.15 mmol) was dissolved in 1,4-dioxane (6 mL) and H₂O (2 mL) at room temperature. 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (0.08 g, 0.31 mmol), Pd(dppf)Cl₂ (0.011 g, 0.015 mmol), and potassium carbonate (0.062 g, 0.45 mmol) were added. The reaction was terminated at 100°C for 4 h. The mixture was cooled, filtered through celite, and purified by column chromatography (PE / EA system) to afford 0.014 g of a yellow solid in 18% yield. MS (ESI) m / z: 489.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.78(s,1H),7.87(d,J=8.2Hz,1H),7.76(d,J=1 .5Hz,1H),7.52–7.49(m,2H),7.43–7.39(m,4H),7.10(d,J=1.9Hz,1H),6.60(s,2H).

[0402] Example 44. Synthesis of 4-amino-3-(benzo[c][1,2,5]thiadiazol-5-yl)-1-(4-difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0403] Step 1: Synthesis of 4-amino-3-(benzo[c][1,2,5]thiadiazol-5-yl)-1-(4-difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 44)

[0404] At room temperature, intermediate 34-3 (0.070 g, 0.16 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[c][1,2,5]thiadiazole (0.061 g, 0.23 mmol), Pd(dppf)Cl2 (0.011 g, 0.02 mmol), and anhydrous potassium carbonate (0.043 g, 0.31 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL). H2O (1 mL) was added, and the reaction was terminated at 100°C for 4 h. The mixture was filtered through celite and concentrated. The residue was purified by thick silica gel prep plate (PE / EA system) to afford 0.05 g of a yellow solid in a 64% yield. MS (ESI) m / z: 506.5 [M+H] +1 HNMR (400MHz, DMSO-d6) δ8.87(s,1H),8.10(s,2H),7.69(s,1H),7.61–7.36(m,5H),7.13(s,1H),6.89(s,2H).

[0405] Example 45. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(pyrazolo[1,5-a]pyridin-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0406] Step 1: Synthesis of dimethyl 2-(pyrazolo[1,5-a]pyridin-5-yl)malonate (Intermediate 45-2)

[0407] At room temperature, 5-bromopyrazolo[1,5-a]pyridine (1.00 g, 4.88 mmol) was dissolved in toluene (10 mL), and dimethyl malonate (0.65 g, 4.88 mmol), Pd2(dba)3 (0.40 g, 0.49 mmol), X-phos (0.42 g, 0.98 mmol), and cesium carbonate (1.87 g, 5.74 mmol) were added. The reaction was terminated at 108°C for 16 h. Filtered through celite and concentrated to obtain 1.30 g of a yellow oily liquid. The product did not need to be purified and could be used directly in the next reaction. Step 2: Synthesis of 2-(pyrazolo[1,5-a]pyridin-5-yl)malonic acid (Intermediate 45-3)

[0408] Intermediate 45-2 (1.30 g, 4.88 mmol) was dissolved in EtOH (16 mL) and H₂O (4 mL) at room temperature. NaOH (0.65 g, 16.29 mmol) was added and the reaction was terminated at 100°C for 16 h. The pH was adjusted to 3-4 with dilute hydrochloric acid, extracted with EA, and concentrated to afford 1.00 g of a yellow solid. The product was used directly in the next reaction without purification.

[0409] Step 3: Synthesis of 2-(pyrazolo[1,5-a]pyridin-5-yl)acetic acid (Intermediate 45-4)

[0410] Intermediate 45-3 (1.0 g, 4.25 mmol) was dissolved in HCl / 1,4-dioxane (10 mL) at room temperature and reacted at 100°C for 16 h. The residue was concentrated and purified by column chromatography (ACN / H2O) to give 0.30 g of a white solid in a 33% yield.

[0411] Step 4: Synthesis of 2-(pyrazolo[1,5-a]pyridin-5-yl)acetyl chloride (Intermediate 45-5)

[0412] Dissolve 2-(pyrazolo[1,5-a]pyridin-5-yl)acetic acid (0.15 g, 0.90 mmol) in DCM (3 mL) at room temperature. Slowly add oxalyl chloride (0.14 g, 1.08 mmol) and a catalytic amount of DMF at 0°C. The reaction is terminated by 1 h at room temperature. Concentrate the residue to obtain the product, which can be directly used in the next step without purification.

[0413] Step 5: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(pyrazolo[1,5-a]pyridin-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 45)

[0414] Intermediate 2-2 (0.15 g, 0.41 mmol) was dissolved in ACN (6 mL) at room temperature. DIPEA (0.24 g, 1.67 mmol), Intermediate 45-5 (0.12 g, 0.77 mmol), and DMAP (0.01 g, 0.06 mmol) were slowly added sequentially at 0°C. The reaction was terminated at 60°C for 12 h. The residue was concentrated and purified by column chromatography (EA / PE system) to afford 0.02 g of a light yellow solid (13% yield). MS (ESI) m / z: 488.5 [M+H] +1HNMR(400MHz,DMSO-d6)δ8.86(d,J=2.0Hz,1H),8.70(dd,J=7.5,1.4Hz,1H),8.00(d,J=2.3Hz,1H),7.74–7.69(m,1H),7.5 4–7.48(m,2H),7.45–7.38(m,3H),7.10(d,J=2.0Hz,1H),6.85(d,J=1.9Hz,1H),6.81(s,2H),6.63(dd,J=2.3,0.9Hz,1H).

[0415] Example 46. Synthesis of 4-amino-3-(1H-benzo[d][1,2,3]triazol-6-yl)-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0416] Step 1: Synthesis of tert-butyl 6-bromo-1H-benzo[d][1,2,3]triazole-1-carboxylate (Intermediate 46-2)

[0417] 6-Bromo-1H-benzo[d][1,2,3]triazole (0.50 g, 2.52 mmol) was dissolved in DCM (8 mL) at room temperature. (Boc)2O (1.10 g, 5.04 mmol) and triethylamine (0.77 g, 7.56 mmol) were added and the reaction was terminated at room temperature for 6 h. The reaction solution was purified by column chromatography (PE / EA system) to obtain 0.47 g of a colorless oily liquid in a 62% yield.

[0418] Step 2: Synthesis of tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole-1-carboxylate (Intermediate 46-3)

[0419] Intermediate 46-2 (0.47 g, 1.58 mmol) and pinacol diboronate (0.61 g, 2.37 mmol) were dissolved in anhydrous 1,4-dioxane (6 mL) at room temperature. Pd(dppf)Cl2 (0.12 g, 0.16 mmol) and potassium acetate (0.31 g, 3.16 mmol) were added, and the reaction was terminated at 100°C for 16 h. The product was filtered through celite and purified by column chromatography (PE / EA system) to obtain 0.37 g of a yellow oily liquid in a 68% yield.

[0420] Step 3: Synthesis of 4-amino-3-(1H-benzo[d][1,2,3]triazol-6-yl)-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 46)

[0421] At room temperature, intermediate 34-3 (0.07 g, 0.15 mmol) was dissolved in anhydrous 1,4-dioxane (6 mL) and H2O (2 mL). Intermediate 46-3 (0.08 g, 0.31 mmol), Pd(dppf)Cl2 (0.011 g, 0.015 mmol), and potassium carbonate (0.062 g, 0.45 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through celite and purified by column chromatography (PE / EA system) to afford 0.010 g of a yellow solid in an 11% yield. MS (ESI) m / z: 489.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ15.70(s,1H),8.86(d,J=1.8Hz,1H),8.11–7.99(m,1H),7.87– 7.68(m,1H),7.59–7.48(m,3H),7.43–7.39(m,3H),7.11(d,J=1.9Hz,1H),6.61(s,2H).

[0422] Example 47. Synthesis of 4-amino-7-chloro-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0423] Step 1: Synthesis of 5-chloro-3-((4-(difluoromethoxy)phenyl)amino)pyridinecarbonitrile (Intermediate 47-2)

[0424] At room temperature, 3-bromo-5-chloropyridinecarbonitrile (1.00 g, 4.60 mmol), 4-difluoromethoxyaniline (0.88 g, 5.50 mmol), palladium acetate (0.10 g, 0.46 mmol), BINAP (0.29 g, 0.46 mmol), and cesium carbonate (3.00 g, 9.20 mmol) were added to a single-necked flask in sequence. The mixture was dissolved in 1,4-dioxane (50 mL) and the reaction was terminated at 100°C for 3 h. The mixture was concentrated and purified by column chromatography (PE / EA) to afford 0.90 g of a yellow solid in a 66% yield. Step 2: Synthesis of N-(5-chloro-2-cyanopyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 47-3)

[0425] At room temperature, intermediate 47-2 (0.90 g, 3.04 mmol) and KOH (0.60 g, 9.12 mmol) were added to a single-necked flask, dissolved in acetic anhydride (10 mL), and reacted at 120°C for 3 h. The mixture was cooled, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.50 g of a light yellow solid, in a 49% yield.

[0426] Step 3: Synthesis of 4-amino-7-chloro-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 47-4)

[0427] At room temperature, intermediate 47-3 (0.50 g, 1.48 mmol) was added to a single-necked flask and dissolved in anhydrous THF (5 mL). NaH (0.18 g, 4.44 mmol) was added at 0°C and the reaction was terminated at room temperature for 8 h. The mixture was cooled, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.16 g of a light yellow solid, in a 32% yield.

[0428] Step 4: Synthesis of 4-amino-3-bromo-7-chloro-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 47-5)

[0429] Intermediate 47-4 (0.16 g, 0.47 mmol) was added to a single-necked flask at room temperature and dissolved in THF (5 mL). N-bromosuccinimide (0.09 g, 0.52 mmol) was added at 0°C and the reaction was terminated at room temperature for 0.5 h. The product was extracted with EA, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 0.22 g of a pale yellow solid, which was used directly in the next step without purification.

[0430] Step 5: Synthesis of 4-amino-7-chloro-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 47)

[0431] At room temperature, intermediate 47-5 (0.07 g, 0.16 mmol), potassium carbonate (0.04 g, 0.32 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.06 g, 0.24 mmol), and Pd(dppf)Cl2 (0.02 g, 0.02 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plating (MeOH / DCM) to afford 0.02 g of a light yellow solid (27% yield). MS (ESI) m / z: 468.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=2.0Hz,1H),8.20(s,1H),7.70(d,J=8.3Hz,1H),7. 57–7.35(m,6H),7.22–7.19(m,1H),6.94(d,J=2.1Hz,1H),6.32(s,2H),3.84(s,3H).

[0432] Example 48. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-7-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0433] Step 1: Synthesis of 1-(5-bromo-2-nitrophenyl)-4-methylpiperazin-2-one (Intermediate 48-2)

[0434] At room temperature, 1-methyl-3-oxopiperazine (1.00 g, 8.80 mmol) was added to a single-necked flask. NaH (0.48 g, 12.00 mmol) was then added using DMF (40 mL). After 0.5 h, 2-fluoro-4-bromonitrobenzene (1.76 g, 8.00 mmol) was added. The reaction was terminated at room temperature for 16 h. The reaction was quenched by addition of saturated aqueous ammonium chloride at 0°C, concentrated, and purified (ACN / H2O system) to afford 0.80 g of a yellow solid in a 32% yield.

[0435] Step 2: Synthesis of 7-bromo-2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (Intermediate 48-3)

[0436] At room temperature, intermediate 48-2 (0.80 g, 2.55 mmol) was added to a single-necked flask and dissolved in acetic acid (10 mL). Iron powder (0.60 g) was added and the reaction was terminated by heating to 110°C for 1 h. The mixture was cooled, concentrated, and purified by column chromatography (MeOH / DCM) to afford 0.65 g of a yellow solid (96% yield).

[0437] Step 3: Synthesis of 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (Intermediate 48-4)

[0438] At room temperature, intermediate 48-3 (0.65 g, 2.44 mmol), potassium acetate (0.35 g, 3.66 mmol), pinacol diboronate (0.93 g, 3.66 mmol), and Pd(dppf)Cl2 (0.18 g, 0.24 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (20 mL) and the reaction was terminated at 100°C for 3 h. The mixture was cooled, filtered, concentrated, and purified by column chromatography (MeOH / DCM) to afford 0.60 g of a light yellow solid (78% yield).

[0439] Step 4: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-7-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 48)

[0440] At room temperature, intermediate 34-3 (0.60 g, 1.33 mmol), potassium carbonate (0.28 g, 2.00 mmol), intermediate 48-4 (0.50 g, 1.60 mmol), and Pd(dppf)Cl2 (0.10 g, 0.13 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (20 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (MeOH / DCM) to obtain 0.38 g of a light yellow solid, in a 51% yield. MS (ESI) m / z: 557.6 [M+H] +1H NMR(400MHz, DMSO-d6)δ8.84(d,J=1.8Hz,1H),7.62(d,J=8.2Hz,1H),7.56–7.38(m,6H),7.23–7.19(m,1H), 7.09(d,J=1.9Hz,1H),6.42(s,2H),4.15(t,J=5.5Hz,2H),3.78(s,2H),2.94(t,J=5.5Hz,2H),2.47(s,3H).

[0441] Example 49. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0442] Step 1: Synthesis of 3-((4-(difluoromethoxy)phenyl)amino)-5-ethoxypyridinecarbonitrile (Intermediate 49-2)

[0443] 3-Bromo-5-ethoxypyridinecarbonitrile (1.00 g, 5.48 mmol) was added to a single-necked flask at room temperature and dissolved in 1,4-dioxane (20 mL). 4-(Difluoromethoxy)aniline (0.87 g, 5.48 mmol), cesium carbonate (3.57 g, 10.96 mmol), BINAP (0.69 g, 1.10 mmol), and palladium acetate (0.25 g, 1.10 mmol) were then added sequentially at room temperature. The reaction was terminated under N₂ for 16 h at room temperature. The mixture was filtered through celite, concentrated, and purified by column chromatography (EA / PE system) to afford 0.75 g of a yellow solid (45% yield).

[0444] Step 2: Synthesis of N-(2-cyano-5-ethoxypyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 49-3)

[0445] Intermediate 49-2 (0.75 g, 2.46 mmol) was added to a single-necked flask at room temperature and dissolved in acetic anhydride (7 mL). KOH (0.41 g, 7.37 mmol) was added at room temperature and the reaction was terminated at 120°C for 16 h. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, and the product was extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to afford 0.53 g of a yellow solid in a 62% yield.

[0446] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-1,5-naphthyridin-2(1H)-one (Intermediate 49-4)

[0447] At room temperature, intermediate 49-3 (0.20 g, 2.46 mmol) was added to a single-necked flask and dissolved in THF (4 mL). Potassium tert-butoxide (0.19 g, 1.73 mmol) was added at room temperature and the reaction was terminated at room temperature for 5 min. The product was concentrated and purified by column chromatography (EA / PE system) to afford 0.20 g of the crude product, which was then slurried in DCM to afford 0.15 g of a yellow solid, a 75% yield.

[0448] Step 4: Synthesis of 4-amino-3-bromo-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-1,5-naphthyridin-2(1H)-one (Intermediate 49-5)

[0449] At room temperature, intermediate 49-4 (0.10 g, 0.29 mmol) was added to a single-necked flask and dissolved in THF (2 mL). NBS (0.06 g, 0.32 mmol) was added at room temperature and the reaction was terminated at room temperature for 10 min. The product was diluted with DCM, washed with saturated sodium bicarbonate solution, concentrated, and slurried with DCM / PE to afford 0.09 g of a yellow solid (73% yield).

[0450] Step 5: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 49)

[0451] Intermediate 49-5 (0.09 g, 0.22 mmol) was added to a single-necked flask at room temperature and dissolved in 1,4-dioxane (2 mL) and H₂O (0.5 mL). 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.08 g, 0.32 mmol), cesium carbonate (0.14 g, 0.44 mmol), and Pd(dppf)Cl₂ (0.02 g, 0.022 mmol) were added sequentially at room temperature. The reaction was terminated at 100°C under N₂ for 16 h. The mixture was filtered through celite, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.02 g of an ochre-colored solid in a 19% yield. MS (ESI) m / z: 478.6 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.26(s,1H),8.12(s,1H),7.68(d,J=8.3Hz,1H),7.57-7.19(m,7 H), 6.29 (s, 1H), 6.16 (s, 2H), 4.02 (q, J = 6.8Hz, 2H), 3.84 (s, 3H), 1.30 (t, J = 6.9Hz, 3H).

[0452] Example 50. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-methyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0453] Step 1: Synthesis of 3-((4-(difluoromethoxy)phenyl)amino)-5-methylpyridinecarbonitrile (Intermediate 50-2)

[0454] At room temperature, 3-bromo-5-methylpyridinecarbonitrile (1.00 g, 5.08 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (20 mL). 4-(Difluoromethoxy)aniline (0.81 g, 5.08 mmol), cesium carbonate (3.30 g, 10.15 mmol), BINAP (0.64 g, 1.02 mmol), and palladium acetate (0.23 g, 1.02 mmol) were then added sequentially at room temperature. The reaction was terminated under N₂ for 16 h at room temperature. The mixture was filtered through celite, concentrated, and purified by column chromatography (EA / PE system) to afford 0.95 g of a yellow solid in a 68% yield.

[0455] Step 2: Synthesis of N-(2-cyano-5-methylpyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 50-3)

[0456] Intermediate 50-2 (0.95 g, 3.45 mmol) was added to a single-necked flask at room temperature and dissolved in acetic anhydride (7 mL). KOH (0.58 g, 10.35 mmol) was added at room temperature and the reaction was terminated at 120°C for 16 h. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the product was extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to afford 0.40 g of a yellow solid in a 37% yield.

[0457] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-methyl-1,5-naphthyridin-2(1H)-one (Intermediate 50-4)

[0458] At room temperature, intermediate 50-3 (0.20 g, 0.63 mmol) was added to a single-necked flask and dissolved in THF (4 mL). Potassium tert-butoxide (0.19 g, 1.73 mmol) was added at room temperature and the reaction was terminated at room temperature for 5 min. The reaction solution was concentrated and purified by column chromatography (EA / PE system) to obtain 0.17 g of a yellow solid, with a yield of 85%.

[0459] Step 4: Synthesis of 4-amino-3-bromo-1-(4-(difluoromethoxy)phenyl)-7-methyl-1,5-naphthyridin-2(1H)-one (Intermediate 50-5)

[0460] At room temperature, intermediate 50-4 (0.10 g, 0.32 mmol) was added to a single-necked flask and dissolved in THF (2 mL). N-bromosuccinimide (0.06 g, 0.35 mmol) was added at room temperature and the reaction was terminated at room temperature for 10 min. The product was diluted with DCM, washed with saturated sodium bicarbonate solution, concentrated, and slurried in DCM / PE to afford 0.08 g of a yellow solid (63% yield).

[0461] Step 5: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-methyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 50)

[0462] Intermediate 50-5 (0.08 g, 0.20 mmol) was added to a single-necked flask at room temperature and dissolved in 1,4-dioxane (2 mL) and H₂O (0.5 mL). 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.08 g, 0.30 mmol), cesium carbonate (0.13 g, 0.40 mmol), and Pd(dppf)Cl₂ (0.02 g, 0.02 mmol) were added sequentially at room temperature. The reaction was terminated at 100°C under N₂ for 16 h. The mixture was filtered through celite, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.02 g of an ochre-colored solid in a 22% yield. MS (ESI) m / z: 448.5 [M+H] + 1 H NMR (400MHz, DMSO-d6) δ8.35(s,1H),8.19(s,1H),7.68(d,J=8.3Hz,1H),7.55( s,1H),7.47-7.19(m,6H),6.64(s,1H),6.32(s,2H),3.84(s,3H),2.32(s,3H).

[0463] Example 51. Synthesis of 4-amino-1-(4-difluoromethoxy)phenyl)-3-(furan-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0464] Step 1: Synthesis of 4-amino-1-(4-difluoromethoxy)phenyl)-3-(furan-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0465] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (PE / EA system) to give 0.021 g of a yellow solid (30% yield). MS (ESI) m / z: 438.0 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.02(s,1H),7.78(s,1H),7.62–7.22(m,5H),7.06(s,1H),6.84(s,1H),6.71(s,2H).

[0466] Example 52. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-ethyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0467] Step 1: Synthesis of 2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (Intermediate 52-2)

[0468] At room temperature, 5-bromo-2-ethyl-2H-indazole (0.20 g, 0.89 mmol), bis(pinacolato) borate (0.15 g, 1.34 mmol), potassium acetate (0.20 g, 1.98 mmol), and Pd(dppf)Cl2 (0.01 g, 0.09 mmol) were added to a single-necked flask, dissolved in 1,4-dioxane (10 mL), and the reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.12 g of a light yellow solid with a yield of 50%.

[0469] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-ethyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 52)

[0470] At room temperature, intermediate 34-3 (0.07 g, 0.17 mmol), potassium carbonate (0.03 g, 0.28 mmol), intermediate 52-2 (0.03 g, 0.27 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (MeOH / DCM system) to obtain 0.032 g of a light yellow solid, with a yield of 45%. MS (ESI) m / z: 516.6 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=2.0Hz,1H),8.40(s,1H),7.72(t,J=1.2Hz,1H),7.65(d,J=8.9Hz,1H),7.53–7.48(m,2H) ,7.41(d,J=8.4Hz,3H),7.23–7.19(m,1H),7.09(d,J=2.0Hz,1H),6.40(s,2H),4.48(q,J=7.3Hz,2H),1.52(t,J=7.3Hz,3H).

[0471] Example 53. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-isopropyl-1H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0472] Step 1: Synthesis of 5-bromo-1-isopropyl-1H-indazole (Intermediate 53-2)

[0473] At room temperature, 1-isopropyl-1H-indazole (0.40 g, 1.69 mmol), potassium carbonate (0.42 g, 3.38 mmol), and isopropyl iodide (0.40 g, 3.38 mmol) were added to a single-necked flask. The mixture was dissolved in DMF (10 mL) and allowed to react at room temperature for 3 h. Water was added, the mixture was extracted with EA, washed with saturated brine, and purified by column chromatography (PE / EA system) to obtain 0.20 g of a light yellow solid, with a yield of 45%.

[0474] Step 2: Synthesis of 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate 53-3)

[0475] At room temperature, intermediate 53-2 (0.20 g, 0.89 mmol), pinacol diboronate (0.15 g, 1.34 mmol), potassium acetate (0.20 g, 1.98 mmol), and Pd(dppf)Cl2 (0.01 g, 0.09 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and the reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to obtain 0.12 g of a light yellow solid (50% yield).

[0476] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-isopropyl-1H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 53)

[0477] At room temperature, intermediate 34-3 (0.07 g, 0.17 mmol), potassium carbonate (0.03 g, 0.28 mmol), intermediate 53-3 (0.03 g, 0.27 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (MeOH / DCM system) to obtain 0.040 g of a light yellow solid, with a yield of 51%. MS (ESI) m / z: 530.6 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.85(dd,J=1.9,0.8Hz,1H),8.09(s,1H),7.79–7.74(m,2H),7.54–7.50(m,5H ),7.44–7.36(m,1H),7.09(d,J=2.1Hz,1H),6.43(s,2H),2.51(p,J=1.9Hz,1H),1.52(d,J=6.6Hz,6H).

[0478] Example 54. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-isopropyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0479] Step 1: Synthesis of 2-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (Intermediate 54-1)

[0480] At room temperature, 5-bromo-2-isopropyl-2H-indazole (0.20 g, 0.89 mmol), bis(pinacolato) borate (0.15 g, 1.34 mmol), potassium acetate (0.20 g, 1.98 mmol), and Pd(dppf)Cl2 (0.01 g, 0.09 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and the reaction was terminated at 100°C for 3 h. The mixture was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.12 g of a light yellow solid, with a yield of 50%.

[0481] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-isopropyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 54).

[0482] At room temperature, intermediate 34-3 (0.07 g, 0.17 mmol), potassium carbonate (0.03 g, 0.28 mmol), intermediate 54-1 (0.03 g, 0.27 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (MeOH / DCM system) to obtain 0.038 g of a light yellow solid, with a yield of 50%. MS (ESI) m / z: 530.6 [M+H] +1 H NMR(400MHz, DMSO-d6)δ8.87–8.82(m,1H),8.04(d,J=0.9Hz,1H),7.80–7.75(m,2H),7 .51(d,J=6.6Hz,6H),7.12–7.06(m,1H),6.42(s,2H),2.50(s,1H),1.26–1.07(m,6H).

[0483] Example 55. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-cyclopropyl-1H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0484] Step 1: Synthesis of 5-bromo-1-cyclopropyl-1H-indazole (Intermediate 55-2)

[0485] At room temperature, 5-bromo-2H-indazole (0.40 g, 1.69 mmol), potassium carbonate (0.42 g, 3.38 mmol), and iodocyclopropane (0.40 g, 3.38 mmol) were added to a single-necked flask. The mixture was dissolved in DMF (10 mL) and allowed to react at room temperature for 3 h. Water was added, the mixture was extracted with EA, washed with saturated brine, and purified by column chromatography (PE / EA system) to obtain 0.20 g of a light yellow solid, in a 45% yield.

[0486] Step 2: Synthesis of 1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate 55-3)

[0487] At room temperature, intermediate 55-2 (0.20 g, 0.89 mmol), pinacol diboronate (0.15 g, 1.34 mmol), potassium acetate (0.20 g, 1.98 mmol), and Pd(dppf)Cl2 (0.01 g, 0.09 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and the reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.12 g of a light yellow solid (50% yield).

[0488] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-cyclopropyl-1H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 55)

[0489] At room temperature, intermediate 34-3 (0.07 g, 0.17 mmol), potassium carbonate (0.03 g, 0.28 mmol), intermediate 55-3 (0.03 g, 0.27 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (MeOH / DCM system) to obtain 0.034 g of a light yellow solid, with a yield of 48%. MS (ESI) m / z: 528.2 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.43(s,1H),7.72–7.63(m,2H),7.52(s,2H),7.4 5–7.17(m,4H),7.08(s,1H),6.40(s,2H),4.85(p,J=6.6Hz,1H),1.57(d,J=6.6Hz,4H).

[0490] Example 56. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-cyclopropyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0491] Step 1: Synthesis of 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (Intermediate 56-2)

[0492] At room temperature, 5-bromo-2-cyclopropyl-2H-indazole (0.20 g, 0.89 mmol), bis(pinacolato) borate (0.15 g, 1.34 mmol), potassium acetate (0.20 g, 1.98 mmol), and Pd(dppf)Cl2 (0.01 g, 0.09 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and the reaction was terminated at 100°C for 3 h. The mixture was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.12 g of a light yellow solid, with a yield of 50%.

[0493] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-cyclopropyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 56)

[0494] At room temperature, intermediate 34-3 (0.07 g, 0.17 mmol), potassium carbonate (0.03 g, 0.28 mmol), intermediate 56-2 (0.03 g, 0.27 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL) and H2O (2 mL). The reaction was terminated at 100°C for 3 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.033 g of a light yellow solid, with a yield of 43%. MS (ESI) m / z: 528.6 [M+H] +1H NMR (400MHz, DMSO-d6) δ8.84(d,J=1.9Hz,1H),8.48(s,1H),7.69(s,1H),7.63–7.58(m,1H),7.50(d,J=8.6Hz,2H),7.41(d ,J=8.1Hz,3H),7.19(d,J=1.6Hz,1H),7.08(d,J=1.9Hz,1H),6.40(s,2H),4.16(dd,J=7.5,3.7Hz,1H),1.35–1.08(m,4H).

[0495] Example 57. Synthesis of 4-amino-7-(cyclopropylamino)-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0496] Step 1: Synthesis of 3-bromo-5-(cyclopropylamino)pyridinecarbonitrile (Intermediate 57-2)

[0497] 3-Bromo-5-ethoxypyridinecarbonitrile (1.00 g, 5.08 mmol) was added to a single-necked flask at room temperature and dissolved in DMF (20 mL). Cyclopropylamine (0.29 g, 5.08 mmol) and DIPEA (1.29 g, 10.15 mmol) were then added sequentially at room temperature. The reaction was terminated at 80°C for 2 h. Purification by column chromatography (EA / PE system) afforded 1.10 g of a yellow solid in a 91% yield.

[0498] Step 2: Synthesis of 5-(cyclopropylamino)-3-((4-(difluoromethoxy)phenyl)amino)pyridinecarbonitrile (Intermediate 57-3)

[0499] Intermediate 57-2 (1.10 g, 4.62 mmol) was added to a single-necked flask at room temperature and dissolved in 1,4-dioxane (20 mL). 4-(Difluoromethoxy)aniline (0.74 g, 4.62 mmol), cesium carbonate (3.01 g, 9.24 mmol), BINAP (0.57 g, 0.92 mmol), and palladium acetate (0.21 g, 0.92 mmol) were then added sequentially at room temperature. The reaction was terminated under N₂ for 16 h at room temperature. The product was filtered through Celite, concentrated, and purified by column chromatography (EA / PE system) to afford 1.00 g of a yellow solid in a 68% yield.

[0500] Step 3: Synthesis of N-(6-cyano-5-(N-(4-(difluoromethoxy)phenyl)acetamide)pyridin-3-yl)-N-cyclopropylacetamide (Intermediate 57-4)

[0501] Intermediate 57-3 (1.00 g, 3.16 mmol) was added to a single-necked flask at room temperature and dissolved in acetic anhydride (10 mL). KOH (0.53 g, 9.48 mmol) was added at room temperature and the reaction was terminated at 120°C for 16 h. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, extracted with DCM, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to afford 1.10 g of a yellow solid in 87% yield.

[0502] Step 4: Synthesis of N-(8-amino-5-(4-(difluoromethoxy)phenyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)-N-cyclopropylacetamide (Intermediate 57-5)

[0503] At room temperature, intermediate 57-4 (0.90 g, 2.24 mmol) was added to a single-necked flask and dissolved in THF (9 mL). Potassium tert-butoxide (0.76 g, 1.73 mmol) was added at room temperature and the reaction was terminated at room temperature for 5 min. The reaction solution was concentrated and purified by column chromatography (EA / PE system) to obtain 0.80 g of a yellow solid in 89% yield.

[0504] Step 5: Synthesis of 4-amino-7-(cyclopropylamino)-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 57-6)

[0505] At room temperature, intermediate 57-5 (0.80 g, 2.00 mmol) was added to a single-necked flask and dissolved in ethanol (8 mL). 4 mol / L HCl (1 mL) was added and the reaction was terminated at 100°C for 2 h. The reaction solution was concentrated and purified by column chromatography (DCM / MeOH system) to obtain 0.13 g of a yellow solid in an 18% yield. Step 6: Synthesis of 4-amino-3-bromo-7-(cyclopropylamino)-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 57-7)

[0506] At room temperature, intermediate 57-6 (0.13 g, 0.36 mmol) was added to a single-necked flask and dissolved in THF (3 mL). N-bromosuccinimide (0.07 g, 0.40 mmol) was added at room temperature and the reaction was terminated at room temperature for 10 min. The mixture was diluted with DCM, washed with saturated sodium bicarbonate solution, and concentrated to give 0.15 g of a yellow solid (94% yield).

[0507] Step 7: Synthesis of 4-amino-7-(cyclopropylamino)-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 57)

[0508] Intermediate 57-7 (0.15 g, 0.34 mmol) was added to a single-necked flask at room temperature and dissolved in 1,4-dioxane (3 mL) and H₂O (1 mL). 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.11 g, 0.41 mmol), potassium carbonate (0.09 g, 0.68 mmol), and Pd(dppf)Cl₂ (0.03 g, 0.03 mmol) were added sequentially at room temperature. The reaction was terminated at 100°C under N₂ for 16 h. The mixture was filtered through celite, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.04 g of an ochre-colored solid in a 24% yield. MS (ESI) m / z: 489.6 [M+H] + 1 H NMR(400MHz, DMSO-d6)δ8.16(s,1H),8.01(d,J=2.3Hz,1H),7.66(d,J=8.3Hz,1H),7.52(s,1H),7.55-7.20(m,5H),7.18( s,1H),6.92(s,1H),6.08(s,1H),6.01(s,2H),3.84(s,3H),3.18(d,J=5.1Hz,1H),0.61-0.57(m,2H),0.35-0.31(m,2H).

[0509] Example 58. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-pyrrol-3-yl)-7-trifluoromethyl-1,5-naphthyridin-2(1H)one

[0510] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-pyrrol-3-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 58)

[0511] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrrole (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a thick preparative plate (PE / EA system) to give 0.013 g of a yellow solid, in a 19% yield. MS (ESI) m / z: 451.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.82(s,1H),7.59–7.30(m,6H),7.08–6.88(m,2H),6.40(s,3H),3.66(s,3H).

[0512] Example 59. Synthesis of 4-amino-1-((4-difluoromethoxy)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 59)

[0513] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a thick preparative plate (PE / EA system) to obtain 0.021 g of a yellow solid, in a 30% yield. MS (ESI) m / z: 452.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.83(s,1H),8.08(s,1H),7.82(s,1H),7.51–7.38(m,5H),7.03(s,1H),6.63(s,2H),3.89(s,3H).

[0514] Example 60. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-fluoro-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0515] Step 1: Synthesis of 3-((4-(difluoromethoxy)phenyl)amino)-5-fluoropyridinecarbonitrile (Intermediate 60-1)

[0516] To a single-necked flask at room temperature were added 3-bromo-5-fluoropyridinecarbonitrile (2.00 g, 9.95 mmol), 4-(difluoromethoxy)aniline (1.58 g, 9.95 mmol), palladium acetate (0.23 g, 0.99 mmol), BINAP (0.62 g, 0.99 mmol), and cesium carbonate (6.49 g, 19.90 mmol), followed by dissolution with 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times, and the reaction was terminated by heating to 100°C for 5 h. The mixture was cooled and concentrated to obtain a residue, which was purified by column chromatography (EA / PE system) to afford 1.40 g of a yellow solid (50% yield).

[0517] Step 2: Synthesis of N-(2-cyano-5-fluoropyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 60-2)

[0518] Intermediate 60-1 (0.30 g, 1.07 mmol) was dissolved in acetic anhydride (3 mL) at room temperature, and KOH (0.18 g, 3.22 mmol) was added. The reaction was terminated at 120°C for 16 h. The reaction solution was quenched with saturated sodium carbonate solution, extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA system) to afford 0.20 g of a yellow oily liquid in a 58% yield.

[0519] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 60-3)

[0520] At room temperature, intermediate 60-2 (0.20 g, 0.60 mmol) was dissolved in anhydrous THF (4 mL), potassium tert-butoxide (0.21 g, 1.80 mmol) was added, and the reaction was terminated at room temperature for 1 h. The reaction solution was concentrated and purified by column chromatography (PE / EA system) to obtain 0.05 g of a yellow solid, with a yield of 25%.

[0521] Step 4: Synthesis of 4-amino-3-bromo-1-((4-difluoromethoxy)phenyl)-7-fluoro-1,5-naphthyridin-2(1H)one (Intermediate 60-4)

[0522] Intermediate 60-3 (0.05 g, 0.16 mmol) was dissolved in anhydrous THF (3 mL) at room temperature, and N-bromosuccinimide (0.03 g, 0.17 mmol) was added. The reaction was terminated at room temperature for 1 h. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted with EA, dried over anhydrous sodium sulfate, and concentrated to yield 0.07 g of a yellow oily liquid. The product was used directly in the next reaction without purification.

[0523] Step 5: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-fluoro-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 60)

[0524] Intermediate 60-4 (0.07 g, 0.17 mmol) was dissolved in anhydrous 1,4-dioxane (6 mL) and H₂O (2 mL) at room temperature. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.06 g, 0.21 mmol), Pd(dppf)Cl₂ (0.02 g, 0.02 mmol), and potassium carbonate (0.07 g, 0.51 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (DCM / MeOH) to afford 0.04 g of a yellow solid in a 50% yield. MS (ESI) m / z: 452.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.52(d,J=2.4Hz,1H),8.20(s,1H),7.70(d,J=8.3Hz,1H),7.55–7.54(m,1H),7.46(d,J =8.9Hz,2H),7.41–7.36(m,3H),7.20(d,J=6.9Hz,1H),6.77(dd,J=10.4,2.4Hz,1H),6.29(s,2H),3.85(s,3H).

[0525] Example 61. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(methylthio)-1,5-naphthyridin-2(1H)-one

[0526] Step 1: Synthesis of 3-((4-(difluoromethoxy)phenyl)amino)-5-(methylthio)pyridinecarbonitrile (Intermediate 61-1)

[0527] At room temperature, intermediate 60-1 (0.60 g, 2.15 mmol) was dissolved in N,N-dimethylformamide (6 mL), and sodium thiomethoxide (0.23 g, 3.22 mmol) was added. The atmosphere was replaced with N2 three times, and the reaction was terminated by heating to 80°C for 3 h. The reaction solution was cooled, added to ice water, and filtered to obtain 0.96 g of a white solid. The product was used directly in the next reaction without purification.

[0528] Step 2: Synthesis of N-(2-cyano-5-(methylthio)pyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 61-2)

[0529] Intermediate 61-1 (0.31 g, 1.01 mmol) was dissolved in acetic anhydride (4 mL) at room temperature, and KOH (0.34 g, 6.06 mmol) was added. The reaction was terminated at 120°C for 32 h. The reaction solution was quenched with saturated sodium carbonate solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to afford 0.33 g of a yellow oily liquid in a 93% yield.

[0530] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(methylthio)-1,5-naphthyridin-2(1H)-one (Intermediate 61-3)

[0531] Intermediate 61-2 (0.14 g, 0.40 mmol) was dissolved in anhydrous THF (4 mL) at room temperature, and potassium tert-butoxide (0.14 g, 1.20 mmol) was added. The reaction was terminated at room temperature for 1 h. The reaction solution was concentrated and purified by column chromatography (PE / EA) to obtain 0.06 g of a white solid in a yield of 42%.

[0532] Step 4: Synthesis of 4-amino-3-bromo-1-(4-difluoromethoxy)phenyl-7-(methylthio)-1,5-naphthyridin-2(1H)one (Intermediate 61-4)

[0533] Intermediate 61-3 (0.06 g, 0.18 mmol) was dissolved in anhydrous THF (3 mL) at room temperature, and N-bromosuccinimide (0.04 g, 0.20 mmol) was added. The reaction was terminated at room temperature for 1 h. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted with EA, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.07 g of a yellow oily liquid. The product was used directly in the next reaction without purification.

[0534] Step 5: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(methylthio)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 61)

[0535] Intermediate 61-4 (0.07 g, 0.16 mmol) was dissolved in anhydrous 1,4-dioxane (6 mL) and H₂O (2 mL) at room temperature. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole (0.05 g, 0.19 mmol), Pd(dppf)Cl₂ (0.03 g, 0.03 mmol), and potassium carbonate (0.07 g, 0.48 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (DCM / MeOH) to afford 0.022 g of a yellow solid in a 27% yield. MS (ESI) m / z: 480.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.39(d,J=2.0Hz,1H),8.19(s,1H),7.69(d,J=8.3Hz,1H),7.56–7.55(m,1H),7.44(d,J=8 .9Hz,2H),7.39(d,J=7.7Hz,3H),7.22–7.19(m,1H),6.65(d,J=2.0Hz,1H),6.23(s,2H),3.84(s,3H),2.45(s,3H).

[0536] Example 62. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)one

[0537] Step 1: Synthesis of 3-((4-(difluoromethoxy)phenyl)amino)-pyridinecarbonitrile (Intermediate 62-2)

[0538] To a single-necked flask at room temperature were added 3-bromopyridinecarbonitrile (0.40 g, 1.98 mmol), p-methoxydifluoroaniline (0.32 g, 2.94 mmol), palladium acetate (0.04 g, 0.20 mmol), BINAP (0.12 g, 0.20 mmol), and cesium carbonate (1.20 g, 3.86 mmol). The mixture was dissolved in 1,4-dioxane (20 ml). The atmosphere was replaced with N2 three times and the temperature was raised to 100°C for 4 h to terminate the reaction. The mixture was cooled and concentrated to obtain a residue, which was purified by column chromatography (EA / PE system) to afford 0.40 g of a yellow solid (70% yield).

[0539] Step 2: Synthesis of N-(2-cyanopyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 62-3)

[0540] Intermediate 62-2 (0.40 g, 1.31 mmol) was dissolved in acetic anhydride (6 mL) at room temperature, and KOH (0.41 g, 7.24 mmol) was added. The reaction was terminated at 120°C for 24 h. Water was added, and the mixture was extracted with EA. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to obtain 0.33 g of a yellow oily liquid in an 80% yield.

[0541] Step 3: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 62-4)

[0542] At room temperature, intermediate 62-3 (0.25 g, 0.57 mmol) was dissolved in anhydrous THF (8 mL), potassium tert-butoxide (0.21 g, 1.60 mmol) was added, and the reaction was terminated at room temperature for 1 h. The reaction solution was concentrated and purified by column chromatography (PE / EA system) to obtain 0.12 g of a white solid with a yield of 50%.

[0543] Step 4: Synthesis of 4-amino-3-bromo-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 62-5)

[0544] At room temperature, intermediate 62-4 (0.12 g, 0.36 mmol) was dissolved in anhydrous THF (6 mL), and N-bromosuccinimide (0.08 g, 0.40 mmol) was added. The reaction was terminated at room temperature for 1 h. Water was added, and the mixture was extracted with EA and concentrated to obtain 0.13 g of a yellow solid with a yield of 82%.

[0545] Step 5: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 62)

[0546] Intermediate 62-5 (0.07 g, 0.16 mmol) was dissolved in 1,4-dioxane (6 mL) and H₂O (2 mL) at room temperature. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.05 g, 0.19 mmol), Pd(dppf)Cl₂ (0.03 g, 0.03 mmol), and potassium carbonate (0.07 g, 0.48 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (PE / EA system) to afford 0.03 g of a pale yellow solid in a 39% yield. MS (ESI) m / z: 434.5 [M+H] +1H NMR (400MHz, DMSO-d6) δ8.49(dd,J=4.4,1.3Hz,1H),8.20(s,1H),7.70(d,J=8.3Hz,1H),7.56(d,J=1.5Hz,1H),7. 49(d,J=4.4Hz,1H),7.46–7.37(m,5H),7.24–7.18(m,1H),6.97(dd,J=8.5,1.3Hz,1H),6.29(s,2H),3.85(s,3H).

[0547] Example 63. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-methoxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0548] Step 1: Synthesis of 3-bromo-5-methoxypyridinecarbonitrile (Intermediate 63-1)

[0549] Dissolve 3-bromo-5-fluoropyridinecarbonitrile (0.43 g, 2.15 mmol) in methanol (6 mL) at room temperature and add sodium methoxide (0.15 g, 3.22 mmol). The reaction is terminated at 70°C for 4 h. Add water, extract with EA, and concentrate to yield 0.40 g of a white solid. The product can be used directly in the next reaction without purification.

[0550] Step 2: Synthesis of 3-((4-(difluoromethoxy)phenyl)amino)-5-methoxypyridinecarbonitrile (Intermediate 63-2)

[0551] To a single-necked flask at room temperature were added intermediate 63-1 (0.40 g, 1.98 mmol), p-difluoromethoxyaniline (0.32 g, 2.94 mmol), palladium acetate (0.04 g, 0.20 mmol), BINAP (0.12 g, 0.20 mmol), and cesium carbonate (1.20 g, 3.86 mmol). The mixture was dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times and the temperature was raised to 100°C for 4 h. The reaction was terminated after cooling and concentration. The residue was purified by column chromatography (EA / PE system) to afford 0.40 g of a yellow solid in a 70% yield.

[0552] Step 3: Synthesis of N-(2-cyano-5-methoxypyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 63-3)

[0553] Intermediate 63-2 (0.40 g, 1.31 mmol) was dissolved in acetic anhydride (6 mL) at room temperature, and KOH (0.41 g, 7.24 mmol) was added. The reaction was terminated at 120°C for 24 h. Water was added, and the mixture was extracted with EA. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to obtain 0.33 g of a yellow oily liquid in an 80% yield.

[0554] Step 4: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(methoxy)-1,5-naphthyridin-2(1H)-one (Intermediate 63-4)

[0555] At room temperature, intermediate 63-3 (0.25 g, 0.57 mmol) was dissolved in anhydrous THF (8 mL), potassium tert-butoxide (0.21 g, 1.60 mmol) was added, and the reaction was terminated at room temperature for 1 h. The reaction solution was concentrated and purified by column chromatography (PE / EA system) to obtain 0.12 g of a white solid, with a yield of 50%.

[0556] Step 5: Synthesis of 4-amino-3-bromo-1-(4-(difluoromethoxy)phenyl)-7-(methoxy)-1,5-naphthyridin-2(1H)-one (Intermediate 63-5)

[0557] At room temperature, intermediate 63-4 (0.12 g, 0.36 mmol) was dissolved in anhydrous THF (6 mL), and N-bromosuccinimide (0.08 g, 0.40 mmol) was added. The reaction was terminated at room temperature for 1 h. Water was added, and the mixture was extracted with EA and concentrated to obtain 0.13 g of a yellow solid with a yield of 82%.

[0558] Step 6: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-methoxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)one (Example 63)

[0559] Intermediate 63-5 (0.07 g, 0.16 mmol) was dissolved in 1,4-dioxane (6 mL) and H₂O (2 mL) at room temperature. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.05 g, 0.19 mmol), Pd(dppf)Cl₂ (0.03 g, 0.03 mmol), and potassium carbonate (0.07 g, 0.48 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (PE / EA system) to afford 0.017 g of a pale yellow solid in a 20% yield. MS (ESI) m / z: 464.6 [M+H] +1H NMR (400MHz, DMSO-d6) δ8.26(d,J=2.4Hz,1H),8.19(s,1H),7.68(d,J=8.2Hz,1H),7.54(s,1H),7. 48–7.36(m,5H),7.21–7.18(m,1H),6.31(d,J=2.5Hz,1H),6.19(s,2H),3.85(s,3H),3.76(s,3H).

[0560] Example 64. Synthesis of 4-amino-1-((4-difluoromethoxy)phenyl)-3-(2,3-dihydrobenzofuran-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0561] Step 1: Synthesis of 4-amino-1-((4-difluoromethoxy)phenyl)-3-(2,3-dihydrobenzofuran-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 64)

[0562] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 2-(2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a thick preparative plate (PE / EA system) to give 0.024 g of a yellow solid, in a 31% yield. MS (ESI) m / z: 490.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.83 (s, 1H), 7.52–7.36 (m, 5H), 7.25 (s, 1H), 7.11 (dd, J = 8.2, 1.8Hz, 1H), 7. 06(d,J=1.9Hz,1H),6.84(d,J=8.2Hz,1H),6.32(s,2H),4.57(t,J=8.7Hz,2H),3.22(t,J=8.7Hz,2H).

[0563] Example 65. Synthesis of 4-amino-1-((4-difluoromethoxy)phenyl)-3-(2,3-dimethyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0564] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2,3-dimethyl-2H-indazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 65)

[0565] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2H-indazole (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a thick preparative plate (PE / EA system) to give 0.028 g of a yellow solid, in a 34% yield. MS (ESI) m / z: 516.6 [M+H] +1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),7.67(s,1H),7.60–7.39(m,6H),7.17( dd,J=8.9,1.7Hz,1H),7.09(s,1H),6.37(s,2H),4.07(s,3H),2.62(s,3H).

[0566] Example 66. Synthesis of 4-amino-1-((4-difluoromethoxy)phenyl)-3-(2-methylbenzo[d]oxazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0567] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methylbenzo[d]oxazol-5-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 66)

[0568] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (PE / EA system) to give 0.014 g of a yellow solid (18% yield). MS (ESI) m / z: 503.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),7.71(s,1H),7.62(s,1H),7.53–7.31(m,6H),7.09(s,1H),6.47(s,2H),2.64(s,3H).

[0569] Example 67. 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(pyridin-4-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0570] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(pyridin-4-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 67)

[0571] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 4-pyridineboronic acid pinacol ester (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a thick preparative plate (PE / EA system) to obtain 0.016 g of a yellow solid, in a 23% yield. MS (ESI) m / z: 449.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.85 (s, 1H), 8.63 (d, J = 5.0Hz, 2H), 7.53–7.35 (m, 7H), 7.09 (s, 1H), 6.80 (s, 2H).

[0572] Example 68. Synthesis of 4-amino-3-(cinnolin-6-yl)-1-((4-difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one

[0573] Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnoline (Intermediate 68-2)

[0574] At room temperature, 6-bromocinnoline (0.05 g, 0.24 mmol), potassium acetate (0.04 g, 0.48 mmol), bis(pinacolato) borate (0.09 g, 0.36 mmol), and Pd(dppf)Cl2 (0.02 g, 0.02 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and the reaction was terminated at 100°C for 8 h. The mixture was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.050 g of a white solid, which was used directly in the next step without purification.

[0575] Step 2: Synthesis of 4-amino-3-(cinnolin-6-yl)-1-((4-difluoromethoxy)phenyl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)one (Example 68)

[0576] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinnoline (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (PE / EA system) to obtain 0.007 g of a yellow solid, a 9% yield. MS (ESI) m / z: 500.6 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.38(d,J=5.8Hz,1H),8.88(s,1H),8.48(d,J=8.9Hz,1H),8.24(d,J= 5.8Hz,1H),8.12(s,1H),7.94(d,J=8.9Hz,1H),7.60–7.37(m,5H),7.13(s,1H),6.92(s,2H).

[0577] Example 69. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(ethylamino)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0578] Step 1: Synthesis of 3-bromo-5-(ethylamino)pyridinecarbonitrile (Intermediate 69-1)

[0579] At room temperature, 3-bromo-5-fluoropyridinecarbonitrile (0.43 g, 2.15 mmol) was added to a single-necked flask, followed by a 2 mol / L ethylamine solution in THF (1.61 mL, 3.22 mmol). The reaction was terminated at 70°C for 4 h. The organic phase was concentrated and purified by column chromatography (PE / EA system) to afford 0.40 g of a pale yellow solid. The yield was 83%.

[0580] Step 2: Synthesis of 3-((4-(difluoromethoxy)phenyl)amino)-5-(ethylamino)pyridinecarbonitrile (Intermediate 69-2)

[0581] To a single-necked flask at room temperature were added intermediate 69-1 (0.40 g, 1.98 mmol), p-difluoromethoxyaniline (0.32 g, 2.94 mmol), palladium acetate (0.04 g, 0.20 mmol), BINAP (0.12 g, 0.20 mmol), and cesium carbonate (1.20 g, 3.86 mmol). The mixture was dissolved in 1,4-dioxane (20 mL). The atmosphere was replaced with N2 three times and the reaction was terminated by heating to 100°C for 4 h. The residue was cooled and concentrated to obtain a yellow solid, which was purified by column chromatography (EA / PE system) to afford 0.40 g of a yellow solid (70% yield).

[0582] Step 3: Synthesis of N-(6-cyano-5-(N-(4-(difluoromethoxy)phenyl)acetamide)pyridin-3-yl)-N-ethylacetamide (Intermediate 69-3): Intermediate 69-2 (0.40 g, 1.31 mmol) was dissolved in acetic anhydride (6 mL) at room temperature, and KOH (0.41 g, 7.24 mmol) was added. The reaction was terminated at 120°C for 24 h. Water was added, the mixture was extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to afford 0.33 g of a yellow oil in 80% yield.

[0583] Step 4: Synthesis of N-(8-amino-5-(4-(difluoromethoxy)phenyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)-N-ethylacetamide (Intermediate 69-4)

[0584] At room temperature, intermediate 69-3 (0.25 g, 0.57 mmol) was dissolved in anhydrous THF (8 mL), potassium tert-butoxide (0.21 g, 1.60 mmol) was added, and the reaction was terminated at room temperature for 1 h. The reaction solution was concentrated and purified by column chromatography (PE / EA system) to obtain 0.12 g of a white solid, with a yield of 50%.

[0585] Step 5: Synthesis of N-(8-amino-7-bromo-5-(4-(difluoromethoxy)phenyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)-N-ethylacetamide (Intermediate 69-5)

[0586] At room temperature, intermediate 69-4 (0.12 g, 0.36 mmol) was dissolved in anhydrous THF (6 mL), and N-bromosuccinimide (0.08 g, 0.40 mmol) was added. The reaction was terminated at room temperature for 1 h. Water was added, and the mixture was extracted with EA. After concentration, 0.13 g of a yellow solid was obtained, with a yield of 82%.

[0587] Step 6: Synthesis of N-(8-amino-5-(4-(difluoromethoxy)phenyl)-7-(1-methyl-1H-benzo[d]imidazol-6-yl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)-N-ethylacetamide (Intermediate 69-6)

[0588] Intermediate 69-5 (0.07 g, 0.16 mmol) was dissolved in 1,4-dioxane (6 mL) and H₂O (2 mL) at room temperature. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.05 g, 0.19 mmol), Pd(dppf)Cl₂ (0.03 g, 0.03 mmol), and potassium carbonate (0.07 g, 0.48 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (PE / EA system) to afford 0.04 g of a pale yellow solid in a 50% yield.

[0589] Step 7: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(ethylamino)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 69)

[0590] At room temperature, intermediate 69-6 (0.04, 0.08 mmol) was dissolved in ethanol (6 mL) and 4 mol / L hydrochloric acid (2 mL) was added. The reaction was terminated at 90°C for 4 h. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with EA. The organic phase was concentrated, and the solid was dissolved in DCM. Petroleum ether was slowly added dropwise to slurry the mixture, and filtered to obtain 0.028 g of a light yellow solid. The yield was 72%. MS (ESI) m / z: 477.6 [M+H]+ .

[0591] Example 70. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-isopropyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0592] Step 1: Synthesis of 5-bromo-3-((4-(difluoromethoxy)phenyl)amino)pyridinecarbonitrile (Intermediate 70-2)

[0593] At room temperature, 5-bromo-3-fluoropyridinecarbonitrile (2.00 g, 10.00 mmol) was added to a single-necked flask, along with DMSO (30 mL), DIPEA (2.60 g, 20.00 mmol), and p-difluoromethoxyaniline (2.40 g, 15 mmol). The reaction was terminated at 150°C for 6 h. Water was added, extracted with EA, washed with saturated brine, concentrated, and purified by column chromatography (EA / PE system) to afford 2.40 g of a light yellow solid (70% yield).

[0594] Step 2: Synthesis of N-(5-bromo-2-cyanopyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 70-3)

[0595] Intermediate 70-2 (2.40 g, 7.10 mmol) was dissolved in acetic anhydride (20 mL) at room temperature, and KOH (1.19 g, 21.30 mmol) was added. The reaction was terminated at 120°C for 12 h. Water was added, the mixture was extracted with EA, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE / EA system) to obtain 1.7 g of a yellow oil in a 63% yield.

[0596] Step 3: Synthesis of 4-amino-7-bromo-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 70-4)

[0597] Intermediate 70-3 (1.70 g, 4.47 mmol) was dissolved in anhydrous THF (50 mL) at room temperature, and potassium tert-butoxide (1.50 g, 13.42 mmol) was added. The reaction was terminated at room temperature for 1 h. The reaction solution was concentrated and purified by column chromatography (PE / EA system) to obtain 0.80 g of a white solid in a yield of 47%.

[0598] Step 4: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(prop-1-en-2-yl)-1,5-naphthyridin-2(1H)-one (Intermediate 70-5)

[0599] Intermediate 70-4 (0.15 g, 0.39 mmol) was dissolved in 1,4-dioxane (10 mL) and H₂O (2 mL) at room temperature. Isopropenyl borate (0.20 g, 1.17 mmol), Pd(dppf)Cl₂ (0.03 g, 0.04 mmol), and potassium carbonate (0.11 g, 0.78 mmol) were added sequentially. The reaction was terminated at 120°C for 6 h. The organic phase was concentrated and purified by column chromatography (EA / PE) to afford 0.11 g of an off-white solid. The yield was 81%.

[0600] Step 5: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-isopropyl-1,5-naphthyridin-2(1H)-one (Intermediate 70-6)

[0601] At room temperature, intermediate 70-5 (0.15 g, 0.32 mmol) was dissolved in methanol (15 mL), and Pd / C (0.030 g) was added. H2 was replaced three times, and the reaction was terminated at room temperature for 6 h. Pd / C was removed by filtration, and the filtrate was concentrated to obtain 0.10 g of an off-white solid (yield 91%).

[0602] Step 6: Synthesis of 4-amino-3-bromo-1-(4-(difluoromethoxy)phenyl)-7-isopropyl-1,5-naphthyridin-2(1H)-one (Intermediate 70-7)

[0603] At room temperature, intermediate 70-6 (0.10, 0.29 mmol) was dissolved in anhydrous THF (6 mL), and N-bromosuccinimide (0.06 g, 0.32 mmol) was added. The reaction was terminated at room temperature for 1 h. Water was added, and the mixture was extracted with EA and concentrated to obtain 0.10 g of a yellow solid with a yield of 81%.

[0604] Step 7: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-isopropyl-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 70)

[0605] Intermediate 70-7 (0.07 g, 0.16 mmol) was dissolved in 1,4-dioxane (6 mL) and H₂O (2 mL) at room temperature. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.05 g, 0.19 mmol), Pd(dppf)Cl₂ (0.03 g, 0.03 mmol), and potassium carbonate (0.07 g, 0.48 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (PE / EA system) to afford 0.043 g of a pale yellow solid in a 54% yield. MS (ESI) m / z: 476.6 [M+H] +1H NMR (400MHz, DMSO-d6) δ8.45(d,J=1.9Hz,1H),8.20(s,1H),8.01(d,J=12.3Hz,1H),7.59–7.53(m,1H),7.45–7.37(m,5H) ,7.27–7.16(m,1H),6.70(dd,J=8.7,2.3Hz,1H),6.24(s,2H),3.85(s,3H),2.95(q,J=6.9Hz,1H),1.16(d,J=7.0Hz,6H).

[0606] Example 71. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(prop-1-en-2-yl)-1,5-naphthyridin-2(1H)-one

[0607] Step 1: Synthesis of 4-amino-3-bromo-1-(4-(difluoromethoxy)phenyl)-7-(prop-1-en-2-yl)-1,5-naphthyridin-2(1H)-one (Intermediate 71-1): Intermediate 70-5 (0.10 g, 0.29 mmol) was dissolved in anhydrous THF (6 mL) at room temperature. N-bromosuccinimide (0.06 g, 0.32 mmol) was added and the reaction was terminated at room temperature for 1 h. Water was added, the mixture was extracted with EA, and the mixture was concentrated to give 0.10 g of a yellow solid (81% yield).

[0608] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(prop-1-en-2-yl)-1,5-naphthyridin-2(1H)-one (Example 71)

[0609] Intermediate 71-1 (0.07 g, 0.16 mmol) was dissolved in 1,4-dioxane (6 mL) and H₂O (2 mL) at room temperature. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.05 g, 0.19 mmol), Pd(dppf)Cl₂ (0.03 g, 0.03 mmol), and potassium carbonate (0.07 g, 0.48 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (PE / EA system) to afford 0.03 g of a pale yellow solid in a 40% yield. MS (ESI) m / z: 474.6 [M+H] +1H NMR (400MHz, DMSO-d6) δ8.68(d,J=1.9Hz,1H),8.20(s,1H),7.72(s,1H),7.60–7.52(m,1H),7.45(d,J=2.4Hz,2H),7.40(q,J=4.8 ,3.9Hz,3H),7.24–7.19(m,1H),6.86(d,J=1.9Hz,1H),6.27(s,2H),5.46(s,1H),5.26(t,J=1.5Hz,1H),3.85(s,3H),2.02(s,3H).

[0610] Example 72. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methylbenzo[d]thiazol-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

[0611] Step 1: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-3-(2-methylbenzo[d]thiazol-6-yl)-7-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one (Example 72)

[0612] At room temperature, intermediate 34-3 (0.07 g, 0.11 mmol), potassium carbonate (0.04 g, 0.31 mmol), 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (PE / EA system) to give 0.016 g of a yellow solid, in a 19% yield. MS (ESI) m / z: 519.5 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.85(s,1H),8.03(s,1H),7.97(d,J=8.4Hz,1H),7.55–7.35(m,6H),7.10(s,1H),6.56(s,2H),2.83(s,3H).

[0613] Example 73. Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-3-(2-(trifluoromethyl)quinolin-6-yl)-1,5-naphthyridin-2(1H)-one

[0614] Step 1: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)quinoline (Intermediate 73-2)

[0615] At room temperature, 6-bromo-2-(trifluoromethyl)quinoline (0.10 g, 0.36 mmol), potassium acetate (0.07 g, 0.72 mmol), bipyralidoborane (0.13 g, 0.54 mmol), and Pd(dppf)Cl2 (0.02 g, 0.03 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and the reaction was terminated at 100°C for 8 h. The mixture was cooled and concentrated, and the residue was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.11 g of a white solid. The product was used directly in the next reaction without purification.

[0616] Step 2: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-(trifluoromethyl)-3-(2-(trifluoromethyl)quinolin-6-yl)-1,5-naphthyridin-2(1H)-one (Example 73)

[0617] At room temperature, intermediate 73-2 (0.11 g, 0.33 mmol), potassium carbonate (0.06 g, 0.44 mmol), intermediate 34-3 (0.05 g, 0.22 mmol), and Pd(dppf)Cl2 (0.02 g, 0.02 mmol) were added to a single-necked flask. The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL). The reaction was terminated at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (PE / EA system) to obtain 0.025 g of a yellow solid, with a yield of 19%. MS (ESI) m / z: 567.6 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.75(d,J=8.5Hz,1H),8.22(d,J=7.5Hz,2H),8.0 0(d,J=8.7Hz,1H),7.92(d,J=8.9Hz,1H),7.57–7.36(m,5H),7.13(s,1H),6.83(s,2H).

[0618] Example 74. Synthesis of 4-amino-1-(4-difluoromethoxy)phenyl)-3-(1-methyl-1H-benzimidazol-6-yl)-7-(2,2,2-trifluoroethyl)amino-1,5-naphthyridin-2(1H)one

[0619] Step 1: Synthesis of 3-bromo-5-((2,2,2-trifluoroethyl)amino)pyridinecarbonitrile (Intermediate 74-1)

[0620] At room temperature, 3-bromo-5-fluoropicolinonitrile (2.00 g, 9.95 mmol), trifluoroethylamine (2.96 g, 29.85 mmol), and DIPEA (3.88 g, 29.85 mmol) were added to a single-necked flask and dissolved in DMF (20 mL). The reaction was terminated at 100°C for 8 h. The product was extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE / EA system) to obtain 2.51 g of an off-white solid (90% yield).

[0621] Step 2: Synthesis of tert-butyl (5-bromo-6-cyanopyridin-3-yl)(2,2,2-trifluoroethyl)carbamate (Intermediate 74-2)

[0622] Intermediate 74-1 (2.50 g, 8.93 mmol) and DMAP (1.50 g, 11.61 mmol) were added to a single-necked flask at room temperature and dissolved in DCM (20 mL). (Boc)2O (2.14 g, 9.82 mmol) was added and the reaction was terminated at room temperature for 2 h. The product was concentrated, extracted with EA, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.00 g of an off-white solid, which was directly carried on to the next step without purification.

[0623] Step 3: Synthesis of tert-butyl (6-cyano-5-((4-(difluoromethoxy)phenyl)amino)pyridin-3-yl)(2,2,2-trifluoroethyl)carbamate (Intermediate 74-3)

[0624] To a single-necked flask at room temperature was added intermediate 74-2 (3.00 g, 7.89 mmol), 4-difluoromethoxyaniline (1.50 g, 9.47 mmol), cesium carbonate (3.86 g, 11.84 mmol), palladium acetate (0.18 g, 0.79 mmol), and BINAP (0.49 g, 0.79 mmol). The mixture was dissolved in 1,4-dioxane (100 mL) and the reaction was terminated at 100°C for 3 h. The product was cooled, filtered, concentrated, and purified by column chromatography (EA / PE system) to afford 3.20 g of a pale yellow solid, with a two-step yield of 88%.

[0625] Step 4: Synthesis of tert-butyl (6-cyano-5-(N-(4-(difluoromethoxy)phenyl)acetamido)pyridin-3-yl)(2,2,2-trifluoroethyl)carbamate (Intermediate 74-4)

[0626] At room temperature, intermediate 74-3 (3.20 g, 6.99 mmol) and KOH (1.38 g, 20.96 mmol) were added to a single-necked flask, dissolved in acetic anhydride (10 mL), and reacted at 120°C for 3 h. The mixture was cooled, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 1.00 g of a light yellow oil (yield: 29%).

[0627] Step 5: Synthesis of tert-butyl (8-acetylamino-5-(4-(difluoromethoxy)phenyl)-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)(2,2,2-trifluoroethyl)carbamate (Intermediate 74-5)

[0628] At room temperature, intermediate 74-4 (1.00 g, 2.00 mmol) was added to a single-necked flask and dissolved in anhydrous THF (10 mL). NaH (0.24 g, 6.00 mmol) was added at 0°C and the reaction was terminated at room temperature for 8 h. The mixture was cooled, quenched with water, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.28 g of an off-white solid, in a 27% yield.

[0629] Step 6: Synthesis of 4-amino-1-(4-(difluoromethoxy)phenyl)-7-((2,2,2-trifluoroethyl)amino)-1,5-naphthyridin-2(1H)-one (Intermediate 74-6)

[0630] At room temperature, intermediate 74-5 (0.28 g, 0.52 mmol) was added to a single-necked flask and dissolved in EtOH (5 mL). 1 mol / L HCl (2 mL) was added and the reaction was terminated at 80°C for 2 h. The mixture was cooled and concentrated to afford 0.24 g of an off-white solid, which was used directly in the next step without purification.

[0631] Step 7: Synthesis of 4-amino-3-bromo-1-(4-difluoromethoxy)phenyl-7-(2,2,2-trifluoroethyl)amino-1,5-naphthyridin-2(1H)one (Intermediate 74-7)

[0632] At room temperature, intermediate 74-6 (0.24 g, 0.60 mmol) and N-bromosuccinimide (0.07 g, 0.66 mmol) were added to a single-necked flask and dissolved in THF (5 mL). The reaction was terminated at room temperature for 1 h. The mixture was concentrated, dissolved in EA, and washed with saturated sodium bicarbonate. The aqueous phase was discarded, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 0.30 g of a yellow solid. The product was used directly in the next reaction without purification.

[0633] Step 8: Synthesis of 4-amino-1-(4-difluoromethoxy)phenyl)-3-(1-methyl-1H-benzimidazol-6-yl)-7-(2,2,2-trifluoroethyl)amino-1,5-naphthyridin-2(1H)one (Example 74)

[0634] To a single-necked flask at room temperature were added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.05 g, 0.22 mmol), potassium carbonate (0.04 g, 0.29 mmol), intermediate 74-7 (0.07 g, 0.14 mmol), and Pd(dppf)Cl2 (0.01 g, 0.01 mmol). The mixture was dissolved in 1,4-dioxane (5 mL) and H2O (1 mL) and allowed to react at 100°C for 4 h. The product was cooled, filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thick preparative plate (PE / EA system) to afford 0.020 g of a yellow solid (25% yield). MS (ESI) m / z: 531.6 [M+H] +1 H NMR(400MHz,DMSO-d6)1H NMR (400MHz, DMSO-d6) δ8.17(s,1H),8.12(d,J=2.3Hz,1H),7.67(d,J=4.0Hz,1H),7.53–7.50(m,1H),7.42–7.34(m,5H) ,7.19(dd,J=6.8,1.9Hz,1H),7.01(t,J=6.9Hz,1H),6.16(d,J=2.3Hz,1H),6.05(s,2H),4.04–3.95(m,2H),3.84(s,3H).

[0635] Example 75. 4-Amino-7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one

[0636] Step 1: Synthesis of 5-cyclopropyl-3-fluoropyridinecarbonitrile (Intermediate 75-1)

[0637] 5-Bromo-3-fluoropyridinecarbonitrile (1 g, 5.00 mmol) was dissolved in 1,4-dioxane (30 mL) and H₂O (4 mL) at room temperature. Cyclopropylboronic acid (1.72 g, 20 mmol), Pd(dppf)Cl₂ (0.36 g, 0.50 mmol), and potassium carbonate (1.38 g, 10 mmol) were added. The reaction was terminated at 100°C for 4 h. The organic phase was concentrated and purified by column chromatography (PE / EA system) to afford 0.60 g of a pale yellow solid in a 74% yield.

[0638] Step 2: Synthesis of 5-cyclopropyl-3-((4-(difluoromethoxy)phenyl)amino)pyridinecarbonitrile (Intermediate 75-2)

[0639] At room temperature, p-difluoromethoxyaniline (0.71 g, 4.40 mmol) was dissolved in DMF. NaH (0.22 g, 5.55 mmol) was added at 0°C and the reaction was allowed to proceed for 0.5 h. Intermediate 75-1 (0.60 g, 3.70 mmol) was added and the reaction was terminated at room temperature for 2 h. Water was added, the mixture was extracted with EA, washed with saturated brine, concentrated, and purified by column chromatography (EA / PE system) to afford 0.70 g of a yellow solid in a 63% yield.

[0640] Step 3: Synthesis of N-(2-cyano-5-cyclopropylpyridin-3-yl)-N-(4-(difluoromethoxy)phenyl)acetamide (Intermediate 75-3)

[0641] Intermediate 75-2 (0.70 g, 2.32 mmol) was dissolved in acetic anhydride (20 mL) at room temperature, and KOH (0.39 g, 6.96 mmol) was added. The reaction was terminated at 140°C for 24 h. Water was added, and the mixture was extracted with EA. The mixture was dried, concentrated, and purified by column chromatography (PE / EA system) to obtain 0.50 g of a yellow oily liquid in a 63% yield.

[0642] Step 4: Synthesis of 4-amino-7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 75-4)

[0643] At room temperature, intermediate 75-3 (0.50 g, 1.46 mmol) was dissolved in anhydrous THF (25 mL), and potassium tert-butoxide (0.49 g, 4.38 mmol) was added. The reaction was terminated at room temperature for 1 h. The reaction solution was concentrated and purified by column chromatography (PE / EA system) to obtain 0.24 g of a white solid in a yield of 48%.

[0644] Step 5: Synthesis of 4-amino-3-bromo-7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-1,5-naphthyridin-2(1H)-one (Intermediate 75-5)

[0645] At room temperature, intermediate 75-4 (0.10 g, 0.29 mmol) was dissolved in anhydrous THF (6 mL), and N-bromosuccinimide (0.06 g, 0.32 mmol) was added. The reaction was terminated at room temperature for 1 h. Water was added, and the mixture was extracted with EA and concentrated to obtain 0.10 g of a yellow solid (yield 81%).

[0646] Step 6: Synthesis of 4-amino-7-cyclopropyl-1-(4-(difluoromethoxy)phenyl)-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,5-naphthyridin-2(1H)-one (Example 75)

[0647] Intermediate 75-5 (0.07 g, 0.16 mmol) was dissolved in 1,4-dioxane (10 mL) and H₂O (2 mL) at room temperature. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (0.05 g, 0.19 mmol), Pd(dppf)Cl₂ (0.03 g, 0.03 mmol), and potassium carbonate (0.05 g, 0.32 mmol) were added. The reaction was terminated at 100°C for 4 h. The product was filtered through Celite and purified by column chromatography (PE / EA system) to afford 0.021 g of a yellow solid in a 28% yield. MS (ESI) m / z: 474.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.25–8.17(m,2H),7.69(d,J=8.3Hz,1H),7.57–7.53(m,1H),7.43–7.36(m,5H),7.22–7.18(m,1H),6.58 (d,J=1.9Hz,1H),6.21(s,2H),3.84(s,3H),1.99(dt,J=8.6,3.7Hz,1H),1.02(dd,J=6.2,2.1Hz,2H),0.68(dd,J=4.9,2.0Hz,2H)

[0648] Example 76. Synthesis of 5-(4-chlorophenyl)-7-(4-methoxyphenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione Hydrochloride

[0649] Step 1: Synthesis of methyl 2-(4-chlorophenyl)-2-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)acetate (Intermediate 76-3)

[0650] At room temperature, NaH (0.56 g, 14.08 mmol) and DMF (30 mL) were added sequentially to a four-necked flask under N2 protection. Ethyl p-chlorophenylacetate (2.00 g, 10.83 mmol) was added dropwise at 0°C. The reaction was allowed to react for 2 h at room temperature. 3-Chloro-2-cyano-5-trifluoromethylpyridine (2.69 g, 13.00 mmol) was then added dropwise at 0°C. The reaction was terminated by the addition of 3-chloro-2-cyano-5-trifluoromethylpyridine (2.69 g, 13.00 mmol) at room temperature for 2 h. The reaction solution was poured into ice water for quenching, extracted with EA, washed with saturated brine, filtered, and concentrated to obtain a crude brown oil. Purification by column chromatography (EA / PE system) afforded 1.20 g of a light yellow oil (yield: 31%). 1 H NMR (400MHz, CDCl3) δ8.89(s,1H),8.25(s,1H),7.41(d,J=7.1Hz,2H),7.32(d,J=7.4Hz,2H),5.54(s,1H),3.85(s,3H).

[0651] Step 2: Synthesis of 5-(4-chlorophenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Intermediate 76-4)

[0652] At room temperature, intermediate 76-3 (1.20 g, 3.38 mmol) and concentrated hydrochloric acid (5 mL) were added sequentially to a single-necked flask. The mixture was dissolved in 1,4-dioxane (10 mL). The mixture was heated to 100°C for 2 h under N₂ protection and terminated. The mixture was cooled, concentrated, and cooled again. PE was added to precipitate a yellow solid, which was filtered and dried to yield 0.92 g of a yellow solid (80% yield). The product could be directly carried to the next step without purification.

[0653] Step 3: Synthesis of 5-(4-chlorophenyl)-7-(4-methoxyphenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione hydrochloride (Example 76)

[0654] At room temperature, intermediate 76-4 (0.15 g, 0.44 mmol), 4-methoxyphenylboronic acid (0.13 g, 0.88 mmol), anhydrous copper acetate (0.16 g, 0.88 mmol), TEA (0.09 g, 0.88 mmol) were added to a single-necked bottle in sequence. Molecular sieves (2.00 g) were dissolved in DCM (20 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM, washed twice with 1 mol / L HCl, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude brown solid. MBTE was added for dissolution. PE was added to precipitate a khaki solid, which was filtered and dried to obtain 0.15 g of a khaki solid. MS (ESI) m / z: 447.4 [M+H] +1H NMR (400MHz, CDCl3) δ9.17(s,1H),7.86(s,1H),7.41(d,J=8.1Hz,2H),7.17(d,J=8.1Hz,2H),7.07–6.98(m,4H),5.33(s,1H),3.85(s,3H).

[0655] Example 77. 5-(4-chlorophenyl)-7-(2-methyl-2H-indazol-5-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione hydrochloride

[0656] Step 1: Synthesis of 5-(4-chlorophenyl)-7-(2-methyl-2H-indazol-5-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione hydrochloride (Example 77)

[0657] At room temperature, intermediate 76-4 (0.15 g, 0.44 mmol), (2-methyl-2H-indazol-5-yl)boronic acid (0.16 g, 0.88 mmol), anhydrous copper acetate (0.16 g, 0.88 mmol), TEA (0.09 g, 0.88 mmol) were added to a single-necked bottle in sequence. Molecular sieves (1.00 g) were dissolved in DCM (10 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM, washed twice with 1 mol / L HCl, dried, filtered, and concentrated to give 0.15 g of a crude brown solid. Purification on a thick silica gel preparative plate (MeOH / DCM system) afforded 0.02 g of a khaki solid. MS (ESI) m / z: 471.4 [M+H] +1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.43(s,1H),8.07(s,1H),7.69–7.60( m,2H),7.57–7.44(m,4H),7.08(d,J=9.0Hz,1H),5.76(s,1H),4.20(s,3H).

[0658] Example 78. Synthesis of 5-(4-chlorophenyl)-7-(quinolin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)dione

[0659] Step 1: Synthesis of 5-(4-chlorophenyl)-7-(quinolin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)dione (Example 78)

[0660] At room temperature, intermediate 76-4 (0.27 g, 0.79 mmol), 6-quinolineboronic acid (0.27 g, 1.58 mmol), anhydrous copper acetate (0.29 g, 1.58 mmol), TEA (0.16 g, 1.58 mmol) were added to a single-necked bottle in sequence. Molecular sieves (2.00 g) were dissolved in DCM (30 mL) and reacted under O₂ protection at room temperature for 16 h. The product was filtered, extracted with DCM / MeOH, washed twice with 1 mol / L HCl, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude brown solid. Purification on thick preparative silica gel (DCM / MeOH) afforded 0.08 g of a khaki solid (22% yield). MS (ESI) m / z: 468.4 [M+H] +1 H NMR(400MHz, DMSO-d6)δ9.37–9.16(m,2H),8.81(d,J=8.4Hz,1H),8.35–8.26(m,1H),8.15(s,1 H),8.06(s,1H),7.90–7.81(m,2H),7.55(d,J=8.2Hz,2H),7.49(d,J=8.3Hz,2H),5.83(s,1H).

[0661] Example 79. Synthesis of 5-(4-chlorophenyl)-7-(6-methoxypyridin-3-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione Hydrochloride

[0662] Step 1: Synthesis of 5-(4-chlorophenyl)-7-(6-methoxypyridin-3-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione hydrochloride (Example 79)

[0663] At room temperature, intermediate 76-4 (0.15 g, 0.44 mmol), 6-methoxy-3-pyridineboronic acid (0.13 g, 0.88 mmol), anhydrous copper acetate (0.16 g, 0.88 mmol), TEA (0.18 g, 1.76 mmol) were added to a single-necked bottle in sequence. Molecular sieves (1.00 g) were dissolved in DCM (20 mL) and quenched with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM, washed twice with 1 mol / L HCl, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude brown solid. Purification on a thick silica gel prep plate (MeOH / MeOH system) afforded 0.11 g of a brown solid in a 53% yield. MS (ESI) m / z: 448.4 [M+H] +1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.10(s,1H),8.01(s,1H),7.67(dd,J=8.7, 2.5Hz,1H),7.52–7.43(m,4H),6.97(d,J=8.7Hz,1H),5.77(s,1H),3.90(s,3H).

[0664] Example 80. Synthesis of 5-(4-chlorophenyl)-7-(quinoxalin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione Hydrochloride

[0665] Step 1: Synthesis of 5-(4-chlorophenyl)-7-(quinoxalin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione hydrochloride

[0666] At room temperature, intermediate 76-4 (0.15 g, 0.44 mmol), benzopyrazine-6-boronic acid hydrochloride (0.13 g, 0.88 mmol), anhydrous copper acetate (0.16 g, 0.88 mmol), TEA (0.18 g, 1.76 mmol) were added to a single-necked bottle in sequence. Molecular sieves (1.00 g) were dissolved in DCM (20 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filter the filter cake, dissolve it in DCM / MeOH, filter it, extract it, wash it twice with 1 mol / L HCl, dry it over anhydrous sodium sulfate, filter it, and concentrate it to obtain a crude brown solid. Purification on a thick silica gel prep plate (DCM / MeOH system) gave 0.015 g of a khaki solid, a 7% yield. MS (ESI) m / z: 469.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),9.25(s,1H),9.04(d,J=10.3Hz,2H),8.25(d,J=8.9Hz,1H),8.14(s, 1H),8.04(s,1H),7.83(dd,J=8.8,2.1Hz,1H),7.58(d,J=8.1Hz,2H),7.49(d,J=8.2Hz,2H),5.82(s,1H).

[0667] Example 81. Synthesis of 5-(4-bromophenyl)-7-(4-methoxyphenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0668] Step 1: Synthesis of methyl 2-(4-bromophenyl)-2-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)acetate (Intermediate 81-2)

[0669] At room temperature, NaH (0.55 g, 14.15 mmol) was added to a single-necked flask and dissolved in DMF (25 mL). Methyl 2-(4-bromophenyl)acetate (2.50 g, 10.91 mmol) was added dropwise at 0°C under N protection. The reaction was allowed to proceed for 2 h. 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (2.70 g, 13.07 mmol) was added dropwise at 0°C and the reaction was terminated after 16 h at room temperature. The mixture was cooled, quenched with saturated ammonium chloride aqueous solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EA / PE system) to afford 1.00 g of a yellow liquid (yield 21%).

[0670] Step 2: Synthesis of 5-(4-bromophenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Intermediate 81-3)

[0671] At room temperature, intermediate 81-2 (0.90 g, 2.25 mmol) was added to a single-necked flask and dissolved with 1,4-dioxane (4.5 mL) and concentrated hydrochloric acid (4.5 mL). The reaction was heated to 100°C for 2.5 h before termination. The mixture was cooled, concentrated, poured into water, filtered, and the filter cake was rinsed with water and dried under vacuum at 60°C to yield 0.80 g of a yellow solid (92% yield).

[0672] Step 3: Synthesis of 5-(4-bromophenyl)-7-(4-methoxyphenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0673] At room temperature, intermediate 81-3 (0.20 g, 0.52 mmol) was added to a single-necked bottle and dissolved in DCM (6 mL). Triethylamine (0.26 g, 2.60 mmol) was added at room temperature. Molecular sieves (0.60 g), anhydrous copper acetate (0.19 g, 1.04 mmol), and 4-methoxyboric acid (0.16 g, 1.04 mmol) were added under O₂ protection and the reaction was terminated at room temperature for 16 h. The product was filtered through celite, the filtrate was acid-washed, dried, filtered, concentrated, and purified on a thick silica gel prep plate (DCM / MeOH system) to afford 0.13 g of a yellow solid in a 49% yield. MS (ESI) m / z: 491.4 [M+H] +1H NMR (400MHz, DMSO-d6) δ9.21(s,1H),8.04(d,J=2.1Hz,1H),7.60(d,J=8.3Hz,2H),7.41( d,J=8.3Hz,2H),7.18(d,J=8.5Hz,2H),7.03(d,J=8.6Hz,2H),5.65(s,1H),3.80(s,3H).

[0674] Example 82. Synthesis of 5-(2-chlorophenyl)-7-(4-methoxyphenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0675] Step 1: Synthesis of methyl 2-(2-chlorophenyl)-2-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)acetate (Intermediate 82-2)

[0676] At room temperature, NaH (0.70 g, 17.60 mmol) was added to a single-necked flask and dissolved in DMF (25 mL). Methyl 2-(2-chlorophenyl)acetate (2.50 g, 13.54 mmol) was added dropwise at 0°C under N protection. The reaction was allowed to proceed for 2 h. 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (3.30 g, 15.68 mmol) was added dropwise at 0°C and the reaction was terminated after 16 h at room temperature. The mixture was cooled, quenched with saturated ammonium chloride aqueous solution, extracted with EA, washed with saturated brine, dried, filtered, and purified by column chromatography (EA / PE system) to obtain 1.00 g of a yellow liquid (yield 21%).

[0677] Step 2: Synthesis of methyl 2-(2-chlorophenyl)-2-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)acetate (Intermediate 82-3)

[0678] At room temperature, intermediate 82-2 (0.90 g, 2.54 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (4.5 mL) and concentrated hydrochloric acid (4.5 mL). The reaction was heated to 100°C for 2.5 h before termination. The mixture was cooled, concentrated, poured into water, filtered, and the filter cake was rinsed with water and dried under vacuum at 60°C to afford 0.80 g of a yellow solid (92% yield).

[0679] Step 3: Synthesis of 5-(2-chlorophenyl)-7-(4-methoxyphenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 82)

[0680] At room temperature, intermediate 82-3 (0.20 g, 0.59 mmol) was added to a single-necked bottle and dissolved in DCM (6 mL). Triethylamine (0.30 g, 2.95 mmol) was added at room temperature. Molecular sieves (0.60 g), copper acetate (0.21 g, 1.17 mmol), and 4-methoxyboronic acid (0.18 g, 1.17 mmol) were added under O₂ protection and the reaction was terminated at room temperature for 16 h. The product was filtered through celite, the filtrate was acid-washed, dried, filtered, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.14 g of a yellow solid in a 53% yield. MS (ESI) m / z: 447.4 [M+H] +1 H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.86–7.73(m,1H),7.64(s,1H),7.55–7.51(m,1H),7 .48–7.47(m,2H),7.22(d,J=8.1Hz,2H),7.06(d,J=8.1Hz,2H),6.04(s,1H),3.81(s,3H).

[0681] Example 83. Synthesis of 5-(2-chlorophenyl)-7-(quinolin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0682] Step 1: Synthesis of 5-(2-chlorophenyl)-7-(quinolin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 83)

[0683] At room temperature, intermediate 82-3 (0.10 g, 0.29 mmol) was added to a single-necked bottle and dissolved in DCM (3 mL). Triethylamine (0.15 g, 1.45 mmol) was added at room temperature. Molecular sieves (0.30 g), copper acetate (0.11 g, 0.59 mmol), and quinolin-6-ylboronic acid (0.10 g, 0.59 mmol) were added under O₂ protection and the reaction was terminated at room temperature for 16 h. The product was filtered through celite, the filtrate was acid-washed, dried, filtered, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.015 g of a yellow solid in an 11% yield. MS (ESI) m / z: 468.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.26–9.19(m,2H),8.92(d,J=8.1Hz,1H),8.37(d,J=8.8Hz,1H),8.24(s,1H ),7.95–7.93(m,2H),7.83(s,1H),7.70(s,1H),7.60–7.53(m,1H),7.52–7.46(m,2H),6.12(s,1H).

[0684] Example 84. Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-(quinolin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0685] Step 1: Synthesis of methyl 2-(4-(difluoromethoxy)phenyl)acetate (Intermediate 84-2)

[0686] At room temperature, 2-(4-(difluoromethoxy)phenyl)acetic acid (2.00 g, 9.89 mmol) was added to a single-necked flask and dissolved in DCM (5 mL). Oxalyl chloride (5 mL) and a catalytic amount of DMF were added at room temperature. The reaction was allowed to react for 2 h at room temperature. Methanol (2 mL) was added dropwise at 0°C and the reaction was terminated for 16 h at room temperature. The reaction solution was concentrated and poured into water, extracted with EA, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EA / PE system) to obtain 1.30 g of a colorless liquid, with a yield of 61%.

[0687] Step 2: Synthesis of methyl 2-(2-cyano-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(difluoromethoxy)phenyl)acetate (Intermediate 84-3)

[0688] At room temperature, NaH (0.31 g, 7.82 mmol) was added to a single-necked flask and dissolved in DMF (15 mL). Under N protection, intermediate 84-2 (1.30 g, 6.01 mmol) was added dropwise at 0°C. The reaction was allowed to proceed for 2 h. 3-Chloro-5-(trifluoromethyl)pyridinecarbonitrile (1.50 g, 7.21 mmol) was added dropwise at 0°C and the reaction was terminated by the addition of 3-chloro-5-(trifluoromethyl)pyridinecarbonitrile (1.50 g, 7.21 mmol) at 0°C. The ... allowed to proceed for 16 h at room temperature. The product was cooled, quenched with saturated ammonium chloride aqueous solution, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (EA / PE system) to afford 0.60 g of a yellow liquid (yield 26%).

[0689] Step 3: Synthesis of 5-(4-(difluoromethoxy)phenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Intermediate 84-4)

[0690] At room temperature, intermediate 84-3 (0.60 g, 1.55 mmol) was added to a single-necked flask and dissolved in 1,4-dioxane (3 mL) and concentrated hydrochloric acid (3 mL). The reaction was terminated by heating to 100°C for 4 h. The mixture was cooled, concentrated, poured into water, filtered, and the filter cake was rinsed with water. The mixture was dried under vacuum at 60°C to afford 0.27 g of a yellow solid (47% yield).

[0691] Step 4: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-(quinolin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 84)

[0692] At room temperature, intermediate 84-4 (0.20 g, 0.54 mmol) was added to a single-necked bottle and dissolved in DCM (6 mL). Triethylamine (0.27 g, 2.69 mmol) was added successively at room temperature. Molecular sieves (0.60 g), copper acetate (0.19 g, 1.07 mmol), and quinolin-6-ylboronic acid (0.19 g, 1.07 mmol) were added under O₂ protection and the reaction was terminated at room temperature for 16 h. The product was filtered through celite, the filtrate was acid-washed, dried, filtered, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM system) to afford 0.015 g of a yellow solid in an 11% yield. MS (ESI) m / z: 500.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.30–9.11(m,2H),8.86(d,J=8.4Hz,1H),8.35(d,J=8.9Hz,1H),8.17(s,1H),8.0 7(s,1H),7.94–7.83(m,2H),7.58(d,J=8.3Hz,2H),7.33–7.26(m,1H),7.22(d,J=8.1Hz,2H),5.82(s,1H).

[0693] Example 85. Synthesis of 5-(4-bromophenyl)-7-(quinolin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0694] Step 1: Synthesis of 5-(4-bromophenyl)-7-(quinolin-6-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 85)

[0695] At room temperature, intermediate 81-3 (0.20 g, 0.52 mmol) was added to a single-necked bottle and dissolved in DCM (6 mL). Triethylamine (0.26 g, 2.60 mmol) was added at room temperature. Molecular sieves (0.60 g), copper acetate (0.19 g, 1.04 mmol), and quinolin-6-ylboronic acid (0.18 g, 1.04 mmol) were added under O₂ protection and the reaction was terminated at room temperature for 16 h. The product was filtered through celite, acid-washed, dried, filtered, concentrated, and purified on a thick silica gel prep plate (MeOH / DCM) to afford 0.013 g of a yellow solid (5% yield). MS (ESI) m / z: 512.4 [M+H] +1H NMR (400MHz, DMSO-d6) δ9.25(s,1H),9.21(d,J=4.7Hz,1H),8.89(d,J=8.4Hz,1H),8.35(d,J=9.0Hz,1H) ,8.18(s,1H),8.06(s,1H),7.92–7.90(m,2H),7.63(d,J=8.1Hz,2H),7.48(d,J=8.1Hz,2H),5.82(s,1H).

[0696] Example 86. Synthesis of 7-(4-bromophenyl)-5-(4-chlorophenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0697] Step 1: Synthesis of 7-(4-bromophenyl)-5-(4-chlorophenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 86)

[0698] At room temperature, intermediate 76-4 (0.30 g, 0.88 mmol), 4-bromophenylboronic acid (0.35 g, 1.76 mmol), anhydrous copper acetate (0.32 g, 1.76 mmol), TEA (0.18 g, 1.76 mmol) were added to a single-necked bottle in sequence. Molecular sieves (1.00 g) were dissolved in DCM (20 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM, washed twice with 1 mol / L HCl, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.20 g of a brown solid. MS (ESI) m / z: 493.2 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.02(s,1H),7.72(d,J=8.2Hz,2H),7.48(q,J=8.3Hz,4H),7.28(d,J=8.1Hz,2H),5.73(s,1H).

[0699] Example 87. Synthesis of 5-(4-chlorophenyl)-7-(4-trifluoromethoxy)phenyl-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0700] Step 1: Synthesis of 5-(4-chlorophenyl)-7-(4-trifluoromethoxy)phenyl-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 87)

[0701] At room temperature, intermediate 76-4 (0.10 g, 0.29 mmol), p-trifluoromethoxyphenylboronic acid (0.12 g, 0.58 mmol), anhydrous copper acetate (0.11 g, 0.58 mmol), TEA (0.15 g, 1.47 mmol) were added to a single-necked bottle in sequence. Molecular sieves (0.35 g) were dissolved in DCM (5 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM, washed twice with water, dried, filtered, and concentrated to obtain a yellow solid. Purification on a thick silica gel preparative plate (MeOH / DCM system) afforded 0.013 g of a yellow solid, a 9% yield. MS (ESI) m / z: 501.3 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.03 (s, 1H), 7.54–7.49 (m, 4H), 7.47 (d, J = 2.2Hz, 4H), 5.74 (s, 1H).

[0702] Example 88. Synthesis of 5-(4-chlorophenyl)-7-(4-(dimethylphosphoryl)phenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0703] Step 1: Synthesis of 5-(4-chlorophenyl)-7-(4-(dimethylphosphoryl)phenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 88)

[0704] At room temperature, Example 86 (0.10 g, 0.20 mmol), dimethylphosphine oxide (0.03 g, 0.40 mmol), palladium acetate (5 mg, 0.02 mmol), potassium phosphate (0.10 g, 0.24 mmol), and XantPhos (0.01 g, 0.02 mmol) were added sequentially to a microwave vial. The mixture was dissolved in DMF (5 mL), protected with O2, and terminated by microwave heating at 130°C for 1 h. Filtered, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown solid. Slurried with PE / EA and filtered to obtain 0.04 g of a khaki solid, in a 41% yield. MS (ESI) m / z: 493.3 [M+H] + 1 H NMR (400MHz, DMSO-d6) δ9.23(d,J=2.0Hz,1H),8.03(d,J=2.0Hz,1H),7.94–7.89(m,2H),7.52–7.46(m,6H),5.75(s,1H),1.73(s,3H),1.69(s,3H).

[0705] Example 89. Synthesis of 5-(4-chlorophenyl)-7-(4-(difluoromethoxy)phenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0706] Step 1: Synthesis of 5-(4-chlorophenyl)-7-(4-(difluoromethoxy)phenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 89)

[0707] At room temperature, intermediate 76-4 (0.10 g, 0.29 mmol), p-difluoromethoxyphenylboronic acid (0.11 g, 0.58 mmol), anhydrous copper acetate (0.11 g, 0.58 mmol), TEA (0.15 g, 1.47 mmol) were added to a single-necked bottle in sequence. Molecular sieves (0.35 g) were dissolved in DCM (5 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM, washed twice with water, dried, filtered, and concentrated to obtain a yellow solid. Purification on a thick silica gel preparative plate (MeOH / DCM system) afforded 0.011 g of a yellow solid, in an 8% yield. MS (ESI) m / z: 483.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.02(s,1H),7.52–7.44(m,4H),7.38–7.28(m,5H),5.74(s,1H).

[0708] Example 90. Synthesis of 7-(Benzo[d]thiazol-6-yl)-5-(4-chlorophenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0709] Step 1: Synthesis of 7-(benzo[d]thiazol-6-yl)-5-(4-chlorophenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione (Example 90)

[0710] At room temperature, intermediate 76-4 (0.20 g, 0.58 mmol), benzo[d]thiazol-6-ylboronic acid (0.21 g, 1.17 mmol), anhydrous copper acetate (0.21 g, 1.17 mmol), TEA (0.12 g, 1.17 mmol) were added to a single-necked bottle in sequence. Molecular sieves (1.00 g) were dissolved in DCM (30 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM / MeOH, washed twice with 1 mol / L HCl, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown solid. Purification on thick preparative silica gel (DCM / MeOH system) afforded 0.27 g of a khaki solid, a 10% yield. MS (ESI) m / z: 474.3 [M+H] +1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),8.25–8.17(m,1H),8.07(s,1H),7.68(d,J=8.1Hz,1H),7.58–7.48(m,5H),7.39–7.31(m,1H),5.80(s,1H).

[0711] Example 91. Synthesis of 4-(5-(4-chlorophenyl)-6,8-dioxo-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)benzonitrile

[0712] Step 1: Synthesis of 4-(5-(4-chlorophenyl)-6,8-dioxo-3-(trifluoromethyl)-5,8-dihydro-1,7-naphthyridin-7(6H)-yl)benzonitrile (Example 91)

[0713] At room temperature, intermediate 76-4 (0.20 g, 0.58 mmol), 4-cyanophenylboronic acid (0.17 g, 1.17 mmol), anhydrous copper acetate (0.21 g, 1.17 mmol), TEA (0.30 g, 2.94 mmol) were added to a single-necked bottle in sequence. Molecular sieves (0.67 g) were dissolved in DCM (5 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM, washed twice with water, dried, filtered, and concentrated to obtain a brown solid. Purification on a thick silica gel prep plate (DCM / MeOH system) afforded 0.016 g of a yellow solid, a 6% yield. MS (ESI) m / z: 442.4 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.23(s,1H),8.04–7.99(m,3H),7.56(d,J=8.1Hz,2H),7.52(d,J=8.3Hz,2H),7.47(d,J=8.1Hz,2H),5.75(s,1H).

[0714] Example 92. Synthesis of 7-(Benzo[d]oxazol-6-yl)-5-(4-chlorophenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0715] Step 1: Synthesis of benzo[d]oxazol-6-ylboronic acid (Intermediate 92-2)

[0716] At room temperature, 6-bromobenzoxazole (0.50 g, 2.53 mmol), tetrahydroxydiboron (0.34 g, 3.79 mmol), tetramethylammonium acetate (0.67 g, 5.06 mmol), and (AtaPhos)2PdCl2 (20 mg) were added sequentially to a single-necked flask. The mixture was dissolved in THF (20 mL) and MeOH (10 mL). N2 was used for protection and the reaction was terminated by heating to 50°C for 2 h. The mixture was cooled and filtered, and the filtrate was concentrated to obtain a yellow solid. Purification by column chromatography (DCM / MeOH system) gave 0.35 g of a light yellow solid in an 85% yield.

[0717] Step 2: Synthesis of 7-(benzo[d]oxazol-6-yl)-5-(4-chlorophenyl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0718] At room temperature, intermediate 76-4 (0.30 g, 0.88 mmol), intermediate 92-2 (0.29 g, 1.76 mmol), anhydrous copper acetate (0.32 g, 1.76 mmol), TEA (0.18 g, 1.76 mmol) were added to a single-necked bottle in sequence. Molecular sieves (1.00 g) were dissolved in DCM (30 mL) and protected with O2. The reaction was terminated at room temperature for 16 h. Filtered, extracted with DCM, washed twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude brown solid. Purification on thick preparative silica gel (DCM / MeOH system) afforded 0.12 g of a purple solid, a 3% yield. MS (ESI) m / z: 458.4 [M+H] + .

[0719] Example 93. Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-(2-methyl-2H-indazol-5-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0720] Step 1: Synthesis of 5-(4-(difluoromethoxy)phenyl)-7-(2-methyl-2H-indazol-5-yl)-3-(trifluoromethyl)-1,7-naphthyridine-6,8(5H,7H)-dione

[0721] At room temperature, intermediate 76-4 (0.20 g, 0.54 mmol) was added to a single-necked bottle and dissolved in DCM (6 mL). Triethylamine (0.27 g, 2.69 mmol) was added at room temperature. Molecular sieves (0.60 g), copper acetate (0.19 g, 1.07 mmol), (2-methyl-2H-indazol-5-yl)boronic acid (0.19 g, 1.07 mmol), O2 protection, and reaction at room temperature for 16 h. Filter through celite, wash the filtrate with acid, dry, filter, concentrate, and purify on a thick silica gel prep plate (MeOH / DCM system) to give 0.008 g of a yellow solid, 3% yield. MS (ESI) m / z: 501.2 [M+H] +1 H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.42(s,1H),8.08(s,1H),7.66(d,J=9.1Hz,1H),7.62(s,1H),7.53 (d,J=8.8Hz,2H),7.28(t,J=72.0Hz,1H),7.21(d,J=10.8Hz,2H),7.09(s,1H),5.75(s,1H),4.20(s,3H).

[0722] Effect Example 1. Study on in vitro enzyme inhibitory activity of some compounds of the present invention

[0723] Test method: rhMAT2A protein was prepared into a 1.6 μg / mL protein solution using phosphate-free buffer. The target drug concentration was then diluted in a gradient. 40 μL of the MAT2A protein solution and 40 μL of the drug solution were added to an EP tube and incubated for 6 hours. 1.2 mM methionine and 2.4 mM ATP were prepared in phosphate-free buffer, 20 μL of each was mixed to initiate the reaction, and then added to the EP tube containing the drug protein, 40 μL of which was incubated overnight. 10 μL of malachite green reagent A was added to all tubes, mixed, and incubated at room temperature for 10 minutes. 10 μL of malachite green reagent B was added to all tubes, mixed, and incubated at room temperature for 10 minutes. 100 μL of the liquid from the EP tube was added to a 96-well plate. The absorbance of the solution was measured at 620 nm using a microplate reader to calculate the inhibition rate.

[0724] Test results: The results of the in vitro enzyme inhibition activity tests of some compounds of the present invention are shown in Table 1. Where A represents IC 50 <0.01μM; B indicates 0.01μM <IC 50 <0.1μM; C represents 0.1μM <IC 50 <1 μM; D represents IC 50 >1μM.

[0725] Table 1. In vitro inhibitory activity of the example compounds on MAT2A

[0726] Effect Example 2. Study on the pharmacokinetic properties of some compounds of the present invention in vivo

[0727] Mice were weighed and dosed. Approximately 50 μL of whole blood was collected from the orbital venous plexus at 5 min, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after dosing and anticoagulated with EDTA-K2. Blood samples were centrifuged at 4000 rpm / min for 10 min at 4°C. A 20 μL supernatant plasma sample was transferred to an EP tube and immediately stored at -80°C until analysis. 10 μL of plasma sample was transferred to a 96-well plate and 250 μL of acetonitrile (containing an internal standard) was added to precipitate protein. The samples were centrifuged at 4000 rpm / min for 20 min at 4°C. The supernatant was transferred and injected into an LC-MS / MS system for drug concentration analysis. Data were processed using Thermo LC Quan software, and a standard curve was constructed using the internal standard method. The theoretical standard curve concentration was plotted on the horizontal axis, and the peak area ratio (test compound peak area / internal standard peak area) was plotted on the vertical axis. Sample concentrations were calculated using the standard curve. Pharmacokinetic parameters were calculated using WinNonlin 8.2 software.

[0728] Table 2. Pharmacokinetic properties of some compounds of the present invention in mice

[0729] Test results: Some of the compounds of the present invention have good in vivo pharmacokinetic properties. The specific test results are shown in Table 2.

[0730] Effect Example 3. In vivo pharmacodynamic study of some compounds of the present invention

[0731] Test method:

[0732] Cell culture: HCT116 MTAP - / - cells (culture conditions: McCoy's 5A medium + 10% FBS + 1% double antibody, 37°C, 5% CO2).

[0733] Cell collection: Collect HCT116 MTAP cells in the growth phase - / - The tumor cells were cultured and washed three times with McCoy's 5A medium before inoculation. The inoculation site was the right scapula of the experimental animal, with an inoculation density of 2*10 6 cells / 100μL / mouse.

[0734] Grouped dosing: When the average tumor volume reaches 80-150mm 3 At the time of randomization, mice were grouped based on tumor volume, with the coefficient of variation (CV) of tumor volume not exceeding one-third of the mean volume. The day of grouping was defined as day 0, and dosing began on that day. Mice were weighed before dosing, and dosing was based on that day's body weight.

[0735] Experimental observation and data collection: After cell inoculation, the effects of the tumor on the normal behavior of the animals were routinely monitored weekly. Specific content included the activity of the experimental animals, food and water intake, weight gain or loss, eye, fur and other abnormalities. After the start of drug administration, the mice were weighed and dosed daily. The tumor volume was measured twice a week. The tumor volume was calculated as follows: tumor volume (mm 3 ) = 0.52 × tumor long diameter (mm) × tumor short diameter (mm) 2 At the end of the experiment, the following indicators were analyzed: tumor growth curve, mouse body weight curve, tumor weight, and the excised tumors were arranged according to groups and photographed uniformly, and the tumor volume inhibition rate (TGI) was calculated.

[0736] TGI TV (Relative tumor volume inhibition rate) calculation formula:

[0737] V nt : Tumor volume of mouse numbered n on day t;

[0738] V n0 : Tumor volume of mice numbered n on day 0;

[0739] RTV n : Relative tumor volume of mouse numbered n on day t;

[0740] mean RTV treat : Mean RTV value of the drug-treated group;

[0741] mean RTV vehicle : Average RTV of solvent control group;

[0742] Tumor volume and mouse body weight in each group are expressed as mean ± standard deviation (mean ± SD). All data were analyzed using GraphPad Prism 6.0. P < 0.05 was considered significant.

[0743] Table 3. In vivo tumor inhibition effect

[0744] Test results: Some compounds of the present invention have good in vivo pharmacodynamic results. As shown in the table above, compound 13 and compound 21 can significantly inhibit tumor growth at doses of 10 mg / kg / d and 25 mg / kg / d.

[0745] While the present invention has been described with reference to specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be encompassed within the scope of the present invention.

Claims

1. A compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof: Wherein: Ring A is selected from wherein * independently represents respectively in relation to connected to the * end, # indicating separately and independently connected to connected to the # end; R1 is selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1- 6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, 3-8 membered cycloalkylcarbonyl, 3-8 membered cycloalkenylcarbonyl, 3-8 membered heterocyclic group carbonyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkenyloxy or 3-8 membered heterocyclic group oxy, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 5-6 membered heteroaryl, phenyl, 3-8 membered cycloalkylcarbonyl, 3-8 membered cycloalkenylcarbonyl, 3-8 membered heterocyclic group carbonyl, 3-8 membered cycloalkyloxy, 3-8 membered cycloalkenyloxy or 3-8 membered heterocyclic group oxy are unsubstituted or optionally substituted with one to four independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkanoyloxy, C 3-6 cycloalkanoyloxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 substituted by a group of alkynyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group, the heteroatoms of the heterocyclic group and heteroaryl being selected from one or more combinations of N, O or S; R2 and R3 are each independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group is unsubstituted or optionally substituted with one to four groups independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 substituted by a group of alkanecarbonylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic group, 5- to 6-membered heteroaryl or phenyl, and the heteroatoms of the heterocyclic group and heteroaryl are selected from one or more combinations of N, O or S; or R2 and R3 together with the connected N atom form a 3- to 8-membered N-containing heterocyclic group, and the 3- to 8-membered N-containing heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, C 1-6 alkoxycarbonyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 2-8 alkenyl or C 2-8 alkynyl, and the 3- to 8-membered N-containing heterocyclic group may further contain one or more combinations of heteroatoms N, O or S; Ar1 and Ar 11 Each is independently selected from a 3- to 8-membered cycloalkyl which is unsubstituted or optionally substituted with one to four Ra, a 3- to 8-membered heterocyclic group which is unsubstituted or optionally substituted with one to four Ra, a 3- to 8-membered cycloalkenyl which is unsubstituted or optionally substituted with one to four Ra, a phenyl which is unsubstituted or optionally substituted with one to four Ra, a 5- to 6-membered heteroaryl which is unsubstituted or optionally substituted with one to four Ra, and the heteroatoms of the heterocyclic group and heteroaryl are selected from one or more combinations of N, O or S; Each Ra is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, C 3-6 cycloalkylcarbonyloxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, and the heteroatoms of the heterocyclic group are selected from one or more combinations of N, O or S; Ar2 and Ar 22 are each independently selected from an unsubstituted or optionally mono- to tetra-substituted 3- to 8-membered monocyclic group, an unsubstituted or optionally mono- to tetra-substituted 6- to 13-membered bicyclic fused ring group, an unsubstituted or optionally mono- to tetra-substituted 6- to 13-membered bicyclic spiro ring group, an unsubstituted or optionally mono- to tetra-substituted 8- to 21-membered polycyclic fused ring group, an unsubstituted or optionally mono- to tetra-substituted 8- to 21-membered polycyclic spiro ring group, and an unsubstituted or optionally mono- to tetra-substituted 8- to 21-membered polycyclic spiro-fused ring group; Each Rb is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimidyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 6alkanecarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl-R X -, 3-8 membered cycloalkenyl-R X - or 3-8 membered heterocyclic group-R X -, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimidyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkanecarbonylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkyl-R X -, 3-8 membered cycloalkenyl-R X - or 3-8 membered heterocyclic group-R X - is unsubstituted or optionally substituted with one to four independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, C 3-6 cycloalkylcarbonyloxy, C 1-6 alkanecarbonyloxy, C 1-6 alkanecarbamoyloxy, C 2-8 alkynyl, C 2-8 alkenyl, C 1-6 substituted by a group of alkylsulfonyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl, 3- to 8-membered heterocyclic group, phenyl or 5- to 6-membered heteroaryl, and the heteroatoms of the heterocyclic group and heteroaryl are selected from one or more combinations of N, O or S; Each Rx is independently selected from -C 1-6 alkyl-, -C 1-6 alkylaminoC 1-6 alkyl-, -C 1-6 alkoxy-, -C 1-6 alkoxyC 1-6 alkyl- or -(C 1-6 alkyl)2aminoC 1-6 alkyl-.

2. The compound of formula (I) according to claim 1, its isomer or its pharmaceutically acceptable salt: Among them, Ar2 and Ar 22 Each is independently selected from a 3- to 8-membered cycloalkyl group which is unsubstituted or optionally substituted with one to four Rb groups, a 3- to 8-membered heterocyclic group which is unsubstituted or optionally substituted with one to four Rb groups, a 3- to 8-membered cycloalkenyl group which is unsubstituted or optionally substituted with one to four Rb groups, a phenyl group which is unsubstituted or optionally substituted with one to four Rb groups, a 5- to 6-membered heteroaryl group which is unsubstituted or optionally substituted with one to four Rb groups, a 6- to 13-membered bicyclo fused cycloalkyl group which is unsubstituted or optionally substituted with one to four Rb groups, a 6- to 13-membered bicyclo fused cycloalkenyl group which is unsubstituted or optionally substituted with one to four Rb groups, a 6- to 13-membered bicyclo fused heterocyclic group which is unsubstituted or optionally substituted with one to four Rb groups, a 6- to 13-membered bicyclo fused aryl group which is unsubstituted or optionally substituted with one to four Rb groups, a 6- to 13-membered bicyclo fused heteroaryl group which is unsubstituted or optionally substituted with one to four Rb groups, a 6- to 13-membered bicyclo spirocycloalkyl group which is unsubstituted or optionally substituted with one to four Rb groups, a 6- to 13-membered bicyclo spirocycloalkenyl group which is unsubstituted or optionally substituted with one to four Rb groups, a 6- to 13-membered bicyclo spiroheterocyclic group which is unsubstituted or optionally substituted with one to four Rb groups, an 8- to 21-membered tricyclo fused cycloalkyl group which is unsubstituted or optionally substituted with one to four Rb groups, an 8- to 21-membered tricyclo fused cycloalkenyl group which is unsubstituted or optionally substituted with one to four Rb groups, an 8- to 21-membered tricyclo fused heterocyclic group which is unsubstituted or optionally substituted with one to four Rb groups, an 8- to 21-membered tricyclo fused aryl group which is unsubstituted or optionally substituted with one to four Rb groups, an 8- to 21-membered tricyclo fused heteroaryl group which is unsubstituted or optionally substituted with one to four Rb groups, an 8- to 21-membered polycyclo fused spirocycloalkyl group which is unsubstituted or optionally substituted with one to four Rb groups, an 8- to 21-membered polycyclo fused spirocycloalkenyl group which is unsubstituted or optionally substituted with one to four Rb groups, an 8- to 21-membered polycyclo fused spiroheterocyclic group which is unsubstituted or optionally substituted with one to four Rb groups, wherein the heteroatoms of the heterocyclic group and heteroaryl group are selected from one or more combinations of N, O or S, and the C atoms on the ring can be oxidized to C(O).

3. The compound of formula (I) according to claim 1 or 2, its isomer or its pharmaceutically acceptable salt: Among them, Ring A is selected from wherein * independently represents respectively with connected to the * end, # indicating being independently connected to connected to the # end; R1 is selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo-C 1- 6alkylamino, (C 1-6 alkyl)2amino, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8-membered cycloalkyl, 3-8-membered cycloalkenyl, 3-8-membered heterocyclic group, 5-6-membered heteroaryl or phenyl, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo-C 1- 6alkylamino, (C 1-6 alkyl)2amino, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8-membered cycloalkyl, 3-8-membered cycloalkenyl, 3-8-membered heterocyclic group, 5-6-membered heteroaryl or phenyl is unsubstituted or optionally substituted by one to four groups independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo-C 1- 6alkyl, halo-C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, 3-8-membered cycloalkyl, 3-8-membered cycloalkenyl or 3-8-membered heterocyclic group, and the heteroatoms of the heterocyclic group and heteroaryl are selected from one or more combinations of N, O or S; R2 and R3 are each independently selected from hydrogen, C 1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group, wherein the C 1-6 alkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydrogen, deuterium, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl or C 2- 8-ynyl; and the heteroatoms of the heterocyclic group are selected from one or more combinations of N, O or S; or R2 and R3 together with the connected N atom form a 3-8 membered N-containing heterocyclic group, and the 3-8 membered N-containing heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 2-8 alkenyl or C 2-8 alkynyl, and the 3-8 membered N-containing heterocyclic group may further contain one or more combinations of heteroatoms N, O or S; Ar1 and Ar 11 each independently selected from phenyl which is unsubstituted or optionally substituted with one to four Ra, and 5- or 6-membered heteroaryl which is unsubstituted or optionally substituted with one to four Ra, and the heteroatoms of the heteroaryl are selected from one or more combinations of N, O or S; Each Ra is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2-phosphoryl, C 1-6 alkylsulfonimidyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2-phosphoryl, C 1-6 alkylsulfonimidyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2-amino, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 2-8 alkenyl or C 2-8 alkynyl, and the heteroatoms of the heterocyclic group are selected from one or more combinations of N, O or S; Ar2 and Ar 22 are each independently selected from a 5- or 6-membered heterocyclic group which is unsubstituted or optionally substituted with one to four Rb, a phenyl group which is unsubstituted or optionally substituted with one to four Rb, a 5- or 6-membered heteroaryl group which is unsubstituted or optionally substituted with one to four Rb, a 6- to 13-membered bicyclo-fused heterocyclic group which is unsubstituted or optionally substituted with one to four Rb, a 6- to 13-membered bicyclo-fused heteroaryl group which is unsubstituted or optionally substituted with one to four Rb, a 6- to 13-membered bicyclo-fused aryl group which is unsubstituted or optionally substituted with one to four Rb, an 8- to 21-membered tricyclo-fused heterocyclic group which is unsubstituted or optionally substituted with one to four Rb, and an 8- to 21-membered tricyclo-fused spiroheterocyclic group which is unsubstituted or optionally substituted with one to four Rb, wherein the heteroatoms of the heterocyclic group and heteroaryl group are selected from one or more combinations of N, O or S; Each Rb is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimidyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 6-alkylcarbonylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group, wherein said amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimidyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, C 2-8 alkynyl, C 2-8 alkenyl or C 1-6 alkylsulfonyl, and the heteroatoms of said heterocyclic group are selected from one or more combinations of N, O or S.

4. The compound of formula (I) according to any one of claims 1-3, its isomer or its pharmaceutically acceptable salt: Wherein, Ring A is selected from wherein * represents independently of each other and connected to the * end, # indicating separately and independently connected to connected to the # end; R1 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo-C 1-6 alkylamino, halo-C 1-6 alkyl, C 2-8 alkenyl, C 1-6 alkylthio, 3- to 8-membered cycloalkyl or amino substituted by 3- to 8-membered cycloalkyl; R2 and R3 are each independently selected from hydrogen or C 1-6 alkyl; Ar1 and Ar 11 each independently is phenyl or pyridine which is unsubstituted or optionally substituted with one to four Ra; Each Ra is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2-phosphoryl or 3- to 8-membered cycloalkyl; Ar2 and Ar 22 are each independently selected from a 5- or 6-membered heterocyclic group which is unsubstituted or optionally substituted with one to four Rb, a phenyl group which is unsubstituted or optionally substituted with one to four Rb, a 6- to 13-membered bicyclic fused aryl group which is unsubstituted or optionally substituted with one to four Rb, a 5- or 6-membered heteroaryl group which is unsubstituted or optionally substituted with one to four Rb, a 6- to 13-membered bicyclic fused heterocyclic group which is unsubstituted or optionally substituted with one to four Rb, a 6- to 13-membered bicyclic fused heteroaryl group which is unsubstituted or optionally substituted with one to four Rb, an 8- to 21-membered tricyclic fused heterocyclic group which is unsubstituted or optionally substituted with one to four Rb, and an 8- to 21-membered tricyclic fused spiro heterocyclic group, wherein the heteroatoms of the heterocyclic group and heteroaryl group are selected from one or more combinations of N, O or S; Each Rb is independently selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, (C 1- 6alkyl)2phosphoryl, C 1-6 alkylsulfonimidoyl, 3- to 8-membered cycloalkyl or deuterated C 1-6 alkoxy.

5. The compound of formula (I) according to any one of claims 1-4, its isomer or its pharmaceutically acceptable salt: Among them, Ar1 and Ar 11 each independently selected from phenyl which is unsubstituted or optionally substituted with one to four Ra, or Ar2 and Ar 22 are each independently selected from the following groups, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, which are unsubstituted or optionally substituted with one to four Rb In one embodiment, each substituent is independently selected from the following structures, and there may be two or more. When there are two or more substituents, different combinations of groups can be selected: R1 is selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, halo-C 1-3 alkylamino, halo-C 1-3 alkyl, C 2-4 alkenyl, C 1-3 alkylthio, 3- to 6-membered cycloalkyl or amino substituted with 3- to 6-membered cycloalkyl; R2 and R3 are each independently selected from hydrogen or C 1-3 alkyl; Ar1 and Ar 11 each independently is phenyl which is unsubstituted or optionally substituted with one to four Ra; Each Ra is independently selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 alkylthio, (C 1-3 alkyl)2phosphoryl or 3- to 6-membered cycloalkyl; Ar2 and Ar 22 are each independently selected from phenyl or naphthyl which is unsubstituted or optionally substituted with one to four Rb, 5- or 6-membered heteroaryl which is unsubstituted or optionally substituted with one to four Rb, benzo-5- or 6-membered monocyclic heterocyclic group which is unsubstituted or optionally substituted with one to four Rb, 8- to 10-membered bicyclic fused heteroaryl which is unsubstituted or optionally substituted with one to four Rb, 8- to 21-membered tricyclic fused heterocyclic group which is unsubstituted or optionally substituted with one to four Rb; the 8- to 10-membered bicyclic fused heteroaryl refers to a group having 8 to 10 ring atoms formed by fusing a monocyclic heteroaryl ring to a phenyl or monoheteroaryl group; the heteroatoms of the heterocyclic group and heteroaryl are selected from one or more combinations of N, O or S; Each Rb is independently selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, halo-C 1-3 alkyl, halo-C 1-3 alkoxy, (C 1-3 alkyl)2-phosphoryl, C 1-3 alkylsulfonylimide, 3- to 6-membered cycloalkyl or deuterated C 1-3 alkoxy; In one embodiment, Ar1 and Ar 11 each independently is phenyl which is unsubstituted or optionally substituted with one to four Ra; Ra is selected from fluorine, chlorine, bromine, methyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, cyclopropyl, dimethylphosphoryl; Ar2 and Ar 22 each independently selected from the following groups which are unsubstituted or optionally substituted with one to four Rb, phenyl, pyridyl, pyrrolyl, thienyl, furyl, pyrazolyl, Rb is selected from fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, methoxy, deuterated methoxy, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methylthio, cyclopropyl, dimethylphosphoryl, methylsulfonimide; In one embodiment, Ar1 and Ar 11 are each independently selected from In one embodiment, Ar2 and Ar 22 are each independently selected from benzene, 6. The compound of formula (I), its isomer or its pharmaceutically acceptable salt according to any one of claims 1-5, which has the structure shown in general formula (II): R1 is selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1- 6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 5-6 membered heteroaryl or phenyl, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1- 6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 5-6 membered heteroaryl or phenyl unsubstituted or optionally substituted by one to four groups independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1- 6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, and the heteroatoms of the heterocyclic group and heteroaryl are selected from one or more combinations of N, O or S; R2 and R3 are each independently selected from hydrogen, C 1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group, and the C 1-6 alkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from deuterium, hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl or C 2-8 alkynyl, and the heteroatoms of the heterocyclic group are selected from one or more combinations of N, O or S; or R2 and R3 form a 3- to 8-membered heterocyclic group with the connected N atom, and the 3- to 8-membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxyC 1-6 alkoxy, C 1-6 alkylamino, (C 1- 6alkyl)2amino, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 2-8 enyl or C 2-8 alkynyl, and the 3- to 8-membered N-containing heterocyclic group may further contain one or more combinations of heteroatoms N, O or S; Ar1 is selected from phenyl which is unsubstituted or optionally substituted by one to four Ra, 5-6 membered heteroaryl which is unsubstituted or optionally substituted by one to four Ra, and the heteroatoms of the heteroaryl are selected from one or more combinations of N, O or S; Each Ra is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimide, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl or C 2-8 alkynyl, and the heteroatoms of the heterocyclic group are selected from one or more combinations of N, O or S; Ar2 is selected from 5-6 membered heterocyclic group which is unsubstituted or optionally substituted by one to four Rb, phenyl which is unsubstituted or optionally substituted by one to four Rb, 5-6 membered heteroaryl which is unsubstituted or optionally substituted by one to four Rb, 6-13 membered bicycloheterocyclic group which is unsubstituted or optionally substituted by one to four Rb, 6-13 membered bicycloheteroaryl which is unsubstituted or optionally substituted by one to four Rb, 8-21 membered tricycloheterocyclic group which is unsubstituted or optionally substituted by one to four Rb, 8-21 membered tricyclospiroheterocyclic group which is unsubstituted or optionally substituted by one to four Rb, and the heteroatoms of the heterocyclic group and heteroaryl are selected from one or more combinations of N, O or S; the C atoms on the ring can be oxidized to C(O); Each Rb is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2-phosphoryl, C 1-6 alkylsulfonimidoyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 6-alkylcarbonylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group, wherein said amino, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2-phosphoryl, C 1-6 alkylsulfonimidoyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2-amino, C 2-8 alkynyl, C 2-8 alkenyl or C 1-6 alkylsulfonyl, and the heteroatoms of the heterocyclic group are selected from one or more combinations of N, O or S.

7. The compound of formula (I), its isomer or its pharmaceutically acceptable salt according to any one of claims 1-5, which has the structure shown in general formula (III): R1 is selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1- 6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 5-6 membered heteroaryl or phenyl, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halo C 1- 6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkanoyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, C 1-6 alkanoylamino, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclic group, 5-6 membered heteroaryl or phenyl is unsubstituted or optionally substituted by one to four groups independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1- 6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclic group, and the heteroatoms of the heterocyclic group and heteroaryl are selected from one or more combinations of N, O or S; Ar 11 selected from phenyl which is unsubstituted or substituted with one to four Ra's, 5- or 6-membered heteroaryl which is unsubstituted or optionally substituted with one to four Ra's, the heteroatoms of the heteroaryl being selected from one or more combinations of N, O or S; Each Ra is independently selected from hydrogen, deuterium, hydroxy, amino, carboxy, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimidyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonimidyl, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydroxy, amino, carboxy, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 2-8 alkenyl or C 2-8 alkynyl, and the heteroatoms of the heterocyclic group are selected from one or more combinations of N, O or S; Ar 22 selected from a 5- to 6-membered heterocyclic group which is unsubstituted or optionally substituted by one to four Rb, a phenyl group which is unsubstituted or optionally substituted by one to four Rb, a 5- to 6-membered heteroaryl group which is unsubstituted or optionally substituted by one to four Rb, a 6- to 13-membered bicyclo-fused heterocyclic group which is unsubstituted or optionally substituted by one to four Rb, a 6- to 13-membered bicyclo-fused heteroaryl group which is unsubstituted or optionally substituted by one to four Rb, an 8- to 21-membered tricyclo-fused heterocyclic group which is unsubstituted or optionally substituted by one to four Rb, an 8- to 21-membered tricyclo-fused spiroheterocyclic group, the heteroatoms of the heterocyclic group and heteroaryl group are selected from one or more combinations of N, O or S; the C atoms on the ring can be oxidized to C(O); Each Rb is independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, nitro, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonylimide, C 2-8 alkenyl, C 2-8 alkynyl, C 1- 6-alkylcarbonylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group, wherein the amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylthio, (C 1-6 alkyl)2phosphoryl, C 1-6 alkylsulfonylimide, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkylcarbonylamino, 3- to 8-membered cycloalkyl, 3- to 8-membered cycloalkenyl or 3- to 8-membered heterocyclic group is unsubstituted or optionally substituted by one to four groups independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl)2amino, C 2-8 alkynyl, C 2-8 alkenyl or C 1-6 alkylsulfonyl, and the heteroatoms of the heterocyclic group are selected from one or more combinations of N, O or S.

8. The compound of formula (I), its isomer or its pharmaceutically acceptable salt according to any one of claims 1-5, which has the structure shown in general formula (IV): Wherein, R1 is selected from CF3, F, Cl, -CH3, -OCH3, -OCH2CH3, -NHCH2CH3, cyclopropyl, -NHcyclopropyl; Ar2 is selected from benzene, In one embodiment, R1 is selected from CF3, Cl, -OCH3, -NHCH2CH3, cyclopropyl; Ar2 is selected from 9. The compound of formula (I), its isomers or its pharmaceutically acceptable salts according to claim 1, which are selected from the following compounds:

10. A pharmaceutical composition, the pharmaceutical composition comprising the compound according to any one of claims 1-9, its isomer or its pharmaceutically acceptable salt, and optionally comprising at least one pharmaceutically acceptable excipient; for example, the pharmaceutical composition comprises the compound according to any one of claims 1-9, its isomer or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, diluents or excipients.

11. Use of the compound according to any one of claims 1-9, its isomers or its pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for preventing or treating a disease related to the expression or activity of MAT2A.

12. Use according to claim 11, wherein the disease or disorder is selected from tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably a tumor.

13. Use according to claim 12, wherein the tumor is cancer, selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, astrocytoma, ependymoma, glioblastoma multiforme, glioblastoma, neuroblastoma, ganglioneuroma, medulloblastoma, pineal cell tumors, meningioma, neurofibroma, schwannoma, thyroid cancer, Wilms tumor and teratocarcinoma; more preferably selected from non-small cell lung cancer, pancreatic cancer, melanoma, bladder cancer, head and neck squamous cell carcinoma, esophageal cancer and glioblastoma.

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