Methionine adenosyltransferase 2A inhibitors

Abstract

The present invention provides a methionine adenosyltransferase 2A inhibitor, the structure of which is shown in general formula I, the definition of each substituent is as described in the specification, and the present invention further provides a preparation method thereof. The compound of formula I provided in the present invention has significant inhibitory activity against methionine adenosyltransferase 2A, and is used for treating diseases mediated by overexpression of methionine adenosyltransferase 2A. [Formula 1] JPEG2024521900000111.jpg54128

Description

[Technical Field]

[0001] The present invention relates to methionine adenosyltransferase 2A inhibitors for use in the treatment of several cancers. [Background technology]

[0002] Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP and is considered the rate-limiting enzyme in the methionine cycle. SAM is a propylamino donor in polyamine biosynthesis and the major methyl donor for DNA methylation, and is involved in gene transcription, cell proliferation, and secondary metabolite production.

[0003] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosylmethionine (SAM). SAM is the major methyl group donor in cells, used for the methylation of various substrates, including DNA, RNA, and proteins. MTAP (methylthioadenosine phosphorylase) is an enzyme widely expressed in normal tissues and catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthiofuribose-1-phosphate, adenine to adenosine monophosphate, and 5-methylthiofuribose-1-phosphate to methionine and formate. When purine synthesis is blocked, for example, by antimetabolites, MTA can be used as an alternative purine source.

[0004] The gene encoding MTAP resides at a locus on chromosome 9 that is frequently deleted in cells from cancer patients of several tissue origins, including the central nervous system, pancreatic cancer, esophagus, bladder, and lung. Loss of MTAP leads to the accumulation of MTA compared with MTAP-expressing cells, and MTAP-deficient cells are more dependent on SAM production and, consequently, MAT2A activity. In a screen of approximately 400 cancer cell lines, MAT2A knockdown resulted in a greater loss of vitality in MTAP-deficient cells compared with cells normally expressing MTAP. Furthermore, inducible knockdown of MAT2A protein reduced tumor growth in vivo. These results suggest that MAT2A inhibitors may offer a novel therapeutic approach for patients with MTAP-deficient tumors.

[0005] Currently, Chinese patent application CN109890822A discloses pyrazolopyrimidinone MAT2A inhibitors, and WO2020123395A1 discloses 2-oxoquinazoline derivatives as MAT2A inhibitors. The present invention provides novel MAT2A inhibitors. Summary of the Invention

[0006] In one aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof: [ka] (In Formula I, X is CR 4 or N, and Y is selected from CR 5 or N, Z is selected from CR 6 or N, W is selected from CR 7 Or selected from N. where R 1 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, cyano, C2-C6 alkynyl, C8-C10 cycloalkynyl, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 8-, (C1-C6 alkyl)-O-, (C1-C6 alkyl)-S-, C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 10-membered aryl, C2-C6 alkenyl, or C3-C6 cycloalkenyl, and wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O-, C2-C6 alkenyl, C3-C6 cycloalkyl or C3-C6 cycloalkenyl may optionally be selected from the group consisting of halogen, cyano, hydroxy, -NR 8 R 9 , C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, and the 6- to 10-membered aryl is optionally substituted with halogen, hydroxy, cyano, -NR 8 R 9 , NO2, C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, or the 6- to 10-membered aryl is optionally substituted with halogen, hydroxy, cyano, -NR 8 R 9 or is substituted by C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl substituted with NO2.)

[0007] In some embodiments, R 1 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, cyano, C2-C6 alkynyl, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O-, (C1-C6 alkyl)-S-, C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 10-membered aryl, C2-C6 alkenyl group or C3-C6 cycloalkenyl group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or C3-C6 cycloalkenyl optionally may be selected from halogen, cyano, hydroxy, -NR 8 R 9, C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, and the 6- to 10-membered aryl group is optionally substituted with halogen, hydroxy, cyano, -NR 8 R 9 , NO2, C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, or the 6- to 10-membered aryl is optionally substituted with halogen, hydroxy, cyano, -NR 8 R 9 Or substituted by C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl, or C2-C6 alkynyl substituted by NO2. R 2 and R 3 are each independently selected from a 6- to 10-membered aryl or a 9- to 18-membered benzoheterocyclic group, and the 6- to 10-membered aryl or the 9- to 18-membered benzoheterocyclic group optionally contains halogen, hydroxy, cyano, -NR 8 R 9 , NO2, -NR 10 C(O)R 11 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 10 R 11 or 5-7 membered heteroaryl, wherein the C1-C6 alkyl, (C1-C6 alkyl)-O- or 5-7 membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O- or -NR 8 R 9 is replaced by

[0008] In some embodiments, R 2 and R 3 are each independently selected from a 6- to 10-membered aryl or a 9- to 18-membered benzoheterocyclic group, and the 6- to 10-membered aryl or the 9- to 18-membered benzoheterocyclic group optionally contains halogen, hydroxy, cyano, -NR 8 R 9 , NO2, -NR 10 C(O)R 11 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 10 R 11or a 5- to 7-membered heteroaryl, wherein the C1-C6 alkyl or 5- to 7-membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O-, or -NR 8 R 9 is replaced by where R 8 , R 9 , R 10 and R 11 are each independently selected from H or C1 to C6 alkyl. The condition is that at most two of W, X, Y, and Z are simultaneously N.

[0009] In some embodiments, X is CR 4 Selected from.

[0010] In some embodiments, Y is CR 5 Selected from.

[0011] In some embodiments, Z is CR 6 Selected from.

[0012] In some embodiments, W is selected from N.

[0013] In some embodiments, R 1 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl, or 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl optionally may be halogen, cyano, hydroxy or -NR 8 R 9 and the 6- to 10-membered aryl is substituted with C1-C3 alkoxy optionally substituted with halogen.

[0014] In some embodiments, R 1 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl or 6-10 membered aryl, wherein said C1-C6 alkyl or C3-C6 cycloalkyl is optionally selected from halogen, cyano, hydroxy or -NR 8 R 9 and the 6- to 10-membered aryl is substituted with C1-C3 alkoxy optionally substituted with halogen.

[0015] In some embodiments, R 1 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl, or 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl is optionally substituted with halogen, and the 6- to 10-membered aryl is optionally substituted with C1-C3 alkoxy substituted with halogen.

[0016] In some exemplary embodiments, R 1 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 8-, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl or 6-10 membered aryl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with halogen, and the 6-10 membered aryl is optionally substituted with C1-C3 alkoxy substituted with halogen.

[0017] In some embodiments, R 1 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl, or 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl is optionally substituted with fluorine, and the 6- to 10-membered aryl is optionally substituted with C1-C3 alkoxy substituted with fluorine.

[0018] In some exemplary embodiments, R 1 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, halogen, hydroxy, NH2, (C1-C6 alkyl)-NR 8 -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl or 6-10 membered aryl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally substituted with fluorine, and the 6-10 membered aryl is optionally substituted with C1-C3 alkoxy substituted with fluorine.

[0019] In some more exemplary embodiments, R 1 is selected from hydrogen.

[0020] In some more exemplary embodiments, R 4is selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, preferably R 4 is selected from hydrogen, cyclopropyl, or C1-C6 alkyl, preferably R 4 is selected from hydrogen or C1 to C6 alkyl.

[0021] In some more exemplary embodiments, R 4 is selected from hydrogen, methyl or cyclopropyl, preferably R 4 is selected from hydrogen or methyl.

[0022] In some more exemplary embodiments, R 5 is selected from hydrogen or C1 to C6 alkyl.

[0023] In some more exemplary embodiments, R 5 is selected from hydrogen or methyl, preferably R 5 is selected from hydrogen.

[0024] In some more exemplary embodiments, R 6 is selected from hydrogen, chlorine, hydroxy, cyclopropyl, CF3CH2O-, CHF2O-, CF3CH2NH-, 4-difluoromethoxyphenyl or CH3CH2O-, preferably R 6 is selected from cyclopropyl, CF3CH2O-, CF3CH2NH- or CH3CH2O-, more preferably R 6 is selected from cyclopropyl, CF3CH2O- or CF3CH2NH-.

[0025] In some more exemplary embodiments, R 7 is selected from hydrogen.

[0026] In some embodiments, R 2 and R 3 are each independently selected from a phenyl group, a naphthyl group, and a group represented by the following formula: [ka] wherein the group is optionally halogen, hydroxy, cyano, -NR 8 R 9 , NO2, -NR 10 C(O)R 11 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 10 R 11 or 5-7 membered heteroaryl, wherein the C1-C6 alkyl, (C1-C6 alkyl)-O- or 5-7 membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O- or -NR 8 R 9 is replaced by

[0027] In some embodiments, R 2 and R 3 are each independently selected from phenyl, naphthyl, and groups represented by the following formula: [ka] wherein the group is optionally halogen, hydroxy, cyano, -NR 8 R 9 , NO2, -NR 10 C(O)R 11 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 10 R 11 or a 5- to 7-membered heteroaryl, wherein the C1-C6 alkyl or 5- to 7-membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O-, or -NR 8 R 9 is replaced by

[0028] In some embodiments, R 2 and R 3 are each independently selected from phenyl, naphthyl, and groups represented by the following formula: [ka] wherein the group is optionally halogen, hydroxy, cyano, -NR8 R 9 , NO2, -NR 10 C(O)R 11 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 10 R 11 or 5-7 membered heteroaryl, wherein the C1-C6 alkyl, (C1-C6 alkyl)-O- or 5-7 membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O- or -NR 8 R 9 is replaced by

[0029] In some embodiments, R 2 and R 3 are each independently selected from a phenyl group, a naphthyl group, and a group represented by the following formula: [ka] wherein the group is optionally halogen, hydroxy, cyano, -NR 8 R 9 , NO2, -NR 10 C(O)R 11 , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR 10 R 11 or a 5- to 7-membered heteroaryl, wherein the C1-C6 alkyl or 5- to 7-membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O-, or -NR 8 R 9 is replaced by

[0030] In some embodiments, R 2 and R 3 are each independently selected from a phenyl group, a naphthyl group, and a group represented by the following formula: [ka] wherein the group is optionally halogen, cyano, -NR 8 R 9 , -NR 10 C(O)R11 , C1-C6 alkyl, (C1-C6 alkyl)-O- or 5- to 7-membered heteroaryl, wherein the C1-C6 alkyl, (C1-C6 alkyl)-O- or 5- to 7-membered heteroaryl is optionally substituted by methyl, halogen or cyano.

[0031] In some embodiments, R 2 and R 3 are each independently selected from phenyl, naphthyl, and a group represented by the following formula: [ka] wherein the group is optionally halogen, cyano, -NR 8 R 9 , -NR 10 C(O)R 11 , C1-C6 alkyl, (C1-C6 alkyl)-O-, or 5- to 7-membered heteroaryl, wherein the C1-C6 alkyl or 5- to 7-membered heteroaryl is optionally substituted by halogen or cyano.

[0032] In some embodiments, R 8 , R 9 , R 10 and R 11 are each independently selected from H or C1 to C6 alkyl.

[0033] In some embodiments, R 8 , R 9 and R 10 are each independently selected from H.

[0034] In some embodiments, R 11 is selected from C1 to C6 alkyl groups.

[0035] In some embodiments, R 11 is selected from methyl.

[0036] In some embodiments, R 2 is selected from phenyl and groups represented by the following formula: [ka] wherein said group is optionally substituted with difluoromethoxy, methyl, NH2, methoxy, fluorine, cyanomethyl, CH3CONH-, 1-methyl-1H-imidazol-4-yl or 1-methyl-1H-pyrazol-5-yl.

[0037] In some embodiments, R 2 is selected from phenyl and groups represented by the following formula: [ka] wherein the group is optionally substituted with difluoromethoxy, methyl, NH2, methoxy, fluorine, cyanomethyl, or 1-methyl-1H-pyrazol-5-yl (a group represented by the formula below). [ka]

[0038] In some exemplary embodiments, R 2 is selected from groups represented by the following formulas: [ka]

[0039] In some embodiments, R 2 is selected from groups represented by the following formulas: [ka] Preferably, R 2 is selected from groups represented by the following formulas: [ka] More preferably, R 2 is selected from groups represented by the following formulas: [ka]

[0040] In some embodiments, R 3 is selected from phenyl and groups represented by the following formula: [ka] wherein said group is optionally substituted with difluoromethoxy, methyl, NH2, fluorine, methoxy, CH3CONH-, 1-methyl-1H-imidazol-4-yl or 1-methyl-1H-pyrazol-5-yl.

[0041] In some embodiments, R 3 is selected from a phenyl group and a group represented by the following formula: [ka] wherein said group is optionally substituted with difluoromethoxy, methyl, NH2, fluorine, methoxy or 1-methyl-1H-pyrazol-5-yl.

[0042] In some exemplary embodiments, R 3 is selected from groups represented by the following formulas: [ka]

[0043] In some embodiments, R 3 is selected from groups represented by the following formulas: [ka]

[0044] Preferably, R 3 is selected from groups represented by the following formulas: [ka] More preferably, R 3 is selected from groups represented by the following formulas: [ka]

[0045] In some embodiments, the compound of Formula I has the structure shown in Formula II: [ka] (In Formula II, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined for compounds of formula I.

[0046] In some embodiments, the compound of Formula I has the structure shown in Formula III: [ka] (In Formula III, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as defined for compounds of formula I.

[0047] In another aspect, the present invention provides the following compound or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka] [ka]

[0048] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0049] In some embodiments, the present invention provides a method for treating a disease or condition mediated by overexpression of MAT2A in a mammal in need of such treatment, comprising administering to the mammal an effective amount of a compound of Formula I, II or III or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the present invention provides a method of treating MTAP-null cancer in a subject, comprising administering to the subject an effective amount of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the present invention provides a method for inhibiting MAT2A-mediated synthesis of S-adenosylmethionine (SAM) from methionine and ATP in a cell, comprising contacting the cell with an effective amount of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, the invention provides a method of treating cancer in a subject suffering from cancer characterized by reduced or defective methylthioadenosine phosphorylase (MTAP) gene expression, a defect in the MTAP gene, or reduced MTAP protein function, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the present invention provides a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, for use in inhibiting the synthesis of S-adenosylmethionine (SAM) from methionine and ATP by MAT2A in a cell.

[0054] In some embodiments, the present invention provides a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition in a subject suffering from the disease or condition mediated by overexpression of MAT2A.

[0055] In some embodiments, the present invention provides a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject suffering from a cancer characterized by reduced or defective methylthioadenosine phosphorylase (MTAP) gene expression, a defect in the MTAP gene, or reduced MTAP protein function.

[0056] In another aspect, the present invention provides methods for preparing compounds of Formula I, II, or III, including, but not limited to, the following synthetic schemes.

[0057] Synthetic Scheme 1: [ka] where X' is selected from chlorine, bromine or iodine, and R 6 , R 2 and R 3 is defined as in Formula I above.)

[0058] Specifically, the compound of formula 1-1 is condensed with a compound of formula 1-2a or 1-2b under basic conditions to obtain a compound of formula 1-3, the compound of formula 1-3 is reacted with a compound of formula 1-4 (ethyl 3-(trimethylsilyl)propiolate) to obtain a compound of formula 1-5, the trimethylsilyl is eliminated from the compound of formula 1-5 to obtain a compound of formula 1-6, the compound of formula 1-6 is halogenated by the action of a halogenating reagent, compound of formula 1-7, to obtain a compound of formula 1-8, the compound of formula 1-8 is condensed with a compound of formula 1-9a or 1-9b under basic conditions to obtain a compound of formula 1-10, and the compound of formula 1-10 is condensed with a compound of formula 1-11a or 1-11b under basic conditions to obtain a compound of formula 1-12.

[0059] Synthetic Scheme 2: [ka] where X' is selected from chlorine, bromine or iodine, and R a is selected from C1 to C3 alkyl groups, and R 4 , R 5 , R 6 , R 2 and R 3 is defined as in Formula I above.)

[0060] Specifically, the compound of formula 2-1 is halogenated by the action of a halogenating agent to obtain the compound of formula 2-2, the compound of formula 2-2 and the compound of formula 2-3 are subjected to a condensation reaction to obtain the compound of formula 2-6, and the compound of formula 2-6 is subjected to a cyclization reaction under acidic conditions to obtain the compound of formula 2-9; or Compound 2-2 and compound 2-4 are condensed to give compound 2-7, which is then cyclized under acidic conditions and then hydroxyl is removed under acidic conditions to give compound 2-10, or A compound of formula 2-2 and a compound of formula 2-5 are subjected to a condensation reaction under basic conditions to obtain a compound of formula 2-8, and the compound of formula 2-8 is subjected to a cyclization reaction under acidic conditions to obtain a compound of formula 2-11, or The compound of formula 2-2 and the compound of formula 2-12 are subjected to a cyclization reaction to obtain the compound of formula 2-13.

[0061] Synthetic Scheme 3: [ka] where X' is selected from chlorine, bromine or iodine, and R 4 , R 2 and R 3 is defined as in Formula I above.)

[0062] Specifically, the compound of formula 2-10 is reacted with trifluoroethylamine to obtain the compound of formula 3-1, the compound of formula 3-1 is condensed with the compound of formula 3-2a or 3-2b under basic conditions to obtain the compound of formula 3-3, and the compound of formula 3-3 is condensed with the compound of formula 3-4a or 3-4b under basic conditions to obtain the compound of formula 3-5.

[0063] Synthetic Scheme 4: [ka] where X' is selected from chlorine, bromine or iodine, and R 6 , R 2 and R 3 is defined as in Formula I above.)

[0064] Specifically, the compound of formula 2-11 is condensed with the compound of formula 4-1a or 4-1b under basic conditions to obtain the compound of formula 4-2, and the compound of formula 4-2 is condensed with the compound of formula 4-3a or 3-3b under basic conditions to obtain the compound of formula 4-4.

[0065] Synthetic Scheme 5: [ka] where X' is selected from chlorine, bromine or iodine, and R 5 , R 2 and R 3 is defined as in Formula I above.)

[0066] Specifically, the compound of formula 2-9 is reacted with trifluoroethylamine in the presence of a condensing agent to obtain the compound of formula 5-1, the compound of formula 5-1 is condensed with the compound of formula 5-2a or 5-2b under basic conditions to obtain the compound of formula 5-3, the compound of formula 5-3 is condensed with the compound of formula 5-4a or 5-4b under basic conditions to obtain the compound of formula 5-5, or The formula 2-9 compound is condensed with the formula 5-6a compound or the formula 5-6b compound under basic conditions to obtain the formula 5-7 compound, the formula 5-7 compound is condensed with the formula 5-8a compound or the formula 5-8b compound under basic conditions to obtain the formula 5-9 compound, and the formula 5-9 compound is reacted with trifluoroethanol in the presence of a condensing agent to obtain the formula 5-10 compound.

[0067] Synthetic Scheme 6: [ka] where X' is selected from chlorine, bromine or iodine, and R 2 and R 3 is defined as in Formula I above.)

[0068] Specifically, the compound of formula 2-13 is condensed with the compound of formula 6-1a or 6-1b under basic conditions to obtain the compound of formula 6-2, and the compound of formula 6-2 is condensed with the compound of formula 6-3a or 6-3b under basic conditions to obtain the compound of formula 6-4. [Brief explanation of the drawings]

[0069] [Figure 1] FIG. 1 is a graph showing the tumor volume growth curves for each group in Test Example 1. [Figure 2] 1 shows the results of SAM detection in tumors of each group in Test Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0070] <Related definitions> Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0071] A "compound" in the present invention may be an asymmetric compound, e.g., one having one or more chiral centers. Unless otherwise specified, a "compound" in the present invention refers to any one stereoisomer or a mixture of two or more stereoisomers. Stereoisomers include, but are not limited to, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in the present invention may be isolated in the form of pure optically active forms or in the form of mixtures of two or more stereoisomers. Pure optically active forms can be isolated from mixtures of two or more stereoisomers or synthesized using chiral starting materials or chiral reagents.

[0072] The "compound" of the present invention further includes tautomeric forms. Tautomers are derived from the exchange of one single bond with the adjacent double bond, accompanied by the migration of one proton. For example, the compounds shown in the following formulas are tautomeric forms of each other, and the two can be converted under certain conditions. [ka]

[0073] The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and the description includes the occurrence and non-occurrence of the event or circumstance described above.

[0074] In this specification, the term "numerical range" refers to each integer within a given range. For example, "C1 to C6" means that the group may have 1, 2, 3, 4, 5, or 6 carbon atoms, and "C3 to C6" means that the group may have 3, 4, 5, or 6 carbon atoms.

[0075] The term "membered" refers to the number of skeletal atoms or atomic groups forming the ring. For example, "5- to 7-membered" means that the number of skeletal atoms or atomic groups forming the ring is 5, 6, or 7. Thus, for example, pyridine, piperidine, piperazine, and benzene are 6-membered rings, and thiophene and pyrrole are 5-membered rings.

[0076] The term "substituted" means that any one or more hydrogen atoms in a specific group are replaced with a substituent, as long as the valence of the specific group is normal and the resulting compound is stable. For example, "substituted with halogen" means that any one or more hydrogen atoms in a specific group are replaced with halogen, as long as the valence of the specific group is normal and the resulting compound is stable.

[0077] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched-chain saturated hydrocarbon groups, said hydrocarbon group having the indicated number of carbon atoms. For example, the term "C1-C6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, and 3-hexyl.

[0078] The term "alkoxy" refers to a group having the structure "alkyl-O-," where alkyl includes straight- or branched-chain saturated monovalent hydrocarbon groups. For example, "C1-C3 alkoxy" includes methoxy, ethoxy, n-propoxy, and isopropoxy.

[0079] The term "cycloalkyl group" means a monocyclic saturated hydrocarbon system with no heteroatoms and no double bonds. Examples of the term "3- to 6-membered cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0080] The term "halogen" means fluorine, chlorine, bromine and iodine.

[0081] The term "aryl" refers to an all-carbon monocyclic or fused bicyclic aromatic ring group having a conjugated π-electron system derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. This includes bicyclic groups fused to a saturated ring, a partially unsaturated ring, or an aromatic carbocyclic ring, and examples include, but are not limited to, phenyl, naphthyl, anthryl, indene, indane, 1,2-dihydronaphthalene, and 1,2,3,4-tetrahydronaphthalene.

[0082] The term "heteroaryl" refers to a monovalent aryl containing at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. For example, specific examples of "5- to 7-membered heteroaryl" include, but are not limited to, pyridinyl, thienyl, imidazolyl, pyrimidinyl, pyridinyl, furyl, pyrazinyl, and thiazolyl.

[0083] The term "9- to 18-membered benzoheterocyclic group" refers to a ring system having 9 to 18 ring atoms or ring atom groups formed by the condensation of a benzene ring and a heterocyclic ring, in which the benzene ring and the heterocyclic ring share a pair of adjacent ring atoms and the linking site to the core structure is located on the benzene ring moiety. Here, the heterocyclic moiety is a 5- to 12-membered saturated, partially unsaturated, or fully unsaturated ring system having ring carbon atoms and 1 to 4 ring heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are independently selected from nitrogen, sulfur, oxygen, sulfoxide, sulfone, and groups represented by the following formula: [ka]

[0084] The heterocycle may be a monocyclic, bicyclic, or tricyclic ring system, where two or more rings are present in the form of parallel rings, spiro rings, or bridged rings. Specific examples include, but are not limited to, groups of the formula: [ka]

[0085] JPEG0007721686000036.jpg13125 refers to the point of attachment of a chemical bond. When a bicyclic or multiple ring has a "-wavy line-" and the bonding site is not defined, this means that the bonding site is limited to any atom of the single ring where the "-wavy line-" is located, as long as valence allows. For example, the group shown in the formula below indicates that the bonding site is limited to any carbon atom of the benzene ring in the bicyclic ring, and must satisfy the requirements of the valence bond. [ka]

[0086] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free acids and bases of a particular compound without any biologically deleterious effects, such as an acid (including organic and inorganic acids) addition salt or a base (including organic and inorganic bases) addition salt.

[0087] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid or base group by conventional chemical methods. Typically, such salts are prepared by reacting the free acid or base form of the compound with a stoichiometrically appropriate base or acid in water or an organic solvent, or a mixture of both.

[0088] The term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent to produce a desired effect without toxicity. The exact dosage will vary depending on various factors, including subject-dependent variables (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered.

[0089] The term "pharmaceutically acceptable carrier" means a carrier that has no obvious irritating effect on the living body and does not impair the biological activity and properties of the active compound, including, but not limited to, any diluent, disintegrant, adhesive, glidant, or wetting agent approved by the State Food and Drug Administration for use in humans or animals.

[0090] The meanings of the abbreviations used in the claims and specification are as follows: M: mol / L; mM: mmol / L; μM: μmol / L; nM: nmol / L; TBAF: tetrabutylammonium fluoride; Brij35: polyoxyethylene lauryl ether; BSA: bovine serum albumin; DMSO: dimethyl sulfoxide; rpm: revolutions per minute; Tris-HCl: trimethylolaminomethane hydrochloride

[0091] The term "drug composition" means a composition comprising a compound according to the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable ingredient, including, but not limited to, a carrier, a diluent, an adjuvant, an excipient, a preservative, a filler, a disintegrant, a humectant, an emulsifier, a suspending agent, a sweetener, a flavoring agent, a flavoring agent, an antibacterial agent, an antifungal agent, a lubricant, a dispersing agent, a temperature-sensitive material, a temperature regulator, an adhesive, a stabilizer, a suspending aid, and the like, depending on the mode of administration and the nature of the dosage form.

[0092] The drugs or drug compositions of the present disclosure can be administered orally, topically, parenterally, or mucosally (e.g., orally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. Oral administration is usually preferred. The active agent is administered orally in the form of capsules, tablets, etc. (see Remington: The Science and Practice of Pharmacy, 20th Edition).

[0093] The drug or drug composition of the present disclosure can be administered parenterally, i.e., intravenously (iv), intracerebroventricularly (icv), subcutaneously (sc), intraperitoneally (ip), intramuscularly (im), subcutaneously (sd), or intradermally (id), for example, by direct injection via bolus injection or continuous infusion. Injectable formulations can be unit-formulated, for example, in ampoules or multi-dose containers with an added preservative. The composition can take the form of an excipient, such as a suspension, solution, or emulsion in an oily or aqueous carrier, and can contain formulation reagents such as, for example, antisettling agents, stabilizers, and / or dispersants. Optionally, the active ingredient can be reconstituted in powder form with a suitable carrier (e.g., sterile, pyrogen-free water) before use.

[0094] Drugs or drug compositions according to the present disclosure may also be formulated for rectal administration, for example, as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).

[0095] The term "treatment" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.

[0096] The use of the terms "reduce," "inhibit," "reduce," or "reduce" refers to a comparison to a control. One of skill in the art can readily determine an appropriate control for each experiment. For example, comparing a reduced response in subjects or cells treated with a compound to a response in subjects or cells not treated with the compound.

[0097] The methods for preparing the compounds according to the present invention will be explained in more detail below, but these specific preparation methods are not intended to limit the scope of the present invention in any way. Furthermore, the reaction conditions, such as the amounts of reactants, solvents, bases, and compounds used, reaction temperature, reaction time, etc., are not limited to the specific examples below.

[0098] The compounds according to the present invention can also be easily produced by any combination of various synthesis methods described herein or known to those skilled in the art, and such combinations can be easily carried out by those skilled in the art.

[0099] Example 1: 1,3,8-tri(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one [ka] a) Preparation of ethyl 3-(trimethylsilyl)propiolate Ethyl propiolate (10 g), trimethylchlorosilane (14.40 g), and dichloromethane (200 ml) were placed in a flask in that order, and triethylamine (10.31 g) was added dropwise under a nitrogen gas atmosphere, followed by a reaction with stirring for 3 hours at 40° C. After completion of the reaction, the mixture was quenched by adding 100 ml of water, extracted with 200 ml of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 8 / 1 (V / V)) to obtain 5.2 g of the title compound. b) Preparation of 1-(4-chloropyridin-2-yl)-4-(trimethylsilyl)-3-butyn-2-one A flask was charged with 4-chloro-2-methylpyridine (5 g) and tetrahydrofuran (100 ml), in that order. The mixture was cooled to -78°C in a dry ice ethanol bath under nitrogen gas. Diisopropylaminolithium (39.19 ml, 2 M tetrahydrofuran solution) was added dropwise and allowed to react at this temperature for 30 minutes. Ethyl 3-(trimethylsilyl)propiolate (7.01 g) was added and allowed to react at -78°C for 1 hour. After completion of the reaction, the mixture was quenched by adding saturated ammonium chloride solution (200 ml). The mixture was extracted three times with 100 ml of ethyl acetate. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain the title compound (5 g). LCMS m / z = 253.5 [M+1] + . c) Preparation of 1-(4-chloropyridin-2-yl)-3-butyn-2-one 1-(4-chloropyridin-2-yl)-4-(trimethylsilyl)-3-butyl-2-one (1 g), tetrabutylammonium fluoride (1.56 ml, 1 M tetrahydrofuran solution), and tetrahydrofuran (20 ml) were added to a flask in this order, and the mixture was stirred at 0°C for 30 minutes under a nitrogen atmosphere. After completion of the reaction, the mixture was quenched by adding 10 ml of water, extracted with 50 ml of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was used directly in the next step to obtain 0.6 g of the title compound. LCMS m / z=180.0 [M+1] + . d) Preparation of 1,3-dibromo-8-chloro-2H-quinolizin-2-one A flask was charged with 1-(4-chloropyridin-2-yl)-3-butyn-2-one (0.3 g), dichloromethane (100 mL), and N-bromosuccinimide (0.89 g), which were then reacted at room temperature for 2 h under a nitrogen atmosphere. After completion of the reaction, the mixture was quenched with saturated sodium thiosulfate solution (30 mL), extracted three times with 30 mL of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was used directly in the next step to obtain 0.5 g of the title compound. e) Preparation of 1,3,8-tri-(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one 1,3-Dibromo-8-chloro-2H-quinolizin-2-one (1.3 g), 4-(difluoromethoxy)phenylboronic acid (2.17 g), potassium carbonate (1.6 g), [1,1'-bis(di-t-butylphosphino)ferrocene]dichloropalladium (0.25 g), dioxane (26 ml), and water (5.2 ml) were placed in a flask in this order, and the mixture was reacted under nitrogen gas atmosphere at 80°C for 1 hour with stirring. After the reaction was completed, the reaction mixture was quenched by adding 30 ml of water, extracted with 60 ml of ethyl acetate, the organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: dichloromethane / methanol = 40 / 1 (V / V)) to obtain 1,3,8-tri(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one and 8-chloro-1,3-bis(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one. Structural confirmation data for 1,3,8-tri-(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one 1 H NMR(400 MHz, DMSO-d6) δ 8.70 (s,H), 8.34 (d,J=7.4 Hz,1H), 7.90-7.82(m,2H), 7.69 - 7.62 (m, 2H), 7.47 - 7.39 (m,2H),7.29(m,8H),7.26(d,J=2.3Hz,1H),7.22-7.10(m,2H).LCMSm / z=572[M+1] + .

[0100] Example 2: 8-chloro-1,3-bis(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one [ka] Prepared according to the method of Example 1, data for confirming the structure of 8-chloro-1,3-bis(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one 1 H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.29-8.23(m,1H),7.85-7.79(m,2H),7.55-7.13(m,8H),6.89-6.83(m,2H).LCMS m / z=464[M+1] + .

[0101] Example 3: 8-Cyclopropyl-1,3-bis(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one [ka] a) Preparation of 4-cyclopropyl-2-methylpyridine A flask was charged with 4-bromo-2-methylpyridine (10 g), cyclopropylboronic acid (14.98 g), potassium phosphate (49.36 g), [1,1'-bis(di-t-butylphosphino)ferrocene]dichloropalladium (0.25 g), water (40 ml), and dioxane (200 ml), in that order, and the reaction was stirred under a nitrogen atmosphere at 80 °C for 2 h. After completion of the reaction, the mixture was quenched with 200 ml of water, extracted three times with 100 ml of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 9 / 1 (V / V)) to obtain 7.5 g of the title compound. LCMS m / z = 134 [M+1] + . b) Preparation of 1-(4-cyclopropylpyridin-2-yl)-4-(trimethylsilyl)-3-butyn-2-one Prepare according to the preparation method of Example 1, replacing 4-chloro-2-methylpyridine with 4-cyclopropyl-2-methylpyridine in step b). LCMS m / z=258 [M+1] + . c) Preparation of 1-(4-cyclopropylpyridin-2-yl)-3-butyn-2-one Prepare according to the preparation method of Example 1 / 2, and replace 1-(4-chloropyridin-2-yl)-4-(trimethylsilyl)-3-butyl-2-one with 1-(4-cyclopropylpyridin-2-yl)-4-(trimethylsilyl)-3-butyn-2-one in step c). LCMS m / z=185.95[M+1] + . d) Preparation of 8-cyclopropyl-1,3-diiodo-2-H-quinolizin-2-one 1-(4-Cyclopropylpyridin-2-yl)-3-butyn-2-one (0.6 g), dichloromethane (12 ml), and N-iodosuccinimide (1.82 g) were added to a flask in this order, and the reaction was carried out at 0 °C for 1 hour under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was quenched by adding saturated sodium thiosulfate solution (30 mL), extracted three times with 30 ml of ethyl acetate, and the organic phase was concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 1 / 1 (V / V)) to obtain 0.3 g of the title compound. LCMS m / z = 437.8 [M+1] + . e) Preparation of 8-cyclopropyl-1,3-bis(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one It can be prepared by referring to the preparation method of Example 1, and in step e) 1,3-dibromo-8-chloro-2H-quinolizin-2-one can be replaced with 8-cyclopropyl-1,3-diiodo-2-H-quinolizin-2-one. 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.14(d,J=7.4Hz,1H),7.87-7.78(m,2H),7.49-7.13(m,4H),7.26(t,J=11.4Hz,4H), 6.72(d,J=2.1Hz,1H),6.39(dd,J=7.4,2.0Hz,1H),1.84(tt,J=8.4,4.8Hz,1H),1.02-0.92(m,2H),0.78-0.70(m,2H).LCMS m / z= 470 [M+1] + .

[0102] Example 4: 8-ethyl-1,3-bis(4-(difluoromethoxy)phenyl)-2H-quinolizin-2-one [ka] a) Preparation of 4-ethoxy-2-methylpyridine 4-Chloro-2-methylpyridine (5 g), sodium ethoxide (13.34 g), and dimethyl sulfoxide (100 ml) were placed in a flask in that order, and the mixture was reacted under nitrogen gas at 50° C. for 2 hours with stirring. After the reaction was completed, the mixture was quenched by adding 200 ml of water, extracted three times with 100 ml of ethyl acetate, and the organic phase was concentrated to dryness to obtain 4.6 g of the title compound. b) Preparation of 1-(4-ethoxypyridin-2-yl)-4-(trimethylsilyl)-3-butyn-2-one. Prepare according to the preparation method of Example 1 / 2, replacing 4-chloro-2-methylpyridine with 4-ethyl-2-methylpyridine in step b). LCMS m / z=262 [M+1] + . c) Preparation of 1-(4-ethoxypyridin-2-yl)-3-butyn-2-one Prepare according to the preparation method of Example 1 / 2, and replace 1-(4-chloropyridin-2-yl)-4-(trimethylsilyl)-3-butyl-2-one with 1-(4-ethoxypyridin-2-yl)-4-(trimethylsilyl)-3-butyn-2-one in step c). LCMS m / z=189.90 [M+1] + . d) Preparation of 8-ethoxy-1,3-diiodo-2-H-quinolizin-2-one Prepare according to the preparation method of Example 3, substituting 1-(4-ethoxypyridin-2-yl)-3-butyn-2-one for 1-(4-cyclopropylpyridin-2-yl)-3-butyn-2-one in step d). LCMS m / z=441.8 [M+1] + . e) Preparation of 1,3-bis(4-(difluoromethoxy)phenyl)-8-ethoxy-2H-quinolizin-2-one It can be prepared by referring to the preparation method of Example 1 / 2, and in step e) 1,3-dibromo-8-chloro-2H-quinolizin-2-one can be replaced with 8-ethoxy-1,3-diiodo-2-H-quinolizin-2-one. 1H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.18(d,J=7.7Hz,1H),7.85-7.76(m,2H),7.41-7.33(m,2H),7.49-7.12(t,J=72Hz,2H), 7.30-7.20(m,4H),6.58(dd,J=7.7,2.7Hz,1H),6.12(d,J=2.7Hz,1H),3.88(q,J=6.9Hz,2H),1.26(q,J=5.9,4.9Hz,3H).LCMS m / z=474[M+1] + .

[0103] Example 5: 1,3-bis(3-amino-2-methyl-2H-indazol-5-yl)-8-cyclopropylquinolizin-2-one [ka] a) Preparation of 1,3-bis(3-amino-2-methyl-2H-indazol-5-yl)-8-cyclopropylquinolizin-2-one 2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-amine (180 mg), 1,4-dioxane (3.60 mL), water (0.80 mL), 8-cyclopropyl-1,3-diiodoquinolizin-2-one (86.40 mg), potassium carbonate (273.23 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (53.68 mg) were placed in a flask in this order, and the mixture was stirred at 30°C for 48 hours under a nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure, and 4.7 mg of the title compound was isolated. Preparation and isolation conditions: (Column: YMC-Actus Triart C18, 30*150mm, 5μm; Mobile phase A: water (10mmol / L ammonium formate), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 30% B to 60% B in 8 min, 60% B; Detection wavelength: 220nm; Retention time (min): 7.93; Column temperature: 25℃). 1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.16(d,J=7.5Hz,2H),7.51(s,1H),7.37(dd,J=9. 0,1.7Hz,1H),7.19(dd,J=16.4,8.9Hz,2H),6.92(dd,J=8.9,1.6Hz,1H),6.78(d,J=2.0H) z,1H),6.30(dd,J=7.3,2.0Hz,1H),6.14(s,2H),6.03(s,2H),3.79(d,J=10.9Hz,6H),1 .77(tt,J=8.5,4.9Hz,1H),0.95-0.88(m,2H),0.70(t,J=2.8Hz,2H).LCMSm / z=476[M+1] +

[0104] Example 6: 3-(3-amino-2-methyl-2H-indazol-5-yl)-8-cyclopropyl-1-(2,2-difluoro-1,3-benzodioxazol-5-yl)quinolizin-2-one hydrochloride [ka] a) Preparation of 3-(3-amino-2-methyl-2H-indazol-5-yl)-8-cyclopropyl-1-iodoquinolizin-2-one It can be prepared by referring to the preparation method of Example 5. b) Preparation of 3-(3-amino-2-methyl-2H-indazol-5-yl)-8-cyclopropyl-1-(2,2-difluoro-1,3-benzodioxazol-5-yl)quinolizin-2-one hydrochloride 2,2-Difluoro-1,3-benzodioxazol-5-ylboronic acid (10.62 mg), 1,4-dioxane (0.5 mL), water (0.1 mL), 3-(3-amino-2-methyl-2H-indazol-5-yl)-8-cyclopropyl-1-iodoquinolizin-2-one (16 mg), potassium carbonate (14.54 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.86 mg) were added to a flask, and the mixture was stirred at 80°C for 1 hour in a nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure, and 2.6 mg of the title compound was isolated. Preparation and isolation conditions: (Column: YMC-Actus Triart C18, 30*150mm, 5μm; Mobile phase A: water (10mmol / L ammonium formate), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 15% B to 44% B in 8 min, 44% B; Detection wavelength: 220nm; Retention time (min): 7.32; Column temperature: 25℃). 1 H NMR(400MHz,DMSO-d6)δ8.70(d,J=4.1Hz,1H),8.51(d,J=4.4Hz,1H),8.29(s,1H),7.90(d,J=8.8Hz,1H),7.52(dd,J=8.5,6.4Hz,2H),7.35(d,J= 1.6Hz,1H),7.12(dd,J=8.2,1.5Hz,1H),6.88(s,1H),6.53(s,1H),3.83( s,3H),1.96(d,J=9.5Hz,1H),1.08-0.97(m,2H),0.88-0.76(m,2H).LCMS m / z=487 [M+1] +

[0105] Example 7: 8-Cyclopropyl-1-(2,2-difluoro-1,3-benzodioxazol-5-yl)-3-[2-methyl-3-(2-methylpyrazol-3-yl)indazol-5-yl]quinolizin-2-one [ka] a) Preparation of 5-bromo-3-iodo-2-methylindazole A flask was charged with 5-bromo-2-methylindazole (5 g), pyrazine (2.9 g), and dichloromethane (50 mL). Phenyl-3-iodobis(2,2,2-trifluoroacetic acid ester) (12.2 g) was added with stirring. The mixture was stirred at 30°C for 30 minutes in a nitrogen gas atmosphere, and iodine (7.22 g) was added. The mixture was then stirred for 24 hours. The reaction solution was washed with dichloromethane (2 x 100 mL) to give 4.1 g of the title compound. b) Preparation of 5-bromo-2-methyl-3-(2-methylpyrazol-3-yl)indazole A flask was charged with 5-bromo-3-iodo-2-methylindazole (1 g), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.54 g), 1,4-dioxane / water = 5:1 (20 ml), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.73 g), and potassium phosphate (4.41 g). The mixture was stirred at 80°C for 24 hours under a nitrogen atmosphere. The reaction was quenched with water at room temperature, extracted with ethyl acetate (2 x 20 mL), concentrated under reduced pressure, and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 3 / 10 (V / V)) to give 290 mg of the title compound. c) Preparation of 2-methyl-3-(2-methylpyrazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole To a flask were added 5-bromo-2-methyl-3-(2-methylpyrazol-3-yl)indazole (200 mg), bis(pinacolato)diboron (261.7 mg), and 1,4-dioxane (20 mL). Under a nitrogen gas atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (5 mg) and potassium acetate (200 mg) were further added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 3 / 10 (V / V)) to give 130 mg of the title compound. d) Preparation of 8-cyclopropyl-1-iodo-3-[2-methyl-3-(2-methylpyrazol-3-yl)indazol-5-yl]quinolizin-2-one Prepare by referring to the preparation method of Example 6, and replace 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-3-amine in step a) with 2-methyl-3-(2-methylpyrazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole. e) Preparation of 8-cyclopropyl-1-(2,2-difluoro-1,3-benzodioxazol-5-yl)-3-[2-methyl-3-(2-methylpyrazol-3-yl)indazol-5-yl]quinolizin-2-one It can be prepared by referring to the preparation method in step b) in Example 6. 1 H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.17(d,J=7.4Hz,1H),8.01(d,J=1.3Hz,1H),7. 70(dd,J=6.5,1.6Hz,3H),7.46(d,J=8.2Hz,1H),7.32(d,J=1.6Hz,1H),7.08(dd,J=8. 3,1.6Hz,1H),6.74(dd,J=24.9,1.9Hz,2H),6.37(dd,J=7.4,2.0Hz,1H),4.08(s,3H) ,3.75(s,3H),1.94-1.85(m,1H),0.96(dd,J=8.2,2.4Hz,2H),0.81-0.69(m,2H).LCMS m / z=552[M+1] +

[0106] Example 8: 8-Cyclopropyl-1,3-bis[2-methyl-3-(2-methylpyrazol-3-yl)indazol-5-yl]quinolizine 2-one [ka] It may be prepared by referring to the preparation method of Example 7. 1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.14(d,J=7.4Hz,1H),7.98(t,J=1.3Hz,1H),7.78 -7.61(m,5H),7.36(t,J=1.2Hz,1H),7.22(dd,J=8.9,1.5Hz,1H),6.81(d,J=2.0Hz,1H) ,6.70(dd,J=3.9,1.9Hz,2H),6.36(dd,J=7.4,2.0Hz,1H),4.08(d,J=8.9Hz,6H),3.75( d,J=4.0Hz,6H),1.78(tt,J=8.5,4.9Hz,1H),0.99-0.86(m,2H),0.76-0.62(m,2H).LCMS m / z=606[M+1] +

[0107] Example 9: 9-[4-(Difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]-8H-pyrido[1,2-a]pyrimidin-8-one [ka] a) Preparation of 3,3-diethoxypropionic acid Ethyl 3,3-diethoxypropionate (20 g) was added in batches to a solution of sodium hydroxide (5.47 g) in water (30 mL), purged with nitrogen, and stirred at 100 °C for 1 h. The mixture was then cooled to room temperature. The pH was adjusted to 6 with 3 M dilute hydrochloric acid at 0 °C and extracted with ethyl acetate (6 × 30 mL). The organic phase was washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (16.7 g). b) Preparation of 2-amino-3,5-dibromopyridin-4-ol A flask was charged with 2-aminopyridin-4-ol (10 g), N,N-dimethylformamide (150 mL), and N-bromosuccinimide (35.56 g), in that order, and the mixture was protected by purging with nitrogen gas. The mixture was stirred at room temperature for 4 h, and then filtered. The precipitated solid was collected and washed with acetonitrile (3 × 30 mL) to give 14 g of the title compound. c) Preparation of N-(3,5-dibromo-4-hydroxypyridin-2-yl)-3,3-diethoxypropionamide Under a nitrogen atmosphere, 3,3-diethoxypropionic acid (12.11 g), 1-hydroxybenzotriazole (12.61 g), dicyclohexylcarbodiimide (19.25 g), and N,N-dimethylformamide (200 mL) were added to a flask in this order and stirred at room temperature. N,N-diisopropylethylamine (24.12 g) was then added and stirred for 5 minutes. 2-amino-3,5-dibromopyridin-4-ol (10 g) was added and stirred at 80 °C for 4 hours. The mixture was then cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with N,N-dimethylformamide (3 × 20 mL). The filtrate was concentrated under reduced pressure to prepare a sample, which was purified by column chromatography (mobile phase: dichloromethane / methanol=15 / 1 (V / V)) to obtain 1.5 g of the title compound and 1.5 g of 7,9-dibromo-1H-pyrido[1,2-a]pyrimidine-2,8-dione. d) Preparation of 7,9-dibromo-1H-pyrido[1,2-a]pyrimidine-2,8-dione N-(3,5-dibromo-4-hydroxypyridin-2-yl)-3,3-diethoxypropionamide (2 g) was added to dilute hydrochloric acid (6 M, 60 mL), and the mixture was protected by purging with nitrogen gas and stirred at 50° C. for 12 hours. The reaction mixture was then concentrated under reduced pressure. Acetonitrile (4 mL) was added to the crude product, and the mixture was suspended and purified. The precipitated solid was filtered and collected to give 1 g of the title compound. e) Preparation of 7,9-dibromo-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one A flask was charged with 7,9-dibromo-1H-pyrido[1,2-a]pyrimidine-2,8-dione (500 mg), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (813.27 mg), 2,2,2-trifluoroethylamine (309.61 mg), N,N-dimethylformamide (7.5 mL), and N,N-diisopropylethylamine (403.96 mg), in that order. The flask was protected by purging with nitrogen gas and stirred at room temperature for 3 hours. The reaction was then quenched with ice water (15 ml). The precipitated solid was collected by filtration, washed with acetonitrile (2 × 3 ml), and dried under vacuum to give 400 mg of the title compound. f) Preparation of 9-bromo-7-(2-methyl-2H-indazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]-8H-pyrido[1,2-a]pyrimidin-8-one In a flask, 7,9-dibromo-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one (280 mg), 2-methyl-2H-indazol-5-ylboronic acid (245.77 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (56.98 mg), potassium phosphate (444.67 mg) were sequentially placed, and 1,4-dioxane (6 mL) and water (1.2 mL) were added. The mixture was purged with nitrogen gas and protected. After stirring at 80 ° C. for 2 h, the reaction mixture was concentrated under reduced pressure and precipitated. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to obtain 120 mg of the title compound. g) Preparation of 9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]-8H-pyrido[1,2-a]pyrimidin-8-one In a flask, 9-bromo-7-(2-methyl-2H-indazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]-8H-pyrido[1,2-a]pyrimidin-8-one (40 mg), 4-(difluoromethoxy)phenylboronic acid (33.25 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (7.21 mg), potassium phosphate (56.32 mg) were added in that order, and 1,4-dioxane (1 mL) and water (0.2 mL) were added, and the mixture was substituted with nitrogen gas for protection. The mixture was stirred at 80 ° C. for 2 hours, and the reaction mixture was cooled to room temperature. 10 mg of the title compound was isolated. Preparation and isolation conditions: (Column: XBridge Prep OBD C18, 30*150mm, 5μm; Mobile phase A: water (10mmol / L ammonium formate), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 25% B to 65% B in 8 min, 65% B; Detection wavelength: 220nm; Retention time (min): 7.22; Column temperature: 25℃). 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.38(s,1H),8.24(d,J=8.2Hz,2H),8.06(s,1H),7.59(d,J=9.1Hz,1H),7. 55-7.46(m,3H),7.24(t,J=49.6Hz1H),7.15-7.03(m,2H),6.35(d,J=7.4Hz,1H),4.18(s,3H),4.05(s,2H).LCMS m / z=516[M+1] +

[0108] Example 10: 7,9-Bis[4-(difluoromethoxy)phenyl]-2-[(2,2,2-trifluoroethyl)amino]-8H-pyrido[1,2-a]pyrimidin-8-one [ka] a) Preparation of 7,9-bis[4-(difluoromethoxy)phenyl]-2-[(2,2,2-trifluoroethyl)amino]-8H-pyrido[1,2-a]pyrimidin-8-one 7,9-Dibromo-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one (20 mg), 4-(difluoromethoxy)phenylboronic acid (70.31 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.16 mg), potassium phosphate (79.41 mg) were added to the flask in this order, and 1,4-dioxane (2 mL) and water (0.5 mL) were added, and the mixture was substituted with nitrogen gas for protection. The mixture was stirred at 80 ° C. for 4 hours, and the reaction mixture was cooled to room temperature. 10 mg of the title compound was isolated. Preparation and isolation conditions: (Column: XBridge Prep OBD C18, 30*150mm, 5μm; Mobile phase A: water (10mmol / L ammonium formate), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 25% B to 65% B in 8 min, 65% B; Detection wavelength: 220nm; Retention time (min): 7.83; Column temperature: 25℃). 1 H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.20(t,J=3.9Hz,2H),7.75(d,J=8.5Hz,2H),7.47 (t,J=7.4Hz,2H),7.41-6.98(m,6H),6.35(d,J=7.5Hz,1H),4.03(d,J=10.0Hz,2H).LCMS m / z=528[M+1] +

[0109] Example 11: 7,9-bis[(4-methoxyphenyl)]-2-[(2,2,2-trifluoroethyl)amino]-8H-pyrido[1,2-a]pyrimidin-8-one [ka] It can be prepared by referring to the preparation method of Example 10, and by substituting 4-(difluoromethoxy)phenylboronic acid with 4-methoxyphenylboronic acid in step a). 1H NMR(400MHz,DMSO-d6)δ8.48(t,J=6.3Hz,1H),8.19(d,J=7.5Hz,1H),8.11(s,1H),7.64(d,J=8.5Hz,2H),7.37(d,J=8.3Hz,2H) ,6.97(d,J=8.5Hz,2H),6.84(d,J=8.4Hz,2H),6.30(d,J=7.5Hz,1H),4.05(dd,J=9.9,6.5Hz,2H),3.78(d,J=10.5Hz,6H).LCMS m / z=456[M+1] +

[0110] Example 12: 7,9-bis[(2-methyl-2H-indazol-5-yl)]-2-[(2,2,2-trifluoroethyl)amino]-8H-pyrido[1,2-a]pyrimidin-8-one [ka] It can be prepared by referring to the preparation method of Example 10, and in step a), 4-(difluoromethoxy)phenylboronic acid is replaced with 2-methyl-2H-indazol-5-ylboronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.50(t,J=6.3Hz,1H),8.38(s,1H),8.23(dd,J=9.5,7.2Hz,3H),8.08(t,J=1.3Hz,1H),7.73(s,1H),7.62-7 .52(m,2H),7.43(d,J=9.0Hz,1H),7.32(dd,J=9.0,1.6Hz,1H),6.33(d,J=7.5Hz,1H),4.17(d,J=8.5Hz,6H),4.09-3.90(m,2H).LCMS m / z=504[M+1] +

[0111] Example 13: 9-{6,7-dihydro-2H-spiro[1-benzofuran-3,1′-cyclopropan]-5-yl}-7-{2H-spiro[1-benzofuran-3,1′-cyclopropan]-5-yl}-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] a) Preparation of 5-bromobenzofuran-2(3H)-one 2-(5-Bromo-2-hydroxyphenyl)acetic acid (5.8 g) and toluene (50 mL) were added to a flask and heated to 100°C. Then, 0.5 mL of concentrated sulfuric acid was added dropwise, and the mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added while stirring until no bubbles were generated. The organic phase was separated and washed with saturated brine. The organic phase was concentrated to dryness to obtain 3.8 g of the title compound. b) Preparation of 5-bromo-2H-spiro[benzofuran-3,1'-cyclopropan]-2-one 5-Bromobenzofuran-2(3H)-one (2.1 g), (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (6.6 g), and N,N-dimethylformamide (50 mL) were added to a flask and stirred at room temperature for 5 minutes. After stirring, triethylamine (3.1 g) was added and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, ethyl acetate (150 mL) was added and the mixture was washed with saturated brine (3 x 50 mL). The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain the title compound (1 g). c) Preparation of 4-bromo-2-(1-(methylol)cyclopropyl)phenol 5-Bromo-2H-spiro[benzofuran-3,1'-cyclopropan]-2-one (880 mg) and tetrahydrofuran (20 mL) were placed in a flask, protected with nitrogen gas, and cooled to 0 °C. Lithium aluminum hydride (70 mg) was added and stirred for 1 hour. The reaction was monitored by thin-layer chromatography. If the reaction was not complete, additional lithium aluminum hydride (35 mg) was added and stirred for 1 hour until the starting materials were completely reacted. After the reaction was complete, water (20 mL) and aqueous hydrochloric acid (2 M, 5 mL) were added and stirred for 10 minutes. The mixture was then extracted with ethyl acetate (3 × 20 mL). The organic phase was collected, dried, and concentrated. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1 (V / V)) to obtain 820 mg of the title compound. d) Preparation of 5-bromo-2H-spiro[benzofuran-3,1'-cyclopropane] 4-Bromo-2-(1-(methylol)cyclopropyl)phenol (486 mg) and dimethyl carbonate (10 mL) were placed in a flask and stirred. Potassium t-butoxide was added, and the mixture was heated to 85°C and allowed to react for 10 hours. After the completion of the reaction was confirmed by monitoring with a thin-layer chromatography plate, the mixture was cooled to room temperature. The reaction mixture was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 20 / 1 (V / V)) to obtain 320 mg of the title compound. e) Preparation of 4,4,5,5-tetramethyl-2-(2H-spiro[benzofuran-3,1'-cyclopropan]-5-yl)-1,3,2-dioxaborolane 5-Bromo-2H-spiro[benzofuran-3,1'-cyclopropane] (280 mg), bis(pinacolato)diboron (434 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (80 mg), potassium acetate (335 mg), and 1,4-dioxane (10 mL) were added to a flask, protected with nitrogen gas, and reacted at 90°C for 3 hours. After completion of the reaction, the solid was removed by filtration, and the filtrate was collected and concentrated to dryness. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 25 / 1 (V / V)) to give 300 mg of the title compound. f) Preparation of 9-{6,7-dihydro-2H-spiro[1-benzofuran-3,1'-cyclopropan]-5-yl}-7-{2H-spiro[1-benzofuran-3,1'-cyclopropan]-5-yl}-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one It can be prepared by referring to the preparation method of Example 10, and in step a) 4-(difluoromethoxy)phenylboronic acid can be replaced with 4,4,5,5-tetramethyl-2-{2H-spiro[1-benzofuran-3,1′cyclopropan]-5-yl}-1,3,2-dioxaborolane. 1 H NMR(400MHz,DMSO-d6)δ8.46(t,J=6.3Hz,1H),8.15(d,J=7.5Hz,1H),8.05(s,1H), 7.37(dd,J=8.4,1.8Hz,1H),7.12-7.01(m,2H),6.83-6.73(m,2H),6.67(d,J=8.2Hz ,1H),6.28(d,J=7.5Hz,1H),4.49(d,J=15.3Hz,4H),4.04(dt,J=16.1,8.0Hz,2H), 1.08(d,J=4.0Hz,2H),1.03(dt,J=6.1,3.2Hz,4H),0.95(q,J=5.0,4.4Hz,2H).LCMS m / z=532[M+1] +

[0112] Example 14: 9'-{9-[4-(difluoromethoxy)phenyl]-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one [ka] a) Preparation of 5-bromo-N-(1-(methylol)cyclopropyl)-2H-indazole-3-formamide 5-Bromo-2H-indazole-3-carboxylic acid (6 g), (1-aminocyclopropyl)methanol hydrochloride (3.69 g), 1-hydroxybenzotriazole (4.04 g), triethylamine (5.04 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.73 g) were mixed in N,N-dimethylformamide (60 mL) and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was quenched by adding water, and the reaction solution was extracted three times with 100 mL of dichloromethane. The combined organic phase was washed three times with 100 mL of saturated brine. The organic phase was concentrated to dryness, 100 mL of diethyl ether was added, and the mixture was suction filtered. The filter cake was washed twice with 100 mL of diethyl ether to obtain 2.8 g of the title compound. MS(ESI+): 311.75(M+H). b) Preparation of 9'-bromo-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one Under a nitrogen gas atmosphere, 5-bromo-N-(1-(methylol)cyclopropyl)-2H-indazole-3-formamide (400 mg), (1-aminocyclopropyl)methanol hydrochloride (3.69 g), and triphenylphosphine (575.06 mg) were mixed in tetrahydrofuran (40 mL), and di-t-butyl azodicarboxylate (504.84 mg) was added dropwise at 0°C. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was quenched by adding water, and the reaction solution was extracted three times with 100 mL of ethyl acetate. The combined organic phase was washed three times with 100 mL of saturated brine. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane = 0-1 / 10 (V / V)) to obtain 300 mg of the title compound. c) Preparation of 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one Under a nitrogen atmosphere, 9'-bromo-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one (100 mg), bis(pinacolato)diboron (104.31 mg), and potassium acetate (100.78 mg) were mixed in 1,4-dioxane (10 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13.94 mg) was added. The mixture was heated to 80 °C and stirred for 2 hours. After completion of the reaction, the mixture was suction filtered, and the filter cake was washed three times with 50 mL of dichloromethane. The combined organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane = 0-1 / 10 (V / V)) to obtain 100 mg of the title compound. MS(ESI+): 339.90(M+H). d) Preparation of 9'-{9-bromo-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one A flask was charged with 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one (100 mg), 7,9-dibromo-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one (10 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (2.03 mg), and potassium phosphate (13.23 mg), in that order, and 1,4-dioxane (1 The reaction mixture was cooled to room temperature and concentrated under reduced pressure to precipitate, which was then purified by column chromatography (mobile phase: dichloromethane / methanol=10 / 1 (V / V)) to give 60 mg of the title compound. e) Preparation of 9'-{9-[4-(difluoromethoxy)phenyl]-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one In a flask, 9'-{9-bromo-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one (60 mg), 4-(difluoromethoxy)phenylboronic acid (42.29 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (9.16 mg), potassium phosphate (59.70 mg) were added in that order, and 1,4-dioxane (6 mL) and water (1.2 mL) were added, and the mixture was substituted with nitrogen gas for protection. The mixture was stirred at 80 ° C. for 2 hours, and the reaction mixture was cooled to room temperature and concentrated under reduced pressure to dryness. 10.1 mg of the title compound was isolated. Preparation and isolation conditions: (Column: YMC-Actus Triart C18, 30*150mm, 5μm; Mobile phase A: water (10mmol / L ammonium formate), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 20% B to 60% B in 8 min, 60% B; Detection wavelength: 220nm; Retention time (min): 7.23; Column temperature: 25℃). 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.54(s,1H),8.36(t,J=1.3Hz,1H),8.31-8.24(m,2H),7.78(d,J=8.9Hz,1H),7.69(dd,J=9.0,1.6Hz,1H),7 .57-7.48(m,2H),7.44-7.02(m,3H),6.35(d,J=7.5Hz,1H),4.64(s,2H), 4.05(t,J=8.3Hz,2H),0.99(d,J=4.1Hz,2H),0.95(d,J=4.3Hz,2H).LCMS m / z=597[M+1] +

[0113] Example 15: 9'-{9-[4-(difluoromethoxy)phenyl]-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one [ka] a) Preparation of 9'-bromo-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one 9'-Bromo-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one (500 mg) was placed in a flask, N,N-dimethylformamide (5 mL) was added, the temperature was lowered to 0°C, sodium hydride (82.15 mg) was added, and methyl iodide (364.40 mg) was added dropwise at 25°C. The mixture was stirred for 1 hour, and the reaction was quenched with water at 0°C. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed three times with saturated sodium bicarbonate, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (460 mg). b) Preparation of 2'-methyl-9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one A flask was charged with 9'-bromo-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one (200 mg), 1,4-dioxane (20 mL), bis(pinacolato)diboron (199 mg), potassium acetate (192.33 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (26.61 mg). The mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1 (V / V)) to give 180 mg of the title compound. c) Preparation of 9'-{9-[4-(difluoromethoxy)phenyl]-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one It can be prepared by referring to the preparation method of Example 14, and in step a), 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one is replaced with 2'-methyl-9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one. 1 H NMR(400MHz,DMSO-d6)δ8.59(t,J=6.1Hz,1H),8.35(t,J=1.3Hz,1H),8.28(d,J=7 .2Hz,2H),7.77(dd,J=9.0,0.9Hz,1H),7.68(dd,J=9.0,1.6Hz,1H),7.55-7.50(m ,2H),7.24(t,J=76.4Hz,1H),7.13-7.07(m,2H),6.36(d,J=7.5Hz,1H),4.67(s,2 LCMS m / z=611[M+1] +

[0114] Example 16: 9'-{9-[4-(difluoromethoxy)phenyl]-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}-2',4'-dihydrospiro[cyclopropane-1,1'-pyrazino[1,2-b]indazol]-3'-one [ka] a) Preparation of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-nitrile Under a nitrogen gas atmosphere, sodium hydride (2.81 g) was mixed with tetrahydrofuran (110 mL), and a solution of 5-bromo-1H-indazole-3-nitrile (13 g) in tetrahydrofuran (85 mL) was added dropwise in batches at -20°C. The mixture was stirred for 45 minutes while maintaining the temperature at -20°C, and then [2-(chloromethoxy)ethyl]trimethylsilane (19.52 g) was added. The mixture was stirred for 45 minutes while maintaining the temperature at -20°C, and then stirred at room temperature for 30 minutes. After the reaction was completed, water was added to quench the reaction. The aqueous phase was extracted three times with 70 mL of ethyl acetate. The combined organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to obtain 20.73 g of the title compound. b) Preparation of 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)cyclopropyl-1-amine Under a nitrogen gas atmosphere, tetraisopropyl titanate (1.56 g) was mixed with diethyl ether (50 mL) and a solution of ethylmagnesium bromide (1.46 g) was added dropwise in batches at -70 °C. The mixture was stirred for 1 hour while maintaining the temperature at -70 °C. Then, 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-nitrile (1.76 g) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was quenched by the addition of 1 N hydrochloric acid (15 mL) and 10% sodium hydroxide solution (50 mL), respectively. The aqueous phase was extracted three times with 70 mL of ethyl acetate. The combined organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1 (V / V)) to obtain 1.22 g of the title compound. MS(ESI+): 382 (M+H). c) Preparation of 1-(5-bromo-1H-indazol-3-yl)cyclopropyl-1-amine Under a nitrogen atmosphere, 1-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)cyclopropyl-1-amine (10 g) was mixed with N,N-dimethylformamide (200 mL), tetrabutylammonium bromide (1 M tetrahydrofuran solution, 130 mL) and ethylenediamine (15.72 g) were added, heated to 70 °C, stirred for 5 hours, and then cooled to room temperature. The reaction mixture was diluted with 500 mL of ethyl acetate and washed twice with 200 mL of water. The aqueous phase was extracted three times with 100 mL of ethyl acetate. The combined organic phase was washed three times with 100 mL of saturated brine. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane = 0-1 / 10 (V / V)) to give 5 g of the title compound. MS(ESI+): 252 (M+H). d) Preparation of N-(1-(5-bromo-1H-indazol-3-yl)cyclopropyl)-2-chloroacetamide Under a nitrogen gas atmosphere, 1-(5-bromo-1H-indazol-3-yl)cyclopropyl-1-amine (4 g) and triethylamine (3.21 g) were mixed in dichloromethane (120 mL), and chloroacetyl chloride (2.33 g) was added dropwise at -10 °C. The mixture was stirred for 4 hours while maintaining the temperature at -10 °C. After the reaction was completed, the mixture was quenched by adding water at 0 °C. The reaction mixture was extracted three times with 100 mL of a 1 / 10 (V / V) mixture of methanol and dichloromethane. The combined organic phases were washed with 100 mL of saturated brine. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: 0-1 / 10 (V / V) methanol / dichloromethane) to obtain 2.5 g of the title compound. MS (ESI+): 328 (M+H). e) Preparation of 9'-bromo-2'H-spiro[cyclopropane-1,1'-pyrazino[1,2-b]indazol]-3'(4'H)-one Under a nitrogen gas atmosphere, N-(1-(5-bromo-1H-indazol-3-yl)cyclopropyl)-2-chloroacetamide (2 g) was mixed with N-methylpyrrolidone (200 mL), potassium carbonate (1.68 g) was added, and the mixture was heated to 80 °C and stirred for 5 hours, after which it was cooled to room temperature. The reaction mixture was diluted with 300 mL of ethyl acetate and 300 mL of water, and the mixture was extracted three times with 300 mL of ethyl acetate. The combined organic phase was washed twice with 200 mL of saturated brine. The organic phase was concentrated to 20 mL, suction filtered, and the filter cake was washed three times with 5 mL of ethyl acetate to obtain the title compound. MS(ESI+): 292 (M+H). f) Preparation of 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2'H-spiro[cyclopropane-1,1'-pyrazino[1,2-b]indazol]-3'(4'H)-one Under a nitrogen atmosphere, 9'-bromo-2'H-spiro[cyclopropane-1,1'-pyrazino[1,2-b]indazol]-3'(4'H)-one (160 mg), bis(pinacolato)diboron (167 mg), and potassium acetate (134.48 mg) were mixed in 1,4-dioxane (3 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (44.62 mg) was added. The mixture was heated to 80 °C and stirred for 2 h. After completion of the reaction, the mixture was suction filtered, and the filter cake was washed three times with 30 mL of dichloromethane. The organic phases were combined and concentrated to dryness. The crude product was purified by column chromatography (mobile phase: methanol / dichloromethane = 0 to 1 / 10 (V / V)) to give 130 mg of the title compound. MS (ESI+): 340.05 (M+H). g) Preparation of 9'-{9-[4-(difluoromethoxy)phenyl]-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}-2',4'-dihydrospiro[cyclopropane-1,1'-pyrazino[1,2-b]indazol]-3'-one It can be prepared by referring to the preparation method of Example 14, and in step d), 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one can be replaced with 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',4'-dihydrospiro[cyclopropane-1,1'-pyrazino[1,2-b]indazol]-3'-one. 1 H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.57(t,J=6.3Hz,1H),8.23(d,J=12.6Hz, 2H),7.84(d,J=1.5Hz,1H),7.58(d,J=1.2Hz,2H),7.52-7.44(m,2H),7.23(t,J =74.0Hz,1H),7.15-7.04(m,2H),6.35(d,J=7.5Hz,1H),5.16(s,2H),4.03(dt, J=16.0,8.1Hz,2H),1.78-1.72(m,2H),1.56-1.45(m,2H).LCMSm / z=597[M-+1] +

[0115] Example 17: 9-[4-(Difluoromethoxy)phenyl]-7-{2H-spiro[1-benzofuran-3,1'-cyclopropan]-5-yl}-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] Prepare the compound by referring to the preparation method of Example 14, and replace 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one with 4,4,5,5-tetramethyl-2-{2H-spiro[1-benzofuran-3,1'-cyclopropane]-5-yl}-1,3,2-dioxaborolane in step a). 1H NMR(400MHz,DMSO-d6)δ8.53(t,J=6.2Hz,1H),8.19(d,J=7.5Hz,1H),8.10(s ,1H),7.50-7.42(m,2H),7.41-7.34(m,1H),7.22(t,J=74.4Hz,1H),7.14(d, J=1.9Hz,1H),7.11-7.05(m,2H),6.80(d,J=8.3Hz,1H),6.32(d,J=7.4Hz,1H ),4.51(s,2H),4.10-3.89(m,2H),1.12-1.06(m,2H),1.06-0.97(m,2H).LCMS m / z=530.05[M+1] +

[0116] Example 18: 7-(2-amino-1,3-benzothiazol-6-yl)-9-bromo-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] Prepare according to the preparation method of Example 14, by replacing 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-amine in step a). 1 H NMR(400MHz,DMSO-d6)δ8.55(t,J=6.3Hz,1H),8.22(d,J=8.2Hz,2H),8.03(d,J=1.7Hz,1H),7.57-7.46(m,5H) ,7.36(d,J=8.4Hz,1H),7.23(t,J=72Hz,1H),7.13-7.02(m,2H),6.34(d,J=7.5Hz,1H),4.08-3.98(m,2H).LCMS m / z=534[M+1] +

[0117] Example 19: 2-(5-{9-[4-(difluoromethoxy)phenyl]-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}indazol-2-yl)acetonitrile [ka] a) Preparation of 2-(5-bromoindazol-2-yl)acetonitrile A flask was charged with 5-bromo-2H-indazole (6 g), 2-bromoacetonitrile (5.48 g), and N-methylpyrrolidone (60 mL), and the mixture was stirred at 120°C for 1 hour under a nitrogen gas atmosphere. The reaction mixture was cooled to room temperature, diluted with water (180 mL), and extracted with ethyl acetate (3 x 200 mL). The organic layer was washed with saturated brine (3 x 200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5 / 1 (V / V)) to give the title compound (6.29 g). b) Preparation of 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]acetonitrile A flask was charged with 2-(5-bromoindazol-2-yl)acetonitrile (200 mg), bis(pinacolato)diboron (322.71 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (69.19 mg), 1,4-dioxane (8 mL), and potassium acetate (249.44 mg). The mixture was stirred at 80°C for 4 hours under a nitrogen atmosphere. Water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 3 / 1 (V / V)) to give the title compound (210 mg). c) Preparation of 2-(5-{9-[4-(difluoromethoxy)phenyl]-8-oxo-2-[(2,2,2-trifluoroethyl)amino]pyridinyl[1,2-a]pyrimidin-7-yl}indazol-2-yl)acetonitrile Prepare by referring to the preparation method of Example 14, and replace 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one with 2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]acetonitrile in step a). 1 H NMR(400MHz,DMSO-d6)δ8.61-8.53(m,2H),8.24(d,J=8.2Hz,2H),8.12(t,J=1.3Hz,1H),7.67(dt,J=9.1,1.0Hz,1H),7.61(dd,J=9.0,1 .6Hz,1H),7.54-7.48(m,2H),7.24(m,1H),7.09(d,J=8.6Hz,2H),6.36(d,J=7.5Hz,1H),5.86(s,2H),4.05(dd,J=9.7,6.5Hz,2H).LCMS m / z=541[M+1] +

[0118] Example 20: 9-(2,2-Difluoro-1,3-benzodioxazol-5-yl)-7-(2-methyl-2H-indazol-5-yl)-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] It can be prepared by referring to the preparation method of Example 14, except that in step a) 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',4'-dihydrospiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'-one is replaced with 2-methyl-2H-indazol-5-ylboronic acid, and in step b) 4-(difluoromethoxy)phenylboronic acid is replaced with 2,2-difluoro-1,3-benzodioxazol-5-ylboronic acid. 1H NMR(400MHz,DMSO-d6)δ8.62(t,J=6.3Hz,1H),8.38(s,1H),8.25(d,J=7.1Hz,2H),8.06(d,J=1.5Hz,1H),7.59(d,J=9.0Hz,1H),7 .53(dd,J=9.0,1.6Hz,1H),7.39(d,J=1.5Hz,1H),7.35-7.24(m,2H),6.36(d,J=7.5Hz,1H),4.18(s,3H),4.11-3.97(m,2H).LCMS m / z=530[M+1] +

[0119] Example 21: 7,9-bis[4-(difluoromethoxy)phenyl]-1H-pyridinyl[1,2-a]pyrimidine-2,8-dione [ka] It can be prepared by referring to the preparation method of Example 10, and in step a), 7,9-dibromo-2-[(2,2,2-trifluoroethyl)amino]-8H-pyridinyl[1,2-a]pyrimidin-8-one is replaced with 7,9-dibromo-1H-pyrido[1,2-a]pyrimidine-2,8-dione. 1 H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.22(s,1H),8.12(d,J=7.9Hz,1H),7.74-7.65(m,2H),7.31 (d,J=8.6Hz,2H),7.31(t,J=74.0Hz,1H),7.22(dd,J=8.7,3.0Hz,4H),6.04(d,J=7.9Hz,1H).LCMS m / z=447[M+1] +

[0120] Example 22: 9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] a) Preparation of 9-bromo-7-(2-methyl-2H-indazol-5-yl)-1H-pyridine[1,2-a]pyrimidine-2,8-dione A flask was charged with 7,9-dibromo-1H-pyrido[1,2-a]pyrimidine-2,8-dione (500 mg), 2-methyl-2H-indazol-5-ylboronic acid (412.5 mg), N,N-dimethylformamide (50 mL), water (10 mL), potassium phosphate (995.2 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (127.3 mg). The mixture was stirred at 80°C for 2 hours under a nitrogen gas atmosphere, evaporated to dryness under reduced pressure, and purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to give 280 mg of the title compound. b) Preparation of 9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-1H-pyridinyl[1,2-a]pyrimidine-2,8-dione A flask was charged with 9-bromo-7-(2-methyl-2H-indazol-5-yl)-1H-pyridine[1,2-a]pyrimidine-2,8-dione (280 mg), 1,4-dioxane (28 mL), water (5.60 mL), (difluoromethoxy)phenylboronic acid (283.5 mg), potassium phosphate (400.3 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (61.5 mg). The mixture was stirred at 80°C for 2 hours under a nitrogen gas atmosphere, and then evaporated to dryness under reduced pressure. The mixture was purified by column chromatography (mobile phase: dichloromethane / methanol = 10 / 1 (V / V)) to give 150 mg of the title compound. c) Preparation of 9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)-8H-pyridinyl[1,2-a]pyrimidin-8-one A flask was charged with 9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-1H-pyridinyl[1,2-a]pyrimidine-2,8-dione (20 mg), 1H-benzotriazol-1-yloxotris(dimethylamino)phosphonium hexafluorophosphate (40.73 mg), and cesium carbonate (30 mg) in that order, and stirred at room temperature for 10 minutes. Cesium carbonate (30 mg) and trifluoroethanol (92.12 mg) were then added, and the mixture was stirred at room temperature for 2 hours. After monitoring the completion of the reaction by LCMS, the reaction solvent was concentrated under reduced pressure to dryness, and 10 mg of the title compound was isolated. Preparation and isolation conditions: (Column: XBridge Prep OBD C18, 30*150mm, 5μm; Mobile phase A: water (10mmol / L ammonium formate), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 25% B to 65% B (0~8min), 65% B; Detection wavelength: 220nm; Retention time (min): 7.99; Column temperature: 25℃). 1 H NMR(400MHz,DMSO-d6)δ8.57(d,J=7.8Hz,1H),8.47(s,1H),8.42(s,1H),8.11(s,1H),7.62(d,J=9.0Hz,1H),7.55(dd,J=8. 8,6.2Hz,3H),7.28(t,J=74.0Hz,1H),7.16(d,J=8.4Hz,2H),6.69(d,J=7.4Hz,1H),4.84(q,J=8.9Hz,2H),4.19(s,3H).LCMS m / z=517[M+1] +

[0121] Example 23: 2-Cyclopropyl-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] a) Preparation of 2-chloro-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one 7,9-Bis[4-(difluoromethoxy)phenyl]-1H-pyrido[1,2-a]pyrimidine-2,8-dione (50 mg) and thionyl chloride (5 mL) were placed in a flask, in that order, and stirred at 50°C for 2 days. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the concentrate was diluted with dichloromethane (20 mL). The organic phase was washed with saturated brine, washed with saturated sodium bicarbonate, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to precipitate, and the precipitate was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 2 / 1 (V / V)) to give 28 mg of the title compound. b) Preparation of 2-cyclopropyl-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one 2-Chloro-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyrido[1,2-a]pyrimidin-8-one (19 mg), cyclopropylboronic acid (7.02 mg), water (0.2 mL), 1,4-dioxane (1 mL), potassium carbonate (11.30 mg), and bis(triphenylphosphino)palladium dichloride (5.74 mg) were placed in a flask in this order, and the mixture was protected by replacing with nitrogen gas and stirred at 80°C for 2 hours. The resulting reaction solution was concentrated under reduced pressure, and 2.4 mg of the title compound was prepared and isolated. Preparation and isolation conditions: (Column: YMC-Actus Triart C18, 30*150mm, 5μm; Mobile phase A: water (10mmol / L ammonium formate), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 45% B to 69% B in 8 min, 69% B; Detection wavelength: 220nm; Retention time (min): 7.50; Column temperature: 25℃). 1 H NMR(400MHz,DMSO-d6)δ8.44-8.37(m,2H),7.84-7.76(m,2H),7.50-7.42(m,2H),7.26(dd,J=9.3,7.4Hz,3H),7.17-7. 05(m,3H),6.82(d,J=7.2Hz,1H),2.04(tt,J=8.3,4.5Hz,1H),1.05(dq,J=6.9,3.7Hz,2H),0.93(p,J=3.8Hz,2H).LCMS m / z=471[M+1] +

[0122] Example 24: 7,9-bis[4-(difluoromethoxy)phenyl]-2-(2,2,2-trifluoroethoxy)-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] Prepare by referring to the preparation method of Example 22, and replace 9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-1H-pyridinyl[1,2-a]pyrimidine-2,8-dione in step a) with 7,9-bis[4-(difluoromethoxy)phenyl]-1H-pyridinyl[1,2-a]pyrimidine-2,8-dione. 1 H NMR(400MHz,DMSO-d6)δ8.54(d,J=7.6Hz,1H),8.45(s,1H),7.84-7.74(m,2H),7.58-7.44(m, 2H),7.31-7.23(m,3H),7.18-7.07(m,3H),6.70(d,J=7.4Hz,1H),4.83(q,J=8.9Hz,2H).LCMS m / z=529[M+1] +

[0123] Example 25: 2-Cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] a) Preparation of 3-cyclopropyl-3-oxoprop-1-en-1-ol sodium Under nitrogen atmosphere, sodium hydride (2.85 g) was added in batches to a solution of cyclopropyl methyl ketone (10 g) in tetrahydrofuran (150 mL) at 0°C, the reaction system was stirred at 0°C for 1 hour, and then methyl formate (7.85 g) was added dropwise, and the reaction system was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated under reduced pressure, filtered, and the washed solid was collected and washed with petroleum ether (3 x 30 mL) and methyl t-butyl ether (3 x 30 mL) to obtain 10 g of the title compound. b) Preparation of (2E)-3-chloro-1-cyclopropylprop-2-en-1-one Under a nitrogen atmosphere, (2Z)-1-cyclopropyl-3-(dioxy)prop-2-en-1-one (15 g) was added to a solution of dichloromethane (300 mL) and oxalyl chloride (28.39 g) was added dropwise. The reaction system was stirred at room temperature for 2 hours. After completion of the reaction, saturated sodium bicarbonate (100 mL) was added to quench the reaction, followed by extraction with dichloromethane (3 × 100 mL). The organic layers were combined, washed with saturated brine (1 × 200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography (mobile phase: dichloromethane / petroleum ether = 3 / 10 (V / V)) to obtain 6.5 g of the title compound. c) Preparation of 2-amino-3,5-dibromo-1-[(1E)-3-cyclopropyl-3-oxoprop-1-en-1-yl]pyridin-4-one (2E)-3-Chloro-1-cyclopropylprop-2-en-1-one (6.5 g) and 2-amino-3,5-dibromopyridin-4-ol (14.67 g) were added to a flask, and N,N-dimethylformamide (130 mL) and potassium carbonate (20.64 g) were added at room temperature under a nitrogen atmosphere. The mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic phase was washed with saturated brine (2 × 300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 1 (V / V)) to give the title compound (5.3 g). d) Preparation of 7,9-dibromo-2-cyclopropyl-8H-pyridine[1,2-a]pyrimidin-8-one A flask was charged with 2-amino-3,5-dibromo-1-[(1E)-3-cyclopropyl-3-oxypropionate-1-en-1-yl]pyridin-4-one (5.3 g), and hydrogen chloride (4 M, 50 mL) and 1,4-dioxane (50 mL) were added under nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), adjusted to pH 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (3 × 100 mL), the combined organic phases were washed with saturated brine (1 × 40 mL), dried over anhydrous sulfuric acid, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (mobile phase: methanol / dichloromethane = 1 / 10 (V / V)) afforded 2.3 g of the title compound. e) Preparation of 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazol-5-yl)-8H-pyridinyl[1,2-a]pyrimidin-8-one A flask was charged with 7,9-dibromo-2-cyclopropyl-8H-pyridine[1,2-a]pyrimidin-8-one (100 mg), 2-methyl-2H-indazol-5-ylboronic acid (56.27 mg), 1,4-dioxane (2 mL), potassium carbonate (120.53 mg), water (0.4 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (23.68 mg). The mixture was stirred at 60°C for 1 hour under a nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (mobile phase: methanol / dichloromethane = 3 / 50 (V / V)) to give 50 mg of the title compound. f) Preparation of 2-cyclopropyl-9-[4-(difluoromethoxy)phenyl]-7-(2-methyl-2H-indazol-5-yl)-8H-pyridinyl[1,2-a]pyrimidin-8-one A flask was charged with 9-bromo-2-cyclopropyl-7-(2-methyl-2H-indazol-5-yl)-8H-pyridinyl[1,2-a]pyrimidin-8-one (40 mg), 4-(difluoromethoxy)phenylboronic acid (38.04 mg), 1,4-dioxane (1 mL), water (0.2 mL), potassium carbonate (41.96 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (7.40 mg). The mixture was stirred at 80°C for 1 hour under a nitrogen gas atmosphere, and the reaction mixture was concentrated under reduced pressure to prepare and isolate 15.4 mg of the title compound. Preparation and isolation conditions: (Column: XBridge Prep OBD C18, 30*150mm, 5μm; Mobile phase A: water (10mmol / L ammonium formate), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: 35% B to 75% B in 8 min, 75% B; Detection wavelength: 220nm; Retention time (min): 7.05; Column temperature: 25℃). 1 H NMR(400MHz,DMSO-d6)δ8.52-8.44(m,2H),8.41(s,1H),8.13(t,J=1.3Hz,1 H),7.61-7.56(m,2H),7.52-7.43(m,2H),7.29(t,J=72Hz,1H),7.20-7.08( m,2H),6.82(d,J=7.2Hz,1H),4.19(s,3H),2.05(ddd,J=16.9,8.3,4.2Hz,1 H),1.05(dq,J=6.7,3.7,3.2Hz,2H),0.93(dq,J=7.4,4.1,3.6Hz,2H).LCMS m / z=459[M+1] +

[0124] Example 26: 2-Cyclopropyl-9-(2,2-difluoro-1,3-benzodioxazol-5-yl)-7-(2-methyl-2H-indazol-5-yl)-8H-pyrido[1,2-a]pyrimidin-8-one [ka] It can be prepared by referring to the preparation method of Example 25, and in step f) 4-(difluoromethoxy)phenylboronic acid is replaced with 2,2-difluoro-1,3-benzodioxazol-5-ylboronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.49-8.44(m,2H),8.41(s,1H),8.17-8.12(m,1H),7. 65-7.59(m,1H),7.56(dd,J=9.0,1.6Hz,1H),7.41(d,J=1.6Hz,1H),7.37(d,J= 8.4Hz,1H),7.25(dd,J=8.4,1.6Hz,1H),6.85(d,J=7.2Hz,1H),4.19(s,3H),2. 06(dt,J=8.0,3.6Hz,1H),1.11-1.02(m,2H),0.94(dt,J=4.5,3.2Hz,2H).LCMS m / z=473.05[M+1] +

[0125] Example 27: 2-Cyclopropyl-9-(2,2-difluoro-1,3-benzodioxazol-5-yl)-7-[4-(difluoromethoxy)phenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] Prepare by referring to the preparation method of Example 25, replacing 2-methyl-2H-indazol-5-ylboronic acid with 4-(difluoromethoxy)phenylboronic acid in step e), and replacing 4-(difluoromethoxy)phenylboronic acid with 2,2-difluoro-1,3-benzodioxazol-5-ylboronic acid in step f). 1H NMR(400MHz,DMSO-d6)δ8.52-8.31(m,2H),7.86-7.68(m,2H),7.42-7.32(m,2H),7.30(t,J=72.0Hz,1H),7.28-7.17(m ,3H),6.86(d,J=7.2Hz,1H),2.06(dp,J=12.5,4.5,4.0Hz,1H),1.06(dq,J=7.0,3.7Hz,2H),0.93(t,J=3.8Hz,2H).LCMS m / z=485[M+1] +

[0126] Example 28: 7,9-Bis(2H-1,3-benzodioxazol-5-yl)-2-cyclopropyl-8H-pyridine[1,2-a]pyrimidin-8-one [ka] It can be prepared by referring to the preparation method of Example 25, and in step e) and step f), 2-methyl-2H-indazol-5-yl-boronic acid and 4-(difluoromethoxy)phenylboronic acid are replaced with 2H-1,3-benzodioxazol-5-yl-boronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.36(d,J=7.3Hz,1H),8.33(s,1H),7.34(d,J=1.7Hz,1H),7.21(dd,J=8.1,1.7Hz,1H),6.98(d,J=8.1Hz,1H),6.91-6.88(m, 1H),6.88-6.82(m,2H),6.78(d,J=7.2Hz,1H),6.05(s,2H),6.01(s,2H),2 .06-1.97(m,1H),1.07-0.99(m,2H),0.95-0.87(m,2H).LCMSm / z=427[M+1] +

[0127] Example 29: 2-Cyclopropyl-7,9-bis(2-methyl-2H-indazol-5-yl)-8H-pyrido[1,2-a]pyrimidin-8-one [ka] It can be prepared by referring to the preparation method of Example 25, and in step e) and step f), 2-methyl-2H-indazol-5-yl-boronic acid and 4-(difluoromethoxy)phenylboronic acid can be replaced with 2-methyl-2H-indazol-5-yl-boronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.48-8.38(m,3H),8.28(s,1H),8.15(s,1H),7.69(s,1H),7.64-7.54(m,2H),7.49(d,J=8.9Hz,1H),7.24(dd,J=9. 0,1.5Hz,1H),6.81(d,J=7.2Hz,1H),4.18(d,J=5.0Hz,6H),2.01(d,J=4.5Hz,1H),1.00(dd,J=7.7,3.6Hz,2H),0.88(d,J=4.3Hz,2H).LCMS m / z=447[M+1] +

[0128] Example 30: 2-Cyclopropyl-7,9-bis(2,2-difluoro-1,3-benzodioxazol-5-yl)-8H-pyrido[1,2-a]pyrimidin-8-one [ka] It can be prepared by referring to the preparation method of Example 25, and in step e) and step f), 2-methyl-2H-indazol-5-yl-boronic acid and 4-(difluoromethoxy)phenylboronic acid are replaced with 2,2-difluoro-1,3-benzodioxazol-5-yl-boronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.41(d,J=7.2Hz,1H),7.80(d,J=1.6Hz,1H),7.59-7.47(m,2H),7.41-7.33(m,2H),7.22(dd, LCMS m / z=499[M+1] +

[0129] Example 31: 2-Cyclopropyl-7,9-bis(3,4-dimethoxyphenyl)-8H-pyrido[1,2-a]pyrimidin-8-one [ka] It can be prepared by referring to the preparation method of Example 25, and in step e) and step f), 2-methyl-2H-indazol-5-yl-boronic acid and 4-(difluoromethoxy)phenylboronic acid are replaced with 3,4-dimethoxyphenylboronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.38(d,J=7.3Hz,1H),8.34(s,1H),7.43(d,J=2.0Hz,1H),7.29(dd,J=8.4,2.0Hz,1H),7.01(d,J=8.5Hz,1H),6. 98-6.90(m,3H),6.79(d,J=7.2Hz,1H),3.84-3.76(m,9H),3.71(s,3H),2.04(m,1H),1.06-0.98(m,2H),0.92(dd,J=4.9,2.7Hz,2H).LCMS m / z=459[M+1] +

[0130] Example 32: 7-(2H-1,3-benzodioxazol-5-yl)-2-cyclopropyl-9-(2,2-difluoro-1,3-benzodioxazol-5-yl)pyridine[1,2-a]pyrimidin-8-one [ka] Prepare by referring to the preparation method of Example 25, replacing 2-methyl-2H-indazol-5-ylboronic acid with 2H-1,3-benzodioxazol-5-ylboronic acid in step e), and replacing 4-(difluoromethoxy)phenylboronic acid with (2,2-difluoro-2H-1,3-benzodioxazol-5-yl)boronic acid in step f). 1H NMR(400MHz,DMSO-d6)δ8.44-8.35(m,2H),7.41-7.31(m,3H),7.22(td,J=8.1,1.7Hz,2H),6.99(d,J=8.1 Hz,1H),6.84(d,J=7.2Hz,1H),6.05(s,2H),2.08-2.00(m,1H),1.09-1.01(m,2H),0.95-0.88(m,2H).LCMS m / z=463[M+1] +

[0131] Example 33: 2-Cyclopropyl-9-(2,2-difluoro-1,3-benzodioxazol-5-yl)-7-(3,4-dimethoxyphenyl)-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] Prepare by referring to the preparation method of Example 25, replacing 2-methyl-2H-indazol-5-yl-boronic acid with 3,4-dimethoxyphenylboronic acid in step e), and replacing 4-(difluoromethoxy)phenylboronic acid with 2,2-difluoro-1,3-benzodioxazol-5-yl-boronic acid in step f). 1 H NMR(400MHz,DMSO-d6)δ8.43(d,J=7.3Hz,1H),8.39(s,1H),7.45(d,J=2.1Hz ,1H),7.39-7.33(m,2H),7.30(dd,J=8.3,2.0Hz,1H),7.21(dd,J=8.4,1.6Hz, 1H),7.02(d,J=8.4Hz,1H),6.84(d,J=7.2Hz,1H),3.78(d,J=8.1Hz,6H),2.0 4(dt,J=8.0,3.7Hz,1H),1.11-1.01(m,2H),0.92(dt,J=4.5,3.1Hz,2H).LCMS m / z=479[M+1] +

[0132] Example 34: 2-Cyclopropyl-9-(2,2-difluoro-1,3-benzodioxazol-5-yl)-7-[4-(difluoromethoxy)-3-methoxyphenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] a) Preparation of 4-bromo-1-(difluoromethoxy)-2-methoxybenzene A flask was charged with 4-bromo-2-methoxyphenol (2 g) and sodium 2-chloro-2,2-difluoroacetate (1.65 g), and N,N-dimethylformamide (30 mL) was added. Potassium carbonate (1.63 g) was added under a nitrogen atmosphere. The mixture was stirred at 90°C for 23 hours, after which the resulting reaction mixture was filtered and the filter cake was washed with ethyl acetate (2 x 200 mL). The filtrate was concentrated under reduced pressure. The product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 3 / 10 (V / V)) to give 500 mg of the title compound. b) Preparation of 2-[4-(difluoromethoxy)-3-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A flask was charged with 4-bromo-1-(difluoromethoxy)-2-methoxybenzene (200 mg), bis(pinacolato)diboron (301.06 mg), and 1,4-dioxane (4 mL). Potassium acetate (232.71 mg) was added under a nitrogen atmosphere, and the mixture was stirred at 80°C for 3 hours. The reaction mixture was then concentrated under reduced pressure. The mixture was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 1 / 10 (V / V)) to give 200 mg of the title compound. c) Preparation of 9-bromo-2-cyclopropyl-7-[4-(difluoromethoxy)-3-methoxyphenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one It can be prepared by referring to the preparation method of Example 25, and in step e), 2-methyl-2H-indazol-5-yl-boronic acid is replaced with 2-[4-(difluoromethoxy)-3-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. d) Preparation of 2-cyclopropyl-9-(2,2-difluoro-1,3-benzodioxazol-5-yl)-7-[4-(difluoromethoxy)-3-methoxyphenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one It can be prepared by referring to the preparation method of Example 25, and in step f) 4-(difluoromethoxy)phenylboronic acid is replaced with 2,2-difluoro-1,3-benzodioxazol-5-yl-boronic acid. 1 H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.42(d,J=7.3Hz,1H),7.60(d,J=2.0Hz,1H),7.40-7.35(m,2H),7.30(d,J=1.4Hz,1H),7.26-7.20(m,2H) ,7.12(t,J=74Hz,1H),6.87(d,J=7.2Hz,1H),3.85(s,3H),2.06(tt,J=8.1,4.6Hz,1H),1.06(dq,J=6.9,3.7Hz,2H),0.93(p,J=3.7Hz,2H).LCMS m / z=515[M+1] +

[0133] Example 35: 9'-(2-cyclopropyl-9-(4-(difluoromethoxy)phenyl)-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one [ka] a) Preparation of 9'-(9-bromo-2-cyclopropyl-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one In a nitrogen gas atmosphere, 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one (60 mg), 7,9-dibromo-2-cyclopropyl-8H-pyrido[1,2-a]pyrimidin-8-one (60.9 mg), potassium carbonate (73.3 mg) were mixed with 1,4-dioxane (2 mL) and water (0.4 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (9.8 mg) was added, heated to 60 ° C, and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane=0-1 / 24 (V / V)) to obtain 50 mg of the title compound. MS(ESI+):477.85(M+H). b) Preparation of 9'-(2-cyclopropyl-9-(4-(difluoromethoxy)phenyl)-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one In a nitrogen gas atmosphere, 9'-(9-bromo-2-cyclopropyl-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one (60 mg), 4-(difluoromethoxy)phenylboronic acid (47.4 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.3 mg), potassium carbonate (52.23 mg) were mixed with 1,4-dioxane (2 mL) and water (0.4 mL), heated to 80°C, and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by preparative chromatography (column: XBridge Prep OBD C18, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium formate); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 60% B in 8 min, 60% B; detection wavelength: 220 nm; retention time (min): 7.37; column temperature: 25°C) to obtain 14.9 mg of the title compound. 1 H NMR(400MHz,DMSO-d6):δ8.60-8.40(m,4H),7.81(dd,J=9.0,0.9Hz,1H),7.72(dd, J=9.0,1.7Hz,1H),7.52-7.48(m,2H),7.29(t,J=74Hz1H),7.19-7.12(m,2H),6.84 (d,J=7.2Hz,1H),4.65(s,2H),2.05(ddd,J=12.7,8.4,4.8Hz,1H),1.09-1.03(m,2 H),0.99(d,J=4.3Hz,2H),0.94(ddd,J=6.5,4.7,2.4Hz,4H).MS(ESI+):540(M+H).

[0134] Example 36: 9'-(2-cyclopropyl-9-(4-(difluoromethoxy)phenyl)-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one [ka] a) Preparation of 2'-methyl-9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one In a nitrogen atmosphere, 9'-bromo-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one (100 mg), bis(pinacolato)diboron (99.5 mg), and potassium acetate (96.2 mg) were mixed in 1,4-dioxane (10 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13.3 mg) was added. The mixture was heated to 80 °C and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-1 / 1 (V / V)) to obtain 60 mg of the title compound. MS(ESI+):353.95(M+H). b) Preparation of 9'-(9-bromo-2-cyclopropyl-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one In a nitrogen gas atmosphere, 2'-methyl-9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one (50 mg), 7,9-dibromo-2-cyclopropyl-8H-pyrido[1,2-a]pyrimidin-8-one (48.7 mg), potassium carbonate (58.7 mg) were mixed in 1,4-dioxane (5 mL) and water (1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11.5 mg) was added, heated to 60 ° C, and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane=0-1 / 24 (V / V)) to obtain 50 mg of the title compound. MS(ESI+): 491.90(M+H). c) Preparation of 9'-(2-cyclopropyl-9-(4-(difluoromethoxy)phenyl)-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one In a nitrogen gas atmosphere, 9'-(9-bromo-2-cyclopropyl-8-oxo-8H-pyrido[1,2-a]pyrimidin-7-yl)-2'-methyl-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one (50 mg), 4-(difluoromethoxy)phenylboronic acid (38.3 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (8.3 mg), potassium carbonate (42.3 mg) were mixed with 1,4-dioxane (2 mL) and water (0.4 mL), and the mixture was heated to 80°C and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by preparative chromatography (column: YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium formate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 67% B in 8 min, 67% B; detection wavelength: 220 nm; retention time (min): 8.15; column temperature: 25°C) to obtain 12.2 mg of the title compound. 1 H NMR(400MHz,DMSO-d6):δ8.52-8.39(m,3H),7.80(dd,J=9.0,0.9Hz,1H),7.71(dd,J=9 .0,1.7Hz,1H),7.52-7.48(m,2H),7.29(t,J=74Hz,1H),7.19-7.13(m,2H),6.84(d,J= 7.2Hz,1H),4.67(s,2H),2.90(s,3H),2.05(t,J=4.4Hz,1H),1.33-1.22(m,2H),1.09- 1.02(m,2H),1.00(d,J=6.5Hz,2H),0.94(dd,J=5.2,2.6Hz,2H).MS(ESI+):554(M+H).

[0135] Example 37: 2-Cyclopropyl-7,9-bis(4-(difluoromethoxy)-3-methoxyphenyl)-8H-pyrido[1,2-a]pyrimidin-8-one [ka] a) Preparation of 2-cyclopropyl-7,9-bis(4-(difluoromethoxy)-3-methoxyphenyl)-8H-pyrido[1,2-a]pyrimidin-8-one In a nitrogen gas atmosphere, 2-(4-(difluoromethoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg), 7,9-dibromo-2-cyclopropyl-8H-pyrido[1,2-a]pyrimidin-8-one (28.7 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (13.6 mg), and potassium carbonate (69.1 mg) were mixed with 1,4-dioxane (1 mL) and water (0.2 mL), heated to 80°C, and stirred for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by preparative chromatography (column: XBridge Prep OBD C18, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium formate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 65% B in 8 min, 65% B; detection wavelength: 220 nm; retention time (min): 9.28; column temperature: 25°C) to obtain 13.8 mg of the title compound. 1H NMR(400MHz,DMSO-d6):δ8.44(s,1H),8.40(d,J=7.2Hz,1H),7.59(d,J=1.9Hz,1H),7.31(dd,J=8 .5,2.1Hz,1H),7.25(s,1H),7.16(d,J=1.9Hz,1H),7.13(t,J=72Hz,1H),7.11(d,J=2.0Hz,1H),7. 09(t,J=64Hz,1H),6.99(dd,J=8.3,1.9Hz,1H),6.85(d,J=7.2Hz,1H),3.85(s,3H),3.79(s,3H), 2.06(tt,J=8.2,4.5Hz,1H),1.09-1.02(m,2H),0.94(dt,J=4.5,3.2Hz,2H).MS(ESI+):530(M+H).

[0136] Example 38: 2-Cyclopropyl-9-(4-(difluoromethoxy)phenyl)-7-(2'-methyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-9'-yl)-8H-pyrido[1,2-a]pyrimidin-8-one [ka] a) Preparation of 9'-bromo-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] 9'-Bromo-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-1'(2'H)-one (100 mg) was mixed with tetrahydrofuran (2 mL), and borane tetrahydrofuran solution (1 M, 1.7 mL) was added. The mixture was heated to 70°C and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, 20 mL of diethyl ether was added, and the mixture was suction filtered. The filter cake was washed twice with 20 mL of diethyl ether to obtain 25 mg of the title compound. MS(ESI+): 279.65(M+H). b) Preparation of 9'-bromo-2'-methyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] 9'-Bromo-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] (200 mg) and sodium hydride (60%, 86.3 mg) were mixed in N,N-dimethylformamide (10 mL), and methyl iodide (408.2 mg) was added in an ice bath. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was quenched by adding water in an ice bath, and the reaction solution was extracted three times with 30 mL of ethyl acetate. The organic phases were combined and washed with 30 mL of saturated brine. The organic phase was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-100% (V / V)) to obtain 70 mg of the title compound. MS(ESI+): 293.85(M+H). c) Preparation of 2'-methyl-9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] Under a nitrogen atmosphere, 9'-bromo-2'-methyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] (80 mg), bis(pinacolato)diboron (83.4 mg), and potassium acetate (80.62 mg) were mixed in 1,4-dioxane (8 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22.3 mg) was added. The mixture was heated to 80°C and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether = 0-100% (V / V)) to obtain 70 mg of the title compound. MS(ESI+): 339.65(M+H). d) Preparation of 9-bromo-2-cyclopropyl-7-(2'-methyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-9'-yl)-8H-pyrido[1,2-a]pyrimidin-8-one In a nitrogen gas atmosphere, 2'-methyl-9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] (70 mg), 7,9-dibromo-2-cyclopropyl-8H-pyrido[1,2-a]pyrimidin-8-one (71 mg), potassium carbonate (85.6 mg) were mixed with 1,4-dioxane (1.75 mL) and water (0.35 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11.5 mg) was added, heated to 60 ° C, and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane=0-1 / 10 (V / V)) to obtain 60 mg of the title compound. MS(ESI+): 477.90(M+H). e) Preparation of 2-cyclopropyl-9-(4-(difluoromethoxy)phenyl)-7-(2'-methyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-9'-yl)-8H-pyrido[1,2-a]pyrimidin-8-one In a nitrogen gas atmosphere, 9-bromo-2-cyclopropyl-7-(2'-methyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-9'-yl)-8H-pyrido[1,2-a]pyrimidin-8-one (60 mg), 4-(difluoromethoxy)phenylboronic acid (35.5 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.3 mg), potassium carbonate (52.2 mg) were mixed with 1,4-dioxane (2 mL) and water (0.4 mL), heated to 80°C, and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by preparative chromatography (column: XBridge Prep OBD C18, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium formate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 20% B to 58% B in 8 min, 58% B; detection wavelength: 220 nm; retention time (min): 7.58; column temperature: 25°C) to obtain 15.9 mg of the title compound. 1 H NMR(400MHz,DMSO-d6):δ8.46-8.41(m,2H),8.13(d,J=1.3Hz,1H),7.57(d,J=1.3Hz,2H ),7.48-7.45(m,2H),7.27(t,J=72Hz,1H),7.17-7.11(m,2H),6.82(d,J=7.2Hz,1H),4.3 0(d,J=17.1Hz,4H),2.39(s,3H),2.04(tt,J=8.1,4.7Hz,1H),1.04(dd,J=7.9,3.3Hz,2H ),0.93(t,J=3.8Hz,2H),0.82(t,J=2.9Hz,2H),0.76-0.68(m,2H).MS(ESI+):540(M+H).

[0137] Example 39: 2-Cyclopropyl-9-(4-(difluoromethoxy)phenyl)-7-(1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-9'-yl)-8H-pyrido[1,2-a]pyrimidin-8-one [ka] a) Preparation of 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] In a nitrogen atmosphere, 9'-bromo-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] (20 mg), bis(pinacolato)diboron (21.91 mg), and potassium acetate (21.17 mg) were mixed in 1,4-dioxane (2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.93 mg) was added. The mixture was heated to 80 °C and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane = 0-1 / 10 (V / V)) to obtain 26 mg of the title compound. MS(ESI+):326.10(M+H). b) Preparation of 9-bromo-2-cyclopropyl-7-(1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-9'-yl)-8H-pyrido[1,2-a]pyrimidin-8-one In a nitrogen gas atmosphere, 9'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazole] (70 mg), 7,9-dibromo-2-cyclopropyl-8H-pyrido[1,2-a]pyrimidin-8-one (74 mg), potassium carbonate (89.2 mg) were mixed with 1,4-dioxane (2 mL) and water (0.4 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11.9 mg) was added, heated to 60°C, and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated to dryness, and the crude product was purified by column chromatography (mobile phase: methanol / dichloromethane=0-1 / 15 (V / V)) to obtain 60 mg of the title compound. MS(ESI+): 464.00(M+H). c) Preparation of 2-cyclopropyl-9-(4-(difluoromethoxy)phenyl)-7-(1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-9'-yl)-8H-pyrido[1,2-a]pyrimidin-8-one In a nitrogen gas atmosphere, 9-bromo-2-cyclopropyl-7-(1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-pyrazino[1,2-b]indazol]-9'-yl)-8H-pyrido[1,2-a]pyrimidin-8-one (60 mg), 4-(difluoromethoxy)phenylboronic acid (36.6 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.6 mg), potassium carbonate (53.8 mg) were mixed with 1,4-dioxane (2 mL) and water (0.4 mL), heated to 80°C, and stirred for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by preparative chromatography (column: YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L ammonium formate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 50% B in 10 min, 50% B; detection wavelength: 220 nm; retention time (min): 9.28; column temperature: 25°C) to obtain 18.5 mg of the title compound. 1 H NMR(400MHz,DMSO-d6):δ8.45(d,J=7.5Hz,2H),8.13(d,J=1.3Hz,1H),7.56(d,J=1.2Hz, 2H),7.47-7.45(m,2H),7.28(t,J=74Hz,1H),7.17-7.11(m,2H),6.82(d,J=7.1Hz,1H),4 .26(s,4H),3.21(s,2H),2.03(dt,J=8.0,3.6Hz,1H),1.04(dq,J=6.7,3.7,3.2Hz,1H),0 .93(q,J=3.5Hz,2H),0.80-0.72(m,2H),0.69(q,J=5.1,4.3Hz,2H).MS(ESI+):526(M+H).

[0138] Example 40: 4-Cyclopropyl-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] a) Preparation of 1-cyclopropyl-3,3-dimethoxypropylene-1-one Sodium (Z)-3-cyclopropyl-3-oxoprop-1-en-1-ate (10 g), methanol (100 mL), and concentrated sulfuric acid (4.4 mL) were added to a flask and stirred at 60° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was then cooled to 0° C. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 mL). The combined organic layer was washed with saturated brine (1×300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 6 g of the title compound. b) Preparation of 7,9-dibromo-4-cyclopropyl-8H-pyridine[1,2-a]pyrimidin-8-one A flask was charged with 1-cyclopropyl-3,3-dimethoxypropylene-1-one (500 mg), 2-amino-3,5-dibromopyridin-4-ol (564.50 mg), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 10 mL) was added, followed by stirring overnight at room temperature under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give the title compound (720 mg). c) Preparation of 4-cyclopropyl-7,9-bis[4-(difluoromethoxy)phenyl]-8H-pyridinyl[1,2-a]pyrimidin-8-one 27,9-Dibromo-4-cyclopropyl-8H-pyridine[1,2-a]pyrimidin-8-one (500 mg), 1,4-dioxane (10 mL), water (2 mL), 4-(difluoromethoxy)phenylboronic acid (273.16 mg), potassium carbonate (401.75 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (47.36 mg) were added to a flask, and the mixture was stirred at 80°C for 2 hours under a nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure, and 2 mg of the title compound was isolated. Preparation and isolation conditions: (Column: XBridge Prep OBD C18, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L ammonium formate), Mobile phase B: Acetonitrile; Flow rate: 60mL / min; Gradient: 25% B to 65% B in 8 min, 65% B; Detection wavelength: 220nm; Retention time (min): 7.07; Column temperature: 25℃) 1 H NMR(400MHz,DMSO-d6)δ8.78(s,1H),8.40(d,J=4.1Hz,1H),7.91-7.78(m,2H),7.42-7.37(m,2H),7.32-7.25(m,2H),7.29(t,J=74.0Hz,1H), 7.31(t,J=74.0Hz,1H),7.20-7.14(m,2H),6.76(d,J=4.3Hz,1H),2.49-2.42(m,1H),1.27-1.17(m,2H),1.03-0.95(m,2H).LCMSm / z=471[M+1] +

[0139] Example 41: 7,9-bis(4-(difluoromethoxy)phenyl)-4-methyl-2-((2,2,2-trifluoroethyl)amino)-8H-pyrido[1,2-a]pyrimidin-8-one [ka] a) Preparation of 2-(2-methyl-1,3-dioxolan-2-yl)acetic acid Ethyl 2-(2-methyl-1,3-dioxolan-2-yl)acetate (16 g), water (80 mL), and ethanol (80 mL) were placed in a flask and stirred at room temperature. Potassium hydroxide (15.46 g) was added, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was concentrated to 50 mL and acidified to pH 4 with 1 M HCl (aqueous). The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, washed with saturated brine (1 × 100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 12 g of the title compound. b) Preparation of N-(3,5-dibromo-4-hydroxypyridin-2-yl)-2-(2-methyl-1,3-dioxolan-2-yl)acetamide To a stirred solution of 2-(2-methyl-1,3-dioxolan-2-yl)acetic acid (1.64 g) in N,N-dimethylformamide (30 mL) was added 1-hydroxybenzotriazole (1.51 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5.72 g), N,N-diisopropylethylamine (5.79 g), and 2-amino-3,5-dibromopyridin-4-ol (1.5 g). The mixture was stirred at 80°C under nitrogen gas protection for 3 hours. After completion of the reaction, the reaction mixture was concentrated. The residue was crudely fractionated by silica gel column chromatography and eluted with ethyl acetate / petroleum ether (20%-100%) to give 700 mg of the crude product. This was then purified by silica gel column chromatography (ethyl acetate / petroleum ether-methanol / dichloromethane (20%-100%)-(0-10%)) to give 450 mg of the title compound. c) Preparation of 7,9-dibromo-4-hydroxy-4-methyl-3,4-dihydro-2H-pyridine[1,2-a]pyrimidine-2,8(1H)-dione N-(3,5-dibromo-4-hydroxypyridin-2-yl)-2-(2-methyl-1,3-dioxolan-2-yl)acetamide (1 g) and aqueous hydrochloric acid (8 M, 20 mL) were placed in a flask and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to 5 mL. The mixture was filtered and washed with water (1 x 3 mL) to give 500 mg of the title compound. d) Preparation of 7,9-dibromo-4-methyl-2H-pyrido[1,2-a]pyrimidine-2,8(1H)-dione To a solution of 7,9-dibromo-4-hydroxy-4-methyl-3,4-dihydro-2H-pyridine[1,2-a]pyrimidine-2,8(1H)-dione (500 mg) in toluene (20 mL) was added 4-methylphenylsulfonic acid (122 mg). The mixture was stirred at 90°C under nitrogen gas protection for 1 hour. After completion of the reaction, the reaction mixture was concentrated and suspended in acetonitrile. Filtration afforded 120 mg of the title compound. e) Preparation of 7,9-dibromo-4-methyl-2-(((2,2,2-trifluoroethyl)amino)-8H-pyridinyl[1,2-a]pyrimidin-8-one 7,9-Dibromo-4-methyl-2H-pyrido[1,2-a]pyrimidine-2,8(1H)-dione (80 mg), 2,2,2-trifluoroethylamine (48 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (137 mg), and N,N-dimethylformamide (3 mL) were placed in a flask and stirred. N,N-Diisopropylethylamine (92.9 mg) was then added and stirred at room temperature for 2 hours. After completion of the reaction, the resulting mixture was washed with water (1 × 5 mL). The mixture was filtered and washed with water (3 × 5 mL) to give 40 mg of the title compound. f) Preparation of 7,9-bis(4-(difluoromethoxy)phenyl)-4-methyl-2-((2,2,2-trifluoroethyl)amino)-8H-pyrido[1,2-a]pyrimidin-8-one A flask was charged with 7,9-dibromo-4-methyl-2-(((2,2,2-trifluoroethyl)amino)-8H-pyridinyl[1,2-a]pyrimidin-8-one (46 mg), 4-(difluoromethoxy)phenylboronic acid (63 mg), potassium carbonate (61 mg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (18 mg), water (0.4 mL), and 1,4-dioxane (2 mL). The mixture was stirred at 80°C under nitrogen gas protection for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. A preparative HPLC column (Xselect CSH C18 OBD column 30 x 150 mm 5 μm, n; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 8 min) was used. The mixture was purified by HPLC (68%B, 68%B; wavelength: 220 nm; RT1 (min): 7.38; run number: 0; column temperature: 25°C). 22.5 mg of the title compound was obtained. 1 H NMR(400MHz,DMSO-d6)δ8.48(t,J=6.3Hz,1H),8.03(s,1H),7.84-7.75(m,2H),7.48-7.43(m,2H),7.29(t,J=74Hz1H),7.2 3(d,J=8.2Hz,3H),7.09(d,J=8.6Hz,2H),6.26(s,1H),4.00(dq,J=15.9,9.6,7.4Hz,2H),2.64(s,3H).LCMSm / z=542[M+1] +

[0140] Example 42: 7,9-bis(4-(difluoromethoxy)phenyl)-3-methyl-2-(((2,2,2-trifluoroethyl)amino)-8H-pyridinyl[1,2-a]pyrimidin-8-one [ka] a) Preparation of 3,3-dimethoxy-2-methylpropionic acid Methyl 3,3-dimethoxy-2-methylpropionate (9.8 g) and water (40 mL) were placed in a flask and stirred. A solution of sodium hydroxide (2.9 g) in water (20 mL) was added at room temperature. The mixture was stirred at 60°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature and acidified to pH 3 with 1 M aqueous hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give 6.9 g of the title compound. b) Preparation of N-(3,5-dibromo-4-hydroxypyridin-2-yl)-3,3-dimethoxy-2-methylpropionamide 3,3-Dimethoxy-2-methylpropionic acid (2 g), N,N-diisopropylethylamine (2.62 g), and N,N-dimethylformamide (60 mL) were placed in a flask and stirred, and dicyclohexylcarbodiimide (2.79 g) and 1-hydroxybenzotriazole (1.83 g) were added in batches. The resulting solution was stirred for 10 minutes, and 2-amino-3,5-dibromopyridin-4-ol (1.81 g) was added. The mixture was stirred at 80 °C for 22 hours. After the reaction was complete, the resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 15 mL). The filtrate was collected and concentrated to dryness. The crude product was purified by column chromatography (mobile phase: ethyl acetate / petroleum ether (0%-100%)) to give 510 mg of the title compound. c) Preparation of 7,9-dibromo-3-methyl-2H-pyrido[1,2-a]pyrimidine-2,8(1H)-dione N-(3,5-dibromo-4-hydroxypyridin-2-yl)-3,3-dimethoxy-2-methylpropionamide (510 mg) and aqueous hydrochloric acid (8 M, 15 mL) were placed in a flask and stirred at 50°C for 26 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was concentrated to give 200 mg of the target compound. d) Preparation of 7,9-dibromo-3-methyl-2-(((2,2,2-trifluoroethyl)amino)-8H-pyrido[1,2-a]pyrimidin-8-one Crude 7,9-dibromo-3-methyl-2H-pyrido[1,2-a]pyrimidine-2,8(1H)-dione (200 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (342 mg), and N,N-dimethylformamide (6 mL) were placed in a flask, and 2,2,2-trifluoroethylamine (119 mg) and N,N-diisopropylethylamine (232 mg) were added dropwise. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the resulting mixture was concentrated, and the residue was purified using a reverse-phase column (column: C18; mobile phase: acetonitrile / water, gradient increasing from 0% to 50% in 5 minutes; detector: UV at 254 nm). 60 mg of the title compound was obtained. e) Preparation of 7,9-bis(4-(difluoromethoxy)phenyl)-3-methyl-2-(((2,2,2-trifluoroethyl)amino)-8H-pyridinyl[1,2-a]pyrimidin-8-one A flask was charged with 7,9-dibromo-3-methyl-2-(((2,2,2-trifluoroethyl)amino)-8H-pyrido[1,2-a]pyrimidin-8-one (70 mg), 4-(difluoromethoxy)phenylboronic acid (63 mg), potassium phosphate (286 mg), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (21 mg), water (0.2 mL), and 1,4-dioxane (1 mL). The mixture was stirred at 80°C under nitrogen gas protection for 2 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure. A preparative HPLC column (Xselect CSH C18 OBD column 30 × 150 mm) was used. The column was purified using a 5 μm column (mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B to 60% B, 60% B in 8 min; wavelength: 220 nm; RT1 (min): 9.65; run count: 0; column temperature: room temperature). 18.3 mg of the title compound was obtained. 1H NMR(400MHz,DMSO-d6)δ8.24-8.00(m,3H),7.82-7.67(m,2H),7.55-7.44(m,3 LCMS m / z=542[M+1] +

[0141] Biological activity measurement 1. Enzymatic testing method for MAT2A 1. Test steps a) First, a 5x MAT2A test buffer (250 mM Tris-HCl, pH 8.0; 250 mM KCl; 75 mM MgCl2; 0.025% BSA; 0.05% Brij35; 1.5 mM EDTA) was prepared and a portion of it was diluted to 1x. b) Preparation and addition of MAT2A enzyme (BPS, 71401): MAT2A enzyme was prepared at 3.674 ng / μL (1.67×, final concentration 2.20 ng / μL) in 1× MAT2A test buffer, and 15 μL of 1.67× MAT2A enzyme solution was added to the compound test wells and negative control wells using a BioTek (MultiFlo FX) automated separatory dispenser. At the same time, 15 μL of 1× MAT2A test buffer was added to the blank control wells. c) Compound preparation and addition: The compounds to be tested were diluted in DMSO from a 10 mM stock solution to 100 μM. The positive reagent AGI-24512 was also diluted under the same conditions. A Tecan compound titrator (D300e) automatically sprayed each well according to a preset concentration gradient. The sprayed volume was negligible. The concentration gradient started with 1 μM and continued with 1 / 2 log dilutions, resulting in a total of eight steps. The mixture was centrifuged at 2500 rpm for 30 s and incubated at 25°C for 30 min. d) Preparation of ATP: 10 mM ATP (Sigma, A7699) was diluted to 700 μM using 1×MAT2A test buffer. e) Preparation and addition of the substrate and ATP mixture: 5x MAT2A test buffer, 3 μL / well; 750 μM L-methionine (Adamas, 01100469), 2.5 μL / well; 700 μM ATP, 2.5 μL / well; and double-distilled water, 2 μL / well. The total volume of the mixture required for the number of detection wells was prepared, and 10 μL was added per well using a BioTek (MultiFlo FX) automated separator. The mixture was centrifuged at 2500 rpm for 30 seconds and incubated at 25°C for 150 minutes. f) Addition of Biomol Green detection reagent: 50 μL of Biomol Green (Enzo, BML-AK111) was added per well using a BioTek (MultiFlo FX) automatic separator, followed by centrifugation at 2500 rpm for 30 s and incubation at 25°C for 20 min. g) After the reaction is complete, measure the OD using a Perkin Elmer (Envision2105) multifunction plate reader. 620 The value was read.

[0142] 2. Data Analysis The formula for calculating the inhibition rate was as follows:

number

[0143] 2. Cell test method 1. Test steps HCT116 MTAP- / - cells (purchased from Horizon Discovery): MTAP gene-deficient human colorectal cancer cell line was cultured in RPMI 1640 medium with 10% FBS (fetal bovine serum). On day 0 of the experiment, the cells in the logarithmic growth phase were adjusted to a viable cell density of 5,000 cells / ml and seeded into a 96-well plate at 100 μl per well. A blank group was placed in parallel, and the seeded cell plate was cultured overnight in an incubator at 37°C with 5% CO2.

[0144] On test day 1, the cell plates were removed from the overnight culture and the supernatant was discarded. 80 μl of serum-free RPMI 1640 medium was added per well and placed in an incubator for 4 hours of starvation. The test compounds were dissolved in DMSO (dimethyl sulfoxide) to prepare a 10 mM stock solution. After starvation, the cell plates were removed and 80 μl of RPMI 1640 + 20% FBS medium was added per well. The cell plates were then placed on a Tecan D300e automated liquid addition system. The test compound was diluted 3-fold with DMSO to a total of 10 concentrations, with two wells for each concentration. The final DMSO concentration in each well of the 96-well plate was 0.3% v / v. The previously prepared 10 mM stock solution was then removed and the reagents were added following the reagent addition sequence described above. After reagent addition, the cell plates were placed in an incubator and cultured for 120 hours.

[0145] On the sixth day of the test, the cell plates were removed, 50 μl / well of CellTiter-Glo® (purchased from Promega) was added, and the fluorescent signal was measured using Envision (PerkinElmer) according to the process flow in the instruction manual.

[0146] 2. Data Analysis The dose-effect curve (log(inhibitor) vs. response - variable slope) was fitted using GraphPad Prism 5 software to obtain the IC50 value of the compound's inhibition of cell proliferation. The formula for calculating the inhibition rate was:

number

[0147] 3. Test results: The IC50 of AGI-24512 for inhibition of MAT2A measured by the above test method was 23.2 nM, and the IC50 for inhibition of HCT116 MTAP- / - cells was 153.6 nM. IC of test compound inhibition of MAT2A 50 The following evaluation levels were assigned according to the size of the IC: (A) 50 (B) IC<50 nM 50 : 50nm~200nM; (C) IC 50 : 200nM~1000nM; (D) IC 50 :Exceeded 1000nM. IC of inhibition of test compounds against HCT116 MTAP- / - cells 50 The following evaluation levels were assigned according to the size of the IC: (A) 50 (B) IC<150 nM; 50 : 150nm~400nM; (C) IC 50 : 400nM~1000nM; (D) IC 50 :Exceeded 1000nM.

[0148] The test results for the compounds according to the present invention are shown in Table 1 below. [Table 1]

[0149] 3. HCT116 MTAP - / - In vivo efficacy test of subcutaneous xenograft tumors in nude mice 1. Test steps Female Nu / Nu nude mice (6-8 weeks old, Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.) were housed in an SPF animal room with a temperature of 20-25°C, relative humidity of 40%-70%, and a 12-hour light / dark cycle. Animals had free access to food and water. Prior to testing, the animals underwent acclimation.

[0150] HCT116 MTAP - / - Horizon cells were cultured and grown in vitro, and cells in the logarithmic growth phase were resuspended in serum-free RPMI-1640 medium to a cell concentration of 6.0 × 10 7 The cell suspension was adjusted to cells / mL, and 100 μL per mouse was injected subcutaneously into the right front axilla of nude mice using a 1 mL syringe. The condition of the animals was observed periodically to monitor the growth of the transplanted tumor.

[0151] Tumor volume 100-300mm 3 Once the tumor volume reached 100 mg / kg, animals with tumors that were too large, too small, or with uncertain tumor formation were discarded. Tumor-bearing mice in good health and with similar tumor volumes were selected and divided into groups of six using a randomized block design. The treatment group received daily intragastric administration of AG-270 (50 mg / kg, test compound: 1-7.5 mg / kg). The control group received daily intragastric administration of the same volume of blank solvent. During the treatment period, tumor diameters were measured twice weekly, tumor volumes were calculated, and animal weights were weighed and recorded.

[0152] Detection of SAM in transplanted tumors: On day 15 of administration, at the end of the study, animals were euthanized with CO2, tumor tissue was excised, washed with cold PBS, weighed, flash-frozen in liquid nitrogen, and cryopreserved at -80°C. The frozen tumor tissue was removed and thawed in an ice bath. Then, 80% aqueous methanol (containing 1M formic acid) was added at a ratio of 1:10 (w / v) to homogenize the tissue. The homogenized slurry was collected and processed for SAM (S-adenosylmethionine) detection by LC-MS / MS. The AG-270 structure is as follows: [ka]

[0153] 2. Data Analysis Tumor volume (TV) calculation formula: TV = 1 / 2 × a × b 2 In the formula, a represents the tumor's major axis and b represents the tumor's minor axis.

[0154] Relative tumor volume (RTV) calculation formula: RTV = TV t / TV initial ,In the formula, TV initial is the tumor volume measured at the time of administration in the group, and TV t indicates the administration period and the tumor volume at each measurement.

[0155] Calculation formula for relative tumor proliferation rate (T / C (%)): T / C% = (RTV T / RTV C )×100%, in the formula, RTV T indicates the relative tumor volume of the treatment group, and RTV C indicates the relative tumor volume of the vehicle control group.

[0156] Tumor growth inhibition (TGI) is calculated using the following formula: TGI = [1-(TV t(T)-TV initial(T) ) / (TV t(C) -TV initial(C) )]×100%, in the formula, TV t(T) indicates the tumor volume measured at each time point in the treatment group, and TV initial(T) indicates the tumor volume of the treatment group when administered in groups, and TV t(C) indicates the tumor volume of the vehicle control group measured at each time point, and TV initial(C) indicates the tumor volume in the solvent control group when administered in separate groups.

[0157] Calculation formula for animal weight loss rate: Animal weight loss rate = 100% × (BW initial -BW t ) / BW initial ,In the formula, BW t indicates the administration period and the body weight of the animals measured at each time, and BW initial indicates the body weight of the animals at the time of administration in groups.

[0158] Formula for calculating tumor inhibition rate (IR) based on tumor weight: IR = 100% × (W C -W T ) / W C , in the formula, W C indicates the tumor weight in the control group, and W T indicates tumor weight in treatment group.

[0159] Calculations and related statistical processing of test data were performed using Microsoft Office Excel 2007 software. Data are expressed as mean ± standard error (Mean ± SEM) unless otherwise specified, and comparisons between two groups were performed using t-tests.

[0160] 3. Test results: The tumor volume growth curves for each group are shown in FIG. 1, the intratumoral SAM detection results for each group are shown in FIG. 2, and the mean tumor volume values and SEM for each group are shown in Table 2 below. [Table 2]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof. 【Chemical 1】 (In Formula I, X is CR ４ and N, and Y is selected from CR ５ and N, Z is selected from CR ６ and N, W is selected from CR ７ and N, Here, R １ , R ４ , R ５ , and R ７ are each independently hydrogen, cyano, C2-C6 alkynyl, C8-C10 cycloalkynyl, halogen, hydroxy, NH ２ , (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, (C1-C6 alkyl)-S-, C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 10-membered aryl, C2-C6 alkenyl and C3-C6 cycloalkenyl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, C2-C6 alkenyl, C3-C6 cycloalkyl or C3-C6 cycloalkenyl optionally may be selected from the group consisting of halogen, cyano, hydroxy, -NR ８ R ９ , C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, wherein the 6- to 10-membered aryl is optionally substituted with halogen, hydroxy, cyano, -NR ８ R ９ , NO ２ , C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, or the 6- to 10-membered aryl is optionally substituted with halogen, hydroxy, cyano, -NR ８ R ９ Or NO ２ substituted by C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl substituted by R ６ is cyano, C2-C6 alkynyl, C8-C10 cycloalkynyl, halogen, hydroxy, NH ２ , (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, (C1-C6 alkyl)-S-, C1-C6 alkyl, C3-C6 cycloalkyl, 6- to 10-membered aryl, C2-C6 alkenyl and C3-C6 cycloalkenyl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, C2-C6 alkenyl, C3-C6 cycloalkyl or C3-C6 cycloalkenyl optionally may be selected from the group consisting of halogen, cyano, hydroxy, -NR ８ R ９ , C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, wherein the 6- to 10-membered aryl is optionally substituted with halogen, hydroxy, cyano, -NR ８ R ９ , NO ２ , C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl, or the 6- to 10-membered aryl is optionally substituted with halogen, hydroxy, cyano, -NR ８ R ９ Or NO ２ substituted by C1-C3 alkyl, C1-C3 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl substituted by R ２ and R ３ are each independently selected from a 6- to 10-membered aryl and a 9- to 18-membered benzoheterocyclic group, and the 6- to 10-membered aryl or 9- to 18-membered benzoheterocyclic group optionally contains halogen, hydroxy, cyano, -NR ８ R ９ , NO ２ , -NR １０ C(O)R １１ , C1-C6 alkyl group, (C1-C6 alkyl group)-O-, -C(O)NR １０ R １１ or a 5- to 7-membered heteroaryl group, wherein the C1-C6 alkyl group, (C1-C6 alkyl)-O-, or 5- to 7-membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O-, or -NR ８ R ９ is replaced by R ８ , R ９ , R １０ and R １１ are each independently selected from H and C1-C6 alkyl; The condition is that at most two of W, X, Y, and Z are N.

2. 2. The compound of claim 1, wherein the compound is a compound represented by the following formula II or formula III, or a pharmaceutically acceptable salt thereof. 【Chemistry 2】 (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ and R １１ is as defined in claim 1.

3. R １ , R ４ , R ５ , and R ７ are each independently hydrogen, halogen, hydroxy, NH ２ , (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl and 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl optionally may be halogen, cyano, hydroxy or -NR ８ R ９ wherein said 6-10 membered aryl is substituted with C1-C3 alkoxy optionally substituted with halogen; R ６ is halogen, hydroxy, NH ２ , (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl and 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl optionally may be halogen, cyano, hydroxy or -NR ８ R ９ wherein said 6-10 membered aryl is substituted by C1-C3 alkoxy optionally substituted by halogen; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ , R ４ , R ５ , and R ７ are each independently hydrogen, halogen, hydroxy, NH ２ , (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl and 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl is optionally substituted with halogen, and the 6- to 10-membered aryl is optionally substituted with halogen-substituted C1-C3 alkoxy; R ６ is halogen, hydroxy, NH ２ , (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl and 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl is optionally substituted with halogen, and the 6- to 10-membered aryl is substituted with C1-C3 alkoxy optionally substituted with halogen; 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. R １ , R ４ , R ５ , and R ７ are each independently hydrogen, halogen, hydroxy, NH ２ , (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl and 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl is optionally substituted with fluorine, and the 6- to 10-membered aryl is substituted with C1-C3 alkoxy optionally substituted with fluorine; R ６ is halogen, hydroxy, NH ２ , (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O-, C1-C6 alkyl, C3-C6 cycloalkyl and 6- to 10-membered aryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-NR ８ -, (C1-C6 alkyl)-O- or C3-C6 cycloalkyl is optionally substituted with fluorine, and the 6- to 10-membered aryl is substituted with C1-C3 alkoxy optionally substituted with fluorine; 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

6. R 1 is selected from hydrogen; 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

7. R ７ is selected from hydrogen, 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

8. R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

9. R ４ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, cyclopropyl, and C1-C6 alkyl.

10. R ４ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and C1-C6 alkyl.

11. R ４ 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen, a methyl group, and a cyclopropyl group.

12. R ４ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and a methyl group.

13. R ５ The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and C1-C6 alkyl.

14. R ５ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and methyl.

15. R ５ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen.

16. R ６ is chlorine, hydroxy, cyclopropyl, CF ３ CH ２ O-, CHF ２ O-, CF ３ CH ２ NH-, 4-difluoromethoxyphenyl and CH ３ CH ２ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from: O-.

17. R ６ is cyclopropyl, CF ３ CH ２ O-, CF ３ CH ２ NH- and CH ３ CH ２ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from: O-.

18. R ６ is a cyclopropyl group, CF ３ CH ２ O- and CF ３ CH ２ 9. The compound of claim 8, wherein the compound is selected from the group consisting of NH- and NH-; or a pharmaceutically acceptable salt thereof.

19. R ２ and R ３ are each independently selected from phenyl, naphthyl, and groups represented by the following formula: 【Chemistry 3】 wherein the groups are optionally halogen, hydroxy, cyano, -NR ８ R ９ , NO ２ , -NR １０ C(O)R １１ , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR １０ R １１ or 5-7 membered heteroaryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-O- or 5-7 membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O- or -NR ８ R ９ is replaced by 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. R ２ and R ３ are each independently selected from phenyl, naphthyl, and groups represented by the following formula: 【Chemistry 4】 wherein the groups are optionally halogen, hydroxy, cyano, -NR ８ R ９ , NO ２ , -NR １０ C(O)R １１ , C1-C6 alkyl, (C1-C6 alkyl)-O-, -C(O)NR １０ R １１ or 5-7 membered heteroaryl, wherein said C1-C6 alkyl, (C1-C6 alkyl)-O- or 5-7 membered heteroaryl is optionally substituted with halogen, cyano, hydroxy, C1-C3 alkyl, (C1-C3 alkyl)-O- or -NR ８ R ９ is replaced by 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

21. R ２ and R ３ are each independently selected from phenyl, naphthyl, and groups represented by the following formula: 【Chemistry 5】 wherein the group is optionally selected from halogen, cyano, —NR ８ R ９ , -NR １０ C(O)R １１ , substituted by C1-C6 alkyl, (C1-C6 alkyl)-O- or 5- to 7-membered heteroaryl, wherein the C1-C6 alkyl, (C1-C6 alkyl)-O- or 5- to 7-membered heteroaryl is optionally substituted by methyl, halogen or cyano. R ８ , R ９ , R １０ and R １１ are each independently selected from H and C1-C6 alkyl; 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

22. R 8, R ９ and R １０ are each independently selected from H; 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

23. R １１ is selected from C1 to C6 alkyl; 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

24. R １１ 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein is selected from methyl.

25. R ２ is selected from phenyl and a group represented by the formula: 【Chemistry 6】 wherein the group is optionally difluoromethoxy, methyl, NH ２ , methoxy, fluorine, cyanomethyl, CH ３ substituted with CONH-, 1-methyl-1H-imidazol-4-yl or 1-methyl-1H-pyrazol-5-yl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

26. The group may optionally be difluoromethoxy, methyl, NH ２ , substituted by methoxy, fluorine, cyanomethyl or 1-methyl-1H-pyrazol-5-yl; 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

27. R ２ is selected from the group represented by the following formula: 【Chemistry 7】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

28. R ２ is selected from the group represented by the following formula: 【Chemistry 8】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

29. R ２ is selected from the group represented by the following formula: 【Chemistry 9】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

30. R ２ is selected from the group represented by the following formula: 【Chemistry 10】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

31. R ３ is selected from phenyl and groups represented by the following formula: 【Chemistry 11】 wherein the group is optionally difluoromethoxy, methyl, NH ２ , fluorine, methoxy, CH ３ substituted with CONH-, 1-methyl-1H-imidazol-4-yl or 1-methyl-1H-pyrazol-5-yl.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

32. The group may optionally be difluoromethoxy, methyl, NH ２ substituted by fluorine, methoxy or 1-methyl-1H-pyrazol-5-yl; 32. The compound of claim 31, or a pharmaceutically acceptable salt thereof.

33. R ３ is selected from the group represented by the following formula: 【Chemistry 12】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

34. R ３ is selected from the group represented by the following formula: 【Chemistry 13】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

35. R ３ is selected from the group represented by the following formula: 【Chemistry 14】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

36. R ３ is selected from the group represented by the following formula: 【Chemistry 15】 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof.

37. The compound below or a pharmaceutically acceptable salt thereof. 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】

38. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

39. Use of a compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 38, in the preparation of a medicament for the prevention and / or treatment of a disease or disease state mediated by overexpression of MAT2A.

40. A process for preparing the compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, characterized in that the process is selected from the following synthesis schemes: Synthetic Scheme 1: 【Chemistry 20】 wherein X' is selected from chlorine, bromine and iodine; R ６ , R ２ and R ３ are as defined for compounds of formula I. The formula 1-1 compound is condensed with a formula 1-2a compound or a formula 1-2b compound under basic conditions to obtain a formula 1-3 compound, the formula 1-3 compound is reacted with a formula 1-4 compound to obtain a formula 1-5 compound, the formula 1-5 compound is trimethylsilyl-eliminated to obtain a formula 1-6 compound, the formula 1-6 compound is halogenated by the action of a halogenating reagent, formula 1-7 compound, to obtain a formula 1-8 compound, the formula 1-8 compound is condensed with a formula 1-9a compound or a formula 1-9b compound under basic conditions to obtain a formula 1-10 compound, the formula 1-10 compound is condensed with a formula 1-11a compound or a formula 1-11b compound under basic conditions to obtain a formula 1-12 compound, The compound of formula 1-4 is ethyl 3-(trimethylsilyl)propiolate. Synthetic Scheme 2: 【Chemical 21】 wherein X' is selected from chlorine, bromine and iodine; R ａ is selected from C1 to C3 alkyl, R ４ , R ５ , R ６ are as defined for compounds of formula I. The compound of formula 2-1 is halogenated by the action of a halogenating agent to obtain the compound of formula 2-2, and the compound of formula 2-2 and the compound of formula 2-3 are condensed to obtain the compound of formula 2-6, and the compound of formula 2-6 is cyclized under acidic conditions to obtain the compound of formula 2-9, or A condensation reaction between a compound of formula 2-2 and a compound of formula 2-4 to obtain a compound of formula 2-7, which is then cyclized under acidic conditions and the hydroxyl group is removed under acidic conditions to obtain a compound of formula 2-10, or A compound of formula 2-2 and a compound of formula 2-5 are subjected to a condensation reaction under basic conditions to obtain a compound of formula 2-8, and the compound of formula 2-8 is subjected to a cyclization reaction under acidic conditions to obtain a compound of formula 2-11, or The compound of formula 2-2 and the compound of formula 2-12 are subjected to a cyclization reaction to obtain the compound of formula 2-13. Synthetic Scheme 3: 【Chemical 22】 wherein X' is selected from chlorine, bromine and iodine; R ４ , R ２ and R ３ are as defined for compounds of formula I. The compound of formula 2-10 is reacted with trifluoroethylamine to obtain the compound of formula 3-1, the compound of formula 3-1 is condensed with the compound of formula 3-2a or 3-2b under basic conditions to obtain the compound of formula 3-3, and the compound of formula 3-3 is condensed with the compound of formula 3-4a or 3-4b under basic conditions to obtain the compound of formula 3-5. Synthetic Scheme 4: 【Chemical 23】 wherein X' is selected from chlorine, bromine and iodine; R ６ , R ２ and R ３ are as defined for compounds of formula I. The compound of formula 2-11 is condensed with a compound of formula 4-1a or 4-1b under basic conditions to obtain a compound of formula 4-2, and the compound of formula 4-2 is condensed with a compound of formula 4-3a or 4-3b under basic conditions to obtain a compound of formula 4-4. Synthetic Scheme 5: 【Chemistry 24】 wherein X' is selected from chlorine, bromine and iodine; R ５ , R ２ and R ３ are as defined for compounds of formula I. The compound of formula 2-9 is reacted with trifluoroethylamine in the presence of a condensing agent to give the compound of formula 5-1, the compound of formula 5-1 is condensed with the compound of formula 5-2a or 5-2b under basic conditions to give the compound of formula 5-3, the compound of formula 5-3 is condensed with the compound of formula 5-4a or 5-4b under basic conditions to give the compound of formula 5-5, or The compound of formula 2-9 is condensed with the compound of formula 5-6a or 5-6b under basic conditions to obtain the compound of formula 5-7, the compound of formula 5-7 is condensed with the compound of formula 5-8a or 5-8b under basic conditions to obtain the compound of formula 5-9, and the compound of formula 5-9 is reacted with trifluoroethanol in the presence of a condensing agent to obtain the compound of formula 5-10. Synthetic Scheme 6: 【Chemistry 25】 wherein X' is selected from chlorine, bromine and iodine; R ２ and R ３ are as defined for compounds of formula I. The compound of formula 2-13 is condensed with a compound of formula 6-1a or 6-1b under basic conditions to give a compound of formula 6-2, and the compound of formula 6-2 is condensed with a compound of formula 6-3a or 6-3b under basic conditions to give a compound of formula 6-4.

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