Novel compounds for inhibiting protein kinases and pharmaceutical compositions containing the same

Abstract

The present invention relates to novel compounds that inhibit protein kinases and pharmaceutical compositions containing them. More specifically, the compounds according to the present invention can effectively inhibit various protein kinases and can therefore be usefully used in the development of therapeutic drugs for protein kinase-related diseases, particularly cancer.

Description

[Technical Field]

[0001] The present invention relates to novel compounds for protein kinase inhibition and pharmaceutical compositions comprising the same. More specifically, the present invention relates to novel 6′-4-methylphenyl-5,6′-dihydro-7H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-7′-one compounds having protein kinase inhibitory activity, pharmaceutically acceptable salts thereof, hydrates thereof, or stereoisomers thereof, methods for preparing the compound, and pharmaceutical compositions comprising the compound for the prevention, improvement, or treatment of cancer. [Background technology]

[0002] Cells contain various cellular signaling pathways that control cell proliferation, growth, translocation, and apoptosis, and these components are intricately interconnected. When intracellular regulatory functions are disrupted due to genetic or environmental factors, abnormal cell proliferation or disruption of cellular signaling pathways can lead to the transformation of normal cells into malignant cells. Protein tyrosine kinases (PTKs) play a crucial role in cellular signaling involved in cell growth, differentiation, and proliferation. Abnormal mutations or overexpression of specific protein tyrosine kinases can disrupt normal intracellular signaling pathways, potentially leading to a variety of diseases, including cancer, inflammation, metabolic disorders, and neurological disorders. Protein tyrosine kinases (PTKs) catalyze the phosphorylation of tyrosine residues on substrate proteins, thereby mediating the transmission of extracellular growth factor signals to intracellular responses. Under normal conditions, the interaction between growth factors and their receptors regulates cell proliferation, but mutations or overexpression of receptor proteins can lead to abnormal signaling and potentially tumorigenesis. Therefore, there remains an unmet medical need for the development of more selective and effective protein tyrosine kinase inhibitors that exhibit enhanced anticancer efficacy compared to existing protein tyrosine kinase inhibitors. [Overview of the project] [Problems that the invention aims to solve]

[0003] The object of the present invention is to provide a compound having inhibitory activity against protein kinase. Another object of the present invention is to provide a pharmaceutical composition containing a novel compound that inhibits protein kinase for the prevention or treatment of protein kinase-related diseases. Furthermore, an object of the present invention is to provide a health functional food composition containing a novel compound for the improvement or prevention of protein kinase-related diseases. [Means for solving the problem]

[0004] The present invention provides compounds selected from the group consisting of compounds represented by the following formula 1, their stereoisomers, their pharmaceutically acceptable salts, their precursors, or their solvates: [ka] In Equation 1, R 1 and R 2 Each of these elements may be independently selected from hydrogen or (C1-C4) alkyl groups, or together they may form a 3-5 membered ring. X is selected from substituted or unsubstituted (C1-C4) alkyl, (C3-C6) cycloalkyl, (C4-C6) cycloalkenyl, phenyl, benzyl, or a 5 or 6-membered monocyclic or bicyclic heterocyclic, wherein the substituents are (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C2) alkoxy, halo, hydroxy, imidazolyl, or (C1-C2) alkyl One or more selected from the group consisting of midazolyl, (C1-C2)alkoxyphenyl, morpholino, cyano, oxo(=O), (C1-C2)alkoxy(C1-C2)alkyl(C1-C2)alkylamino, piperazinyl, (C1-C2)alkylpiperazinyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl, and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino, A is selected from morpholino or -NH-Y, where Y is hydrogen or a substituted or unsubstituted group selected from phenyl, benzyl, (C1-C4) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, pyridinyl, pyrazolyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or azetidinyl, and the substituent is (C1-C2) alkyl, (C1-C4) alkoxy, piperazinyl, (C1-C2) alkylpiperazinyl, acetylpiperazinyl, morpholino, morpholine-4-carbonyl, (C1-C2) alkylpiperazine-1-carbonyl, oxetanyl, ((C1-C2) alkylpiperazin-1-yl)(C1-C2) alkyl, imidazolyl, pyrrolidinyl, di(C1-C2) alkylaminopyrrolidinyl, piperidinyl, acetylpiperidinyl, di(C1-C2) alkylaminopiperidinyl, ((C1-C2) alkylpiperazin-1-yl)piperidinyl, halo, trifluoro(C1-C2) alkyl, trifluoro(C1-C2) alkoxy, di(C1-C2) alkylamino(C1-C2) alkyl(C1-C2) alkylamino, pyridinyl, furanyl, hydroxy, and tert-butoxy carbonyl (BOC), Z is CH or N; L is CH2 or NH; n1 or n2 may be an integer from 0 to 1. The present invention provides a pharmaceutical composition comprising a novel compound that inhibits protein kinase for the prevention or treatment of protein kinase-related diseases. Furthermore, the present invention provides a health functional food comprising a novel compound for the improvement or prevention of protein kinase-related diseases.

Effect of the Invention

[0005] The compounds according to the present invention are ABL1, ABL2 / ARG, ACK1, ARAF, BLK, BMX / ETK, BRAF, BRK, BTK, C-KIT, C-SRC, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 / HER2, ERBB4 / HER4, FAK / PTK2, FER, FES / FPS, FGFR1, FGFR 2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIPK4, H PK1 / MAP4K1, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / MAP4K5, LATS2, LCK, LIMK1, LIMK2, LOK / STK10, LRRK2, LYN, LYN B, MEK5, MEKK2, MEKK3, MINK / MINK1, MLCK2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MUSK, NEK4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, SIK2, SIK3, SLK / ST This compound effectively inhibits the activity of K2, SRMS, STK32B / YANK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TEC, TESK2, TIE2 / TEK, TNIK, TNK1, TRKA, TRKB, TRKC, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, YES / YES1, YSK4 / MAP3K19, ZAK / MLTK, and various other protein kinases. Therefore, this compound may be useful in the prevention, treatment, or improvement of cancer or cancer-related diseases associated with abnormal cell proliferation. The compound according to the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a pharmaceutical composition containing the same as an active ingredient for the prevention or treatment of cancer or cancer-related diseases exhibit low cytotoxicity, inhibitory activity against cancer cells, and high selectivity in anti-proliferative effects. Therefore, the compound and the composition can be effectively used for the prevention or treatment of various cancers such as gastric cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancer (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphoma (including Hodgkin's disease, non-Hodgkin's lymphoma), psoriasis, or fibroadenoma.

Mode for Carrying Out the Invention

[0006] Hereinafter, the present invention will be described in more detail. The present inventors conducted intensive research to develop a more effective protein kinase inhibitor, and as a result, synthesized novel compounds based on the 6'-4-methylphenyl-5,6'-dihydro-7H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-7'-one group. The present inventors confirmed that these compounds effectively inhibit various protein kinases, thereby completing the present invention. Therefore, the present invention provides a compound selected from the group consisting of a compound represented by the following formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a precursor thereof, or a solvate thereof:

Chemical formula

[0007] More preferably, the compound is represented by formula 1-2, 1-3, 1-4, 1-5, or 1-6: [ka] In Equation 1-2, R 3 From R 5can be the same or different and belong to the group selected from hydrogen, (C1-C2) alkyl, (C1-C2) alkoxy, trifluoromethyl, halo, hydroxy, (C1-C2) alkylimidazolyl, (C1-C2) alkoxyphenyl, morpholino, (C1-C2) alkoxy(C1-C2) alkyl(C1-C2) alkylamino, piperazinyl, (C1-C2) alkylpiperazinyl, ((C1-C2) alkylpiperazin-1-yl)(C1-C2) alkyl, and di(C1-C2) alkylamino(C1-C2) alkyl(C1-C2) alkylamino; A 1 is morpholino or -NH-Y 1 selected from, and Y 1 is selected from hydrogen, (C3-C4) cycloalkyl, benzyl, 1H-pyrazolyl, di(C1-C2) alkyl-1H-pyrazolyl, (oxetan-3-yl)-1H-pyrazolyl, trifluoro(C1-C2) alkyl-1H-pyrazolyl, pyridinyl(C1-C2) alkyl, hydroxy(C1-C2) alkyl, hydroxy(C2-C4) alkenyl, hydroxy(C3-C6) cycloalkyl, morpholino(C3-C4) alkyl, furanyl(C1-C2) alkyl, azetidine substituted with tert-butoxycarbonyl (BOC), tetrahydropyranyl, benzothiazolyl, benzofuranyl, or substituted or unsubstituted phenyl or pyridinyl, and the substituent may be one or more selected from the group of (C1-C2) alkyl, (C1-C2) alkoxy, halo, trifluoro(C1-C2) alkoxy, piperazinyl, (C1-C2) alkylpiperazinyl, acetylpiperazinyl, morpholino, morpholine-4-carbonyl, (C1-C2) alkylpiperazine-1-carbonyl, ((C1-C2) alkylpiperazin-1-yl)(C1-C2) alkyl, imidazolyl, di(C1-C2) alkylaminopyrrolidinyl, piperidinyl, acetylpiperidinyl, di(C1-C2) alkylaminopyperidinyl, ((C1-C2) alkylpiperazin-1-yl)piperidinyl, and di(C1-C2) alkylamino(C1-C2) alkyl(C1-C2) alkylamino groups.

[0008] [ka] In Equation 1-3, X 1 The substituents are selected from (C3-C6)cycloalkyl, oxo(C3-C6)cycloalkyl, (C4-C6)cycloalkenyl, thiophene, (C1-C2)alkylthiophene, furan, thiazole, oxazole, benzothiazole, tetrahydropyran, trifluoro(C1-C3)alkyl; or pyridinyls substituted with substituents selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, trifluoromethyl, halo, and hydroxy. A 2 is Morpholino or -NH-Y 2 Selected from, here Y 2 This may be one or more of the group selected from hydrogen, benzyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, (C1-C2)alkylpyridinyl, pyridinyl(C1-C2)alkyl, hydroxy(C1-C2)alkyl, hydroxy(C2-C4)alkenyl, hydroxy(C3-C6)cycloalkyl, morpholino(C3-C4)alkyl, furanyl(C1-C2)alkyl, ((C1-C2)alkylpiperazine-1-yl)piperidinyl-trifluoro(C1-C2)alkoxypyridinyl, and azetidine groups substituted with tert-butoxycarbonyl (BOC).

[0009] [ka] In Equation 1-4, X 2 is selected from (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C2)alkyl, benzyl, or substituted or unsubstituted phenyl, wherein the substitution is one or more from the group selected from (C1-C2)alkyl, (C1-C2)alkoxy, halo, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, and cyano groups. A 3 is Morpholino or -NH-Y 3 Selected from, Y3 This may be one or more selected from hydrogen or (C1-C2) alkylpyridinyl.

[0010] [ka] In equation 1-5, X 3 The compound is selected from substituted or unsubstituted phenyl, and the substitution is one or more selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, and halo groups. A 4 is Morpholino or -NH-Y 4 Selected from, Y 4 This may be one or more selected from the group consisting of hydrogen, benzyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, morpholino(C3-C4)alkyl, furanyl(C1-C2)alkyl, or pyridinyl(C1-C2)alkyl.

[0011] [ka] In Equation 1-6, X 4 The substitution is selected from substituted or unsubstituted phenyl, and the substitution is one or more selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, halo, and trifluoromethyl. A 5 is Morpholino or -NH-Y 5 Selected from, Y 5 This may be hydrogen or one or more selected from (C1-C2) alkylpyridinyl.

[0012] In one example, the compounds are N-(3-(2'-((1,3-dimethyl-1H-pyrazole-5-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 1), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide 3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 3), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-fluoro-3-(trifluoromethyl)benzamide (compound 4), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-chloro-3-(trifluoromethyl)benzamide (compound 5), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzamide (Compound 6), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (Compound 7), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazole-1-yl)-5- (Trifluoromethyl)benzamide (compound 8), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,4-difluorobenzamide (compound 9), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,4-difluorobenzamide (compound 10) ), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,5-difluorobenzamide (compound 11), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (compound 12),3-Bromo-N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide (compound 13), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2,4-difluorobenz Amide (compound 14), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,5-difluorobenzamide (compound 15), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-methoxybenzamide (compound 16), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-chloro-2-fluoro-5-(trifluoromethyl)benzamide (compound 17), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-fluoro-5-(trifluoromethyl)benzamide (compound 18), N-(3-(2' -amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-methoxy-5-(trifluoromethyl)benzamide (compound 19), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4'-methoxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamide (compound 20), N-(3 -(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-6-(trifluoromethyl)picolinamide (compound 21), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (compound 22), N-(3-(2'-amino-7'-oxo-5'H-spiro[ Cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-hydroxy-5-(trifluoromethyl)benzamide (compound 23), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 24), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-chloro-5-(trifluoromethyl)benzamide (compound 25), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-chloro-5-(trifluoromethyl)benzamide (compound 26), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3- d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 27), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-morpholino-5-(trifluoromethyl)benzamide (compound 28), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3 -d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-morpholino-5-(trifluoromethyl)benzamide (compound 29), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-methoxyethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 30), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclo Lopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-methoxyethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 31), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 32), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 33), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(piperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 34) ), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(piperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 35), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-(dimethylamino)ethyl)(methyl) Mino)-5-(trifluoromethyl)benzamide (compound 36), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 37), N-(4-methyl-3-(2'-((4-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3 -d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 38), N-(3-(2'-((4-(4-acetylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 39), N-(4-methyl-3-(2'-((4-morpholinophenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 40), N-(4-methyl-3-(2'-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 41), N-(3-(2'-((4-(4-ethylpiperazine-1-yl)-2-methoxyphen (L)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 42), N-(4-methyl-3-(2'-((4-((4-methylpiperazine-1-yl)methyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 43), N-(3-(2'-((4-(1H-imidazole-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 44), N-(4-methyl-3-(7'-oxo-2'-((4-(piperazine-1-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(tri Fluoromethyl)benzamide (compound 45), (S)-N-(3-(2'-((4-(3-(dimethylamino)pyrrolidine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 46), N-(4-methyl-3-(7'-oxo-2'-((4-(piperidine-4-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 47), N-(4-methyl-3-(2'-((3-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 48), N-(3-(2'-((4-(1-acetylpiperidine-4-yl)phenyl)amino)-7'-oxo- 5'H-Spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 49), N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-Spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound 50) N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 51), N-(4-methyl-3-(2'-((1-(oxetan-3-yl)-1H-pyrazole-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl )-3-(trifluoromethyl)benzamide (compound 52), N-(3-(2'-((2-methoxy-4-morpholinophenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 53), N-(3-(2'-((2-methoxy-4-(morpholin-4-carbonyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 54), N-(3-(2'-((3-methoxy-4-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 55), N-(3-(2'-((3-methoxy-4-morpholinophen (L)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 56), N-(3-(2'-((4-(4-ethylpiperazine-1-yl)-3-fluorophenyl Benzamide (compound 57), N-(3-(2'-((6-(4-ethylpiperazine-1-yl)-2-methoxypyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 58), N-(4-methyl-3-(7'-oxo-2'-(phenylamino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6 '(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 59), N-(3-(2'-((4-(4-(dimethylamino)piperidine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 60), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound 61), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl)benzamide (compound 62), N-(3-(2'-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl) -4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 63), N-(4-methyl-3-(7'-oxo-2'-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 64), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]- 6'(7'H)-yl)-4-methylphenyl)-4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl)benzamide (compound 65), N-(3-(2'-((4-(4-acetylpiperazine-1-yl)-2-methoxyphenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 66), N-(3-(2'-((3-methoxy-4-(piperazine-1- Il)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 67), N-(3-(2'-((1,3-dimethyl-1H-pyrazole-5-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 68),N-(3-(2'-((2-methoxy-6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 69), N-(3-(2'-(hydroxyamino)-7'-oxo-5'H-spiro[cyclopropane-1, 8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 70), 1-(4-fluorophenyl)-3-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)urea (compound 71), 4-Chloro-N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)benzamide (compound 72), N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)thiophene-2-carboxamide (compound 73), N-(4-methyl-3- (2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)furan-2-carboxamide (compound 74), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclobutanecarboxamide (compound 75), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'- Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-oxocyclobutan-1-carboxamide (compound 76), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclohex-1-en-1-carboxamide (compound 77), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4- Methylphenyl)-4-methylthiophene-2-carboxamide (compound 78), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl) isoxazole-5-carboxamide (compound 79), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl) benzo[d]thiazole-2-carboxamide (compound 80),N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4,4,4-trifluorobutanamide (compound 81), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)thiazole-5-carboxamide (compound 82), N-(3-(2'-amino-7'-oxo-5'H-spiro[cycloprop Pyran-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclopentanecarboxamide (compound 83), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)tetrahydro-2H-pyran-4-carboxamide (compound 84), N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine N-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 85), N-(4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 86), N-(4-methyl-3-(7'-oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d] Pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 87), N-(4-methyl-3-(7'-oxo-2'-((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 88), N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 89), N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 91), N-(4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cy Clopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 92), N-(4-methyl-3-(7'-oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 93), N-(4-methyl-3-(7'-oxo-2'-((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 94), N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 95), N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl (L)-5-(trifluoromethyl)nicotinamide (compound 96), N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(3,5-difluorophenyl)acetamide (compound 97), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrimidine] [4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 98), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(7'-oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 99), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(7'-oxo-2' -((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 100), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 101), 2-(3,5-difluorophenyl)-N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)acetamide (compound 102), N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 103), N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 104), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8' -Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 105), N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 106), N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane- 1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 107), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 108),N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(3,5-difluorophenyl)acetamide (compound 109), 2-(3,5-difluorophenyl)-N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl Nyl)acetamide (compound 110), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 111), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine] Limidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclopropylurea (compound 112), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclobutylurea (compound 113), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclopentylurea (compound 114), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(cyclopropylmethyl)urea (compound 115), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(cyclohexylmethyl)urea (compound 116), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-benzylurea (compound 117), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-(trifluoromethoxy)phenyl)urea (compound 118), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl) -4-methylphenyl)-3-(3-cyanophenyl)urea (compound 119), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(3,4-difluorophenyl)urea (compound 120), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(2-methoxyphenyl)urea ( Compound 121), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea (Compound 122), N-(5-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-6-methylpyridine-3-yl)-3-(trifluoromethyl)benzamide (Compound 123), N-methyl-N- (4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 124), 1-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(m-tolyl)urea (compound 125),N-(3-(2'-((2-hydroxyethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 126), (S)-N-(3-(2'-((1-hydroxypropane-2-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 127), N-(3-(2'-(((1r,3r)-3-hydroxycyclobutyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 128), tert-butyl3-((6'-(2-methyl-5-(3-(trifluoromethyl)benzamide)phenyl)-7'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine [Zin]-2'-yl)amino)azetidine-1-carboxylate (compound 129), N-(3-(2'-((2-hydroxyethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 130), (S)-N-(3-(2'-((1-hydroxypropane-2-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6 '(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 131), N-(3-(2'-(((1r,3r)-3-hydroxycyclobutyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 132), tert-butyl3-((6'-(2-methyl-5-(5-(trifluoromethyl)nicotinamide)phenyl)-7'-oxo-6',The compounds may be selected from the group consisting of 7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-2'-yl)amino)azetidine-1-carboxylate (compound 133) and 3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (compound 134).

[0013] The compounds according to the present invention are ABL1, ABL2 / ARG, ACK1, ARAF, BLK, BMX / ETK, BRAF, BRK, BTK, C-KIT, C-SRC, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 / HER2, ERBB4 / HER4, FAK / PTK2, FER, FES / FPS, FGFR1, FGFR 2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIPK4, H PK1 / MAP4K1, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / MAP4K5, LATS2, LCK, LIMK1, LIMK2, LOK / STK10, LRRK2, LYN, LYN B, MEK5, MEKK2, MEKK3, MINK / MINK1, MLCK2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MUSK, NEK4, P38A / MA PK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, SIK2, SIK3, SLK / STK2, SR It is possible to inhibit one or more protein kinases selected from the group consisting of MS, STK32B / YANK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TEC, TESK2, TIE2 / TEK, TNIK, TNK1, TRKA, TRKB, TRKC, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, YES / YES1, YSK4 / MAP3K19, and ZAK / MLTK.

[0014] [Definition] In this specification, the term “stereoisomer” refers to two compounds having the same molecular formula but different spatial arrangements of atoms. Stereoiomers may be enantiomers, which are mirror images of each other and cannot be superimposed, or diastereomers, which are not mirror images of each other (e.g., cis / trans isomers and conformational isomers). These may include R and S configurations for each chiral center, as well as Z and E double bond isomers, and Z and E conformational isomers. Not only single stereochemical isomers, but also compositions containing enantiomers, diastereomers, and geometric (or conformational) mixtures of the compound are within the scope of the present invention. In this specification, the term “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt or base addition salt. Base addition salts may include, but are not limited to, organic or inorganic base salts such as sodium, potassium, calcium, lithium, magnesium, or cesium salts, as well as aminium, ammonium, triethylammonium, and pyridinium salts. Furthermore, the acid addition salt formed by the free acid may be prepared as a pharmaceutically acceptable salt. The free acid may include inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, bromate, sulfuric acid, sulfurous acid, and phosphoric acid. Examples of organic acids include citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, gluconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, and aspartic acid. Preferably, hydrochloric acid is used as the inorganic acid and methanesulfonic acid is used as the organic acid. Furthermore, the compositions according to the present invention may further include pharmaceutically acceptable salts, as well as all salts, hydrates, or solvates that can be prepared by conventional methods. The addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving the compound in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, then adding an excess amount of organic base or an aqueous solution of inorganic base, followed by precipitation or crystallization. Alternatively, the addition salt can be obtained by evaporating the solvent or excess base from the reaction mixture, followed by drying, or by filtering the precipitated salt under reduced pressure. As used herein, the term “precursor” refers to a compound that, when administered to a subject or patient, can (directly or indirectly) provide the compound of the present invention. Examples of precursors include esterified or hydroxylated compounds in which an ester or hydroxyl group is cleaved in vivo, for example in the intestine, to produce a compound according to formula 1. In this specification, the term "solvate" refers to an adduct between a compound and an inert solvent molecule formed by intermolecular forces. When a compound is treated with water, the solvate is called a hydrate, and for example, the solvate may be a monohydrate, dihydrate, or alkoxide.

[0015] Furthermore, the present invention provides a pharmaceutical composition comprising the compound of the present invention for the treatment or prevention of protein kinase-related diseases. Furthermore, the present invention provides a method for treating protein kinase-related diseases, comprising the step of administering the compound of the present invention to a subject suffering from a protein kinase-related disease. Protein kinases include ABL1, ABL2 / ARG, ACK1, ARAF, BLK, BMX / ETK, BRAF, BRK, BTK, C-KIT, C-SRC, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 / HER2, ERBB4 / HER4, FAK / PTK2, FER, FES / FPS, FGFR1, and FGFR. 2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIPK4, H PK1 / MAP4K1, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / MAP4K5, LATS2, LCK, LIMK1, LIMK2, LOK / STK10, LRRK2, LYN, LYN B, MEK5, MEKK2, MEKK3, MINK / MINK1, MLCK2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MUSK, NEK4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, SIK2, SIK3, SLK / S It may be one or more selected from the group consisting of TK2, SRMS, STK32B / YANK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TEC, TESK2, TIE2 / TEK, TNIK, TNK1, TRKA, TRKB, TRKC, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, YES / YES1, YSK4 / MAP3K19, and ZAK / MLTK. Preferably, the compound exhibits an inhibition rate of 60% or more against protein kinase enzymes when tested at a single concentration of 1 μM. Protein kinase-related diseases may be cancerous, and such cancerous diseases may be selected from, but are not limited to, the group consisting of prostate cancer, endometrial cancer, bladder cancer, gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, urethral cancer, leukemia, multiple myeloma, hematological cancer, lymphoma, and fibroadenoma. The pharmaceutical composition may be administered in combination therapy with one or more anticancer agents selected from the group consisting of cytotoxic anticancer agents, targeted anticancer agents, immuno-oncological agents, and metabolic anticancer agents. The drug composition may, but is not limited to, be provided in one or more dosage forms selected from the group consisting of gels, emulsions, injections, powders, granules, aerosols, pastes, transdermal formulations, and patches, according to conventional methods. In another embodiment of the present invention, the drug composition may further contain one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coatings, swelling agents, lubricants, fluidizers, flavorings, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders, and lubricants commonly used in the manufacture of drug compositions. Specifically, the carrier, excipients, and diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid formulations may be prepared by mixing the composition with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc., and may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories, etc. Non-aqueous solvents and suspensions may contain propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injection esters such as ethyl oleate, etc. Suppository bases may contain witepsol, macrogol, Tween 61, cocoa butter, lauric acid, glycerol gelatin, etc. Pharmaceutical compositions can be administered to subjects by conventional methods via intravenous, intra-arterial, intraperitoneal, intramuscular, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular, or intradermal routes. The preferred dosage of the compound may vary depending on the subject's condition and weight, the type and severity of the disease, the drug form, the route of administration, and the duration, and can be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be, but is not limited to, 0.01 to 200 mg / kg, more specifically 0.1 to 200 mg / kg, and more specifically 0.1 to 100 mg / kg. Administration may be once a day or divided into multiple doses, and the scope of the present invention is not limited thereto. In the present invention, "subject" may be a mammal, including humans, but is not limited to these examples.

[0016] Furthermore, the present invention provides a health functional food containing the compound for improving or preventing protein kinase-related diseases. Protein kinases include ABL1, ABL2 / ARG, ACK1, ARAF, BLK, BMX / ETK, BRAF, BRK, BTK, C-KIT, C-SRC, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 / HER2, ERBB4 / HER4, FAK / PTK2, FER, FES / FPS, FGFR1, and FGFR. 2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIPK4, H PK1 / MAP4K1, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / MAP4K5, LATS2, LCK, LIMK1, LIMK2, LOK / STK10, LRRK2, LYN, LYN B, MEK5, MEKK2, MEKK3, MINK / MINK1, MLCK2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MUSK, NEK4, P38 A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, SIK2, SIK3, SLK One or more selected from the group consisting of / STK2, SRMS, STK32B / YANK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TEC, TESK2, TIE2 / TEK, TNIK, TNK1, TRKA, TRKB, TRKC, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, YES / YES1, YSK4 / MAP3K19, and ZAK / MLTK. Protein kinase-related diseases may include cancers, which may be selected from the group consisting of, but are not limited to, prostate cancer, endometrial cancer, bladder cancer, gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain tumor, bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, urethral cancer, leukemia, multiple myeloma, hematological cancer, lymphoma, and fibroadenoma. In this specification, "health functional foods" refers to foods manufactured or processed using raw materials or ingredients that have beneficial functional properties for the human body, in accordance with the "Act on Health Functional Foods." "Functionality" refers to properties that are consumed with the aim of obtaining health-beneficial effects, such as the regulation of nutrients on the structure and function of the human body, or physiological effects. The aforementioned health functional foods may contain ordinary food additives. Unless otherwise specified, eligibility as a "food additive" shall be determined in accordance with the general rules and general test methods of the "Food Additives Code" established by the Ministry of Food and Drug Safety, and based on the standards and criteria for the item in question. Examples of substances listed in the "Food Additives Code" include chemically synthesized compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon color, licorice extract, crystalline cellulose, sorghum color, and guar gum; and mixed preparations such as L-sodium glutamate preparations, alkaline preparations for noodles, preservative preparations, and tar dye preparations. The effective dose of the active ingredient contained in health functional foods can be used in accordance with the effective dose of a therapeutic drug. However, in the case of long-term intake for health, hygiene, or health regulation purposes, it may be below the aforementioned range, and it is also possible to use the active ingredient in amounts exceeding the aforementioned range, as there are no safety concerns. There are no particular restrictions on the types of health functional foods, and examples include meat, sausages, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes. [Examples]

[0017] The present invention will be described in more detail below with reference to examples. These examples are provided to illustrate the present invention more concretely, and it will be clear that various changes, modifications and substitutions are possible by those skilled in the art without departing from the spirit and scope of the invention, and the present invention is not limited thereto.

[0018] <Example 1> Synthesis route A of compound 51 Compound 51 was synthesized according to synthetic route A shown in Scheme 1, and other compounds were synthesized in a similar manner. The synthesis method will be explained in detail using compound 51 as an example. [Scheme 1] [ka] 1-1) Step 1 5-(hydroxymethyl)pyrimidine-2,4-diol (8.0 g, 56.32 mmol) and phosphorus oxychloride (POCl3) (26.3 mL, 281.47 mmol) were added to toluene (180 mL), and nitrogen gas was passed through for 5 minutes. The reaction vessel was cooled in an ice bath (0 °C), and N,N-diisopropylethylamine (29.4 mL, 168.88 mmol) was slowly added dropwise. The reaction mixture was then refluxed at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and the reaction was stopped by adding water dropwise. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by MPLC (medium-pressure liquid chromatography / ethyl acetate:hexane = 1:30 (v / v)), and the solvent was removed under reduced pressure to obtain 9.3 g of the target compound (yield 84%) as a white solid. MS(m / z): 195.95[M+1] 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 4.64 (s, 2H)

[0019] 1-2) Step 2 2,4-dichloro-5-(chloromethyl)pyrimidine (27.8 g, 140.80 mmol) and 5-methyl-2-nitroaniline (27.8 g, 183.0 mmol) obtained in Step 1 were dissolved in acetone (300 mL). Then, sodium iodide (27.4 g, 183.0 mmol) and potassium carbonate (38.9 g, 281.6 mmol) were added, and the mixture was reacted at 50 °C with stirring and reflux for 3 days. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and concentrated under reduced pressure using a rotary evaporator. The resulting residue was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The resulting organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified with MPLC (ethyl acetate:hexane = 1:20 (v / v)), and the solvent was removed under reduced pressure to obtain 34.8 g of the target compound (yield 78%) as a yellow solid. MS(m / z): 313.0[M+1] 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.61 (dd, J = 8.2, 2.2 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 4.58 (s, 2H), 4.32 (s, 1H), 2.29 (s, 3H)

[0020] 1-3) Step 3 The N-((2,4-dichloropyrimidine-5-yl)methyl)-2-methyl-5-nitroaniline (34.8 g, 111.1 mmol) obtained in Step 2 was dissolved in anhydrous tetrahydrofuran (300 mL), and nitrogen gas was passed through the mixture for 5 minutes to remove dissolved gases. The reaction vessel was cooled in an ice bath (0 °C), and 60% sodium hydride (5.7 g, 144.4 mmol) was added in small amounts, while stirring at room temperature for 30 minutes. Then, the reaction vessel was cooled again in an ice bath (0 °C), and ethyl malonyl chloride (20.9 mL, 166.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was cooled to 0 °C, and the reaction was stopped by adding saturated aqueous ammonium chloride. The remaining organic solvent was removed under reduced pressure using a rotary evaporator, and the residue was diluted with water and extracted with dichloromethane. The resulting organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified with MPLC (ethyl acetate:dichloromethane = 20:1 (v / v)), and the solvent was removed under reduced pressure to obtain 43.1 g of the target compound (90% yield) as a white solid. MS(m / z): 426.9[M+1] 1 H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.21 (dd, J = 8.5, 2.3 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.32 (d, J = 15.4 Hz, 1H), 4.53 (d, J = 15.4 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.15 (dd, J = 37.9, 15.7 Hz, 2H), 2.37 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H)

[0021] 1-4) Step 4 39.2 g, 91.75 mmol of 3-(((2,4-dichloropyrimidine-5-yl)methyl)(2-methyl-5-nitrophenyl)amino)-3-oxopropanoate obtained in Step 3 was dissolved in dimethyl sulfoxide (500 mL), and nitrogen gas was passed through the mixture for 5 minutes to remove dissolved gases. The reaction vessel was cooled in an ice bath (0 °C), and cesium carbonate (44.8 g, 137.6 mmol) was added in small amounts. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was cooled to 0 °C and added dropwise to 500 mL of 1N hydrochloric acid aqueous solution, and stirred slowly for 15 minutes. The resulting yellow solid was filtered using a Celite pad and washed with water to remove any remaining organic solvent. The obtained solid was dried to obtain 35.1 g of the target compound (yield 97%) as a yellow solid. MS (m / z): 391.1 [M+1]

[0022] 1-5) Step 5 Ethyl 2-chloro-6-(2-methyl-5-nitrophenyl)-7-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-8-carboxylate (35.1 g, 89.8 mmol) obtained in Step 4 was dissolved in 1,4-dioxane (250 mL). 4N hydrochloric acid aqueous solution (222.5 mL, 890.1 mmol) was added to the 1,4-dioxane, and the mixture was stirred under reflux at 100°C for 16 hours. After the reaction was complete, the mixed solution was cooled to room temperature, and the remaining solvent was removed under reduced pressure. The remaining mixture was diluted with dichloromethane. The insoluble solid was filtered using a Celite pad, and the recovered filtrate was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (ethyl acetate:dichloromethane = 3:7 (v / v)), and the solution was concentrated under reduced pressure to obtain 16.7 g of the target compound as a yellow solid in 58% yield. MS (m / z): 319.05 [M+1] 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.18 (dd, J = 8.4, 2.3 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 4.97 (d, J = 16.1 Hz, 1H), 4.69 (d, J = 16.1 Hz, 1H), 4.02 (s, 2H), 2.29 (s, 3H)

[0023] 1-6) Step 6 2-chloro-6-(2-methyl-5-nitrophenyl)-5,8-dihydropyrido[4,3-d]pyrimidine-7(6H)-one (10.0 g, 31.3 mmol) obtained in step 5 was dissolved in anhydrous dimethylformamide (150 mL) and nitrogen gas was blown in for 5 minutes. The reaction vessel was placed in an ice bath at 0°C, and 1-bromo-2-chloroethane (4.6 mL, 37.6 mmol) was added, followed by stepwise addition of cesium carbonate (22.4 g, 60.0 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was added dropwise to 150 mL of 1N hydrochloric acid aqueous solution at 0°C and stirred slowly for 15 minutes. The resulting yellow solid was filtered through a Celite pad and washed with water to remove any remaining organic solvent. The resulting solid was dried to obtain 9.23 g of the target compound as a yellow solid in 85% yield. MS (m / z): 344.9 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.21 - 8.10 (m, 2H), 7.50 (d, J = 8.1 Hz, 1H), 5.07 (d, J = 16.1 Hz, 1H), 4.77 (d, J = 16.1 Hz, 1H), 2.31 (s, 3H), 2.08 - 1.98 (m, 2H), 1.98 - 1.91 (m, 1H), 1.91 - 1.77 (m, 1H)

[0024] 1-7) Step 7 2'-chloro-6'-(2-methyl-5-nitrophenyl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-7'-one (1.00 g, 0.77 mmol) obtained in step 6 was dissolved in tetrahydrofuran (10.0 mL), and methanol (5.0 mL) and water (3.0 mL) were added dropwise. Iron (0.81 g, 14.50 mmol) and ammonium chloride (0.77 g, 14.50 mmol) were added at room temperature, and the mixture was stirred under reflux at 80°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was neutralized dropwise by the addition of saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain 0.87 g of the target compound as a yellow solid in 95% yield. MS (m / z): 315.1 [M+1] NMR: 1 H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.73 - 6.66 (m, 1H), 6.63 (d, J = 2.3 Hz, 1H), 4.99 (d, J = 16.9 Hz, 1H), 4.81 (d, J = 16.9 Hz, 1H), 2.04 (s, 3H), 1.89 (d, J = 4.5 Hz, 2H), 1.76 (dd, J = 4.9, 3.6 Hz, 2H)

[0025] 1-8) Step 8 6′-(5-amino-2-methylphenyl)-2′-chloro-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-7′-one (0.87 g, 2.77 mmol) obtained in Step 7 was dissolved in dichloromethane (10.0 mL), then 3-(trifluoromethyl)benzoyl chloride (0.42 mL, 2.77 mmol) and potassium carbonate (0.76 g, 5.55 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with dichloromethane, extracted with water, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (ethyl acetate:hexane = 3:7 (v / v)), and the solution was concentrated under reduced pressure to obtain 0.87 g of the target compound as a yellow solid in 64% yield. MS (m / z): 487.1 [M+1] 1 H NMR (400 MHz, MeOD) δ 8.48 (s, 1H), 8.25 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.59 (dd, J = 8.3, 2.1 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 5.08 (s, 1H), 4.89 (d, J = 16.8 Hz, 1H), 2.19 (s, 3H), 1.91 (t, J = 4.9 Hz, 2H), 1.80 (dt, J = 14.7, 10.5 Hz, 2H)

[0026] 1-9) Step 9 N-(3-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (0.12 g, 0.24 mmol) obtained in Step 8 was dissolved in 2-butanol (10.0 mL), and potassium carbonate (0.17 g, 1.23 mmol), 6-methylpyridine-3-amine (39 mg, 0.36 mmol), and tris(dibenzylideneacetone)dipalladium (0) (46 mg, 0.050 mmol) were added at room temperature. The reaction mixture was stirred at 100°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered through a Celite pad, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (dichloromethane:methanol = 0-10%), and the solution was concentrated under reduced pressure to obtain 95.0 mg of the target compound as a brown solid (compound 51, yield 71%). MS (m / z): 559.2 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.36 (s, 1H), 9.11 (s, 1H), 8.47 (s, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.31 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.71 (d, J = 7.4 Hz, 1H), 7.63 (dd, J = 8.3, 2.0 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 16.2 Hz, 1H), 4.78 (d, J = 16.1 Hz, 1H), 2.59 (s, 3H), 2.11 (s, 3H), 1.82 - 1.63 (m, 4H)

[0027] 1-10) Synthesis of other compounds via synthetic route A In Step 9, instead of 6-methylpyridine-3-amine, the following compounds were synthesized via synthetic route A using pyrazolamine, phenylamine, or pyrimidinamine derivatives corresponding to each final synthesized compound: N-(3-(2'-((1,3-dimethyl-1H-pyrazole-5-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 1), N-(4-methyl-3-(2'-((4-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl) N-(3-(2'-((4-(4-acetylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 39), N-(4-methyl-3-(2'-((4-morpholinophenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3 -d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 40), N-(4-methyl-3-(2'-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 41), N-(3-(2'-((4-(4-ethylpiperazine-1-yl)-2-methoxyphenyl)amino )-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 42), N-(4-methyl-3-(2'-((4-((4-methylpiperazine-1-yl)methyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 43),N-(3-(2'-((4-(1H-imidazole-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 44), N-(4-methyl-3-(7'-oxo-2'-((4-(piperazine-1-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl (L)-3-(trifluoromethyl)benzamide (compound 45), (S)-N-(3-(2'-((4-(3-(dimethylamino)pyrrolidine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 46), N-(4-methyl-3-(7'-oxo-2'-((4-(piperidine-4-yl)phenyl)amino)-5'H-spiro[cyclo Propane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 47), N-(4-methyl-3-(2'-((3-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 48), N-(3-(2'-((4-(1-acetylpiperidine-4- Il)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 49), N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 51),N-(4-methyl-3-(2'-((1-(oxetan-3-yl)-1H-pyrazole-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 52), N-(3-(2'-((2-methoxy-4-morpholinophenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl) -3-(trifluoromethyl)benzamide (compound 53), N-(3-(2'-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 54), N-(3-(2'-((3-methoxy-4-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'- Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 55), N-(3-(2'-((3-methoxy-4-morpholinophenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 56), N-(3-(2'-((4-(4-ethylpiperazine-1-yl)-3-fluorophenyl)amino) -7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 57), N-(3-(2'-((6-(4-ethylpiperazine-1-yl)-2-methoxypyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 58),N-(4-methyl-3-(7'-oxo-2'-(phenylamino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 59), N-(3-(2'-((4-(4-(dimethylamino)piperidine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl (L)benzamide (compound 60), N-(3-(2'-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 63), N-(4-methyl-3-(7'-oxo-2'-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)amino)-5'H-spiro[cyclopropane-1 ,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 64), N-(3-(2'-((4-(4-acetylpiperazine-1-yl)-2-methoxyphenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 66), N-(3-(2'-((3-methoxy-4-(piperazine-1-yl )phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 67), N-(3-(2'-((1,3-dimethyl-1H-pyrazole-5-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 68),N-(3-(2'-((2-methoxy-6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 69), 1-(4-fluorophenyl)-3-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7' H)-yl)phenyl)urea (compound 71), 4-chloro-N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)benzamide (compound 72), N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)thiophene-2-carboxa Mido (compound 73), N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)furan-2-carboxamide (compound 74), N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benz) Compound 103), N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 104), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 105), N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 106), N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5 'H-Spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 107), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-Spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5 -(trifluoromethyl)nicotinamide (compound 108), N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(3,5-difluorophenyl)acetamide (compound 109), 2-(3,5-difluorophenyl)-N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1 , 8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)acetamide (compound 110), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 111).

[0028] <Example 2> Synthesis route B of compound 8 Compound 8 was synthesized via synthetic route B, as shown in Scheme 2 below, and the other compounds were similarly synthesized via synthetic route B. The synthesis method will be described in detail based on compound 8. [Scheme 2] [ka] 2-1) Step 1 2-chloro-6-(2-methyl-5-nitrophenyl)-5,8-dihydropyrido[4,3-d]pyrimidine-7(6H)-one (0.2 g, 0.58 mmol) obtained in step 5 of Example 1 was dissolved in anhydrous dimethylacetamide (5.0 mL), cyclopropylamine (1.2 g, 0.38 mmol) and potassium carbonate (70 mg, 0.51 mmol) were added, and the mixture was stirred under reflux at 120 °C for 16 hours. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane and washed with water. The organic layers were dried together over anhydrous sodium sulfate and concentrated, and the resulting residue was purified with MPLC (dichloromethane:ethyl acetate = 7:3 (v / v)) and concentrated to obtain 97 mg of the target compound in 46% yield. MS (m / z): 366.15 [M+1] 1 H NMR (400 MHz, CDCl3) δ 8.19 - 8.05 (m, 3H), 7.47 (d, J = 9.2 Hz, 1H), 4.93 (d, J = 14.8 Hz, 1H), 4.61 (d, J = 14.8 Hz, 1H), 2.75 (dq, J = 6.6, 3.5 Hz, 1H), 2.30 (s, 3H), 1.87 - 1.68 (m, 4H), 0.82 (td, J = 6.7, 5.2 Hz, 2H), 0.59 - 0.48 (m, 2H)

[0029] 2-2) Step 2 2′-(cyclopropylamino)-6′-(2-methyl-5-nitrophenyl)-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-7′-one (98 mg, 0.22 mmol) obtained in Step 1 was dissolved in tetrahydrofuran (2.0 mL), and methanol (1.0 mL) and water (0.5 mL) were added dropwise. Iron (61 mg, 1.10 mmol) and ammonium chloride (59 mg, 1.10 mmol) were added at room temperature, and the mixture was stirred under reflux at 80°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was neutralized dropwise by the addition of saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain 73 mg of the target compound as a yellow solid in 99% yield. MS (m / z): 336.0 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.32 (s, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.47 (dd, J = 8.1, 2.1 Hz, 1H), 5.00 (s, 2H), 4.71 (d, J = 15.5 Hz, 1H), 4.53 (d, J = 15.4 Hz, 1H), 2.64 (ddd, J = 10.5, 7.1, 3.6 Hz, 1H), 1.91 (s, 3H), 1.65 - 1.47 (m, 4H), 0.68 - 0.58 (m, 2H), 0.48 - 0.37 (m, 2H)

[0030] 2-3) Step 3 6'-(5-amino-2-methylphenyl)-2'-(cyclopropylamino)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-7'-one (50 mg, 0.159 mmol) obtained in Step 2 was dissolved in dichloromethane (2.0 mL), and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzoic acid (60 mg, 0.224 mmol), azabenzotriazoletetramethyluronium hexafluorophosphate (111 mg, 0.298 mmol), and N,N-diisopropylethylamine (77.8 μL, 0.447 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane and washed with water. The organic layers were combined and dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by HPLC (5:95 → 95:5 (v / v), 40 minutes) and concentrated to obtain 21 mg of the target compound (compound 8) in 23% yield. MS (m / z): 588.20 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.50 (s, 1H), 8.57 (s, 1H), 8.42 (s, 2H), 8.15 (d, J = 24.9 Hz, 2H), 7.72 - 7.66 (m, 2H), 7.41 (s, 1H), 7.35 (d, J = 8.9 Hz, 1H), 4.80 (d, J = 15.3 Hz, 1H), 4.65 (d, J = 15.3 Hz, 1H), 2.34 (s, 3H), 2.10 (s, 3H), 1.77 - 1.48 (m, 4H), 0.65 (dd, J = 6.9, 2.3 Hz, 2H), 0.51 - 0.28 (m, 2H)

[0031] 2-4) Synthesis of other compounds via synthetic route B In Step 3, instead of 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzoic acid, the following compounds were also synthesized via synthetic route B using the benzoic acid or pyridinecarboxylic acid derivative corresponding to each final synthesized compound: N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 3), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl) Benzamide (compound 8), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,4-difluorobenzamide (compound 10), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,5-difluorobenzamide (compound 11), N-(3-( 2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (compound 12), 3-bromo-N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide (compound 13), N-(3 -(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 27), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-morpholino-5-(trifluoromethyl)benzamide (compound 28),N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-methoxyethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 30), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl Piperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 32), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(piperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 35), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6' (7'H)-yl)-4-methylphenyl)-3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 36), N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound 50), N-(3-(2'-(cyclo Ropropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl)benzamide (compound 62), N-(3-(2'-(hydroxyamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 70),N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 85), N-(4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 86), N-(4-methyl-3-(7 '-Oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 87), N-(4-methyl-3-(7'-oxo-2'-((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 8 8) N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 89), N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide Zuamide (compound 90), N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 91), N-(4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 92),N-(4-methyl-3-(7'-oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 93), N-(4-methyl-3-(7'-oxo-2'-((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide ( Compound 94), N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (Compound 95), N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound Compound 96), N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(3,5-difluorophenyl)acetamide (Compound 97), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (Compound 98), 2-(3,5-difluoro Phenyl)-N-(4-methyl-3-(7'-oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 99), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(7'-oxo-2'-((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 100),2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 101), 2-(3,5-difluorophenyl)-N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)acetamide Mido (compound 102), N-(3-(2'-((2-hydroxyethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 126), (S)-N-(3-(2'-((1-hydroxypropane-2-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(triflu Oromethyl)benzamide (compound 127), N-(3-(2'-(((1r,3r)-3-hydroxycyclobutyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 128), tert-butyl3-((6'-(2-methyl-5-(3-(trifluoromethyl)benzamide)phenyl)-7'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-py Lido[4,3-d]pyrimidine]-2'-yl)amino)azetidine-1-carboxylate (compound 129), N-(3-(2'-((2-hydroxyethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 130), (S)-N-(3-(2'-((1-hydroxypropane-2-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 131), N-(3-(2'-(((1r,3r)-3-hydroxycyclobutyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)- 5-(trifluoromethyl)nicotinamide (compound 132), tert-butyl 3-((6'-(2-methyl-5-(5-(trifluoromethyl)nicotinamide)phenyl)-7'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-2'-yl)amino)azetidine-1-carboxylate (compound 133).

[0032] <Example 3> Synthesis route C of compound 20 Compound 20 was synthesized via synthetic route C, as shown in Scheme 3 below, and other compounds were similarly synthesized via synthetic route C. The synthesis method will be described in detail based on compound 20. [Scheme 3] [ka] 3-1) Step 1 2′-chloro-6′-(2-methyl-5-nitrophenyl)-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-7′-one (0.10 g, 0.29 mmol) obtained in step 6 of Example 1 was dissolved in dimethylformamide (1.0 mL), and 4-methoxybenzylamine (0.06 mL, 0.43 mmol) and potassium carbonate (0.08 g, 0.58 mmol) were added, and the mixture was stirred under reflux at 90°C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water. This mixture was extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified with MPLC (dichloromethane:ethyl acetate = 7:3 (v / v)), and the solution was concentrated under reduced pressure to obtain 45.0 mg of the target compound as a yellow solid in 45% yield. MS(m / z): 446.20[M+1] 1 H NMR (400 MHz, CDCl3) δ 8.20 - 8.09 (m, 2H), 8.01 (s, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.27 (d, J = 6.9 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.90 (d, J = 14.8 Hz, 1H), 4.58 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 5.7 Hz, 2H), 3.80 (s, 3H), 2.30 (s, 3H), 1.91 - 1.63 (m, 4H)

[0033] 3-2) Step 2 2′-((4-methoxybenzyl)amino)-6′-(2-methyl-5-nitrophenyl)-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-7′-one (5 g, 12.0 mmol) obtained in Step 1 was dissolved in tetrahydrofuran (120 mL), and methanol (60 mL) and water (30 mL) were added dropwise. Iron (2.7 g, 48.3 mmol) and ammonium chloride (2.82 g, 52.7 mmol) were added at room temperature, and the mixture was stirred under reflux at 80°C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was neutralized dropwise by the addition of saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to obtain 4.65 g of the target compound as a yellow solid in 99% yield. MS (m / z): 416.20 [M+1] 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.46 (dd, J = 8.1, 2.2 Hz, 1H), 6.41 (d, J = 2.1 Hz, 1H), 4.99 (s, 2H), 4.68 (d, J = 15.5 Hz, 1H), 4.50 (d, J = 15.5 Hz, 1H), 4.34 (s, 48H), 3.71 (s, 3H), 1.89 (s, 3H), 1.52 (s, 4H)

[0034] 3-3) Step 3 6′-(5-amino-2-methylphenyl)-2′-((4-methoxybenzyl)amino)-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-7′-one (40 mg, 0.10 mmol) obtained in Step 2 was dissolved in dimethylformamide (1.2 mL), and 3-methoxy-5-(trifluoromethyl)benzoic acid (42.8 mg, 0.14 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (73.2 mg, 0.19 mmol) and N,N-diisopropylethylamine (50.0 μL, 0.29 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with ethyl acetate, extracted with water, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (dichloromethane:ethyl acetate = 6:4 (v / v)), and the solution was concentrated under reduced pressure to obtain 40 mg of the target compound as a yellow solid in 60% yield. MS (m / z): 694.20 [M+1] 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 8.14 (s, 2H), 7.86 - 7.77 (m, 2H), 7.74 - 7.59 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.14 - 7.05 (m, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.79 (d, J = 15.4 Hz, 1H), 4.61 (d, J = 15.4 Hz, 1H), 4.36 (d, J = 5.0 Hz, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 2.08 (s, 3H), 1.66 - 1.40 (m, 4H)

[0035] 3-4) Step 4 The 4′-methoxy-N-(3-(2′-((4-methoxybenzyl)amino)-7′-oxo-5′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-6′(7′H)-yl)-4-methylphenyl)-5-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamide (73.3 mg, 0.106 mmol) obtained in Step 3 was dissolved in a mixed solution of dichloromethane (2.0 mL) and trifluoroacetic acid (2.0 mL) and stirred under reflux at 65°C for 48 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by HPLC (5:95 → 95:5 (v / v), 40 minutes) to obtain 8.5 mg of the target compound (compound 20) in 14% yield. MS(m / z): 574.05[M+1] 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.48 (s, 1H), 8.25 - 8.07 (m, 3H), 7.83 (d, J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H), 6.67 (s, 2H), 4.79 (d, J = 15.5 Hz, 1H), 4.62 (d, J = 14.7 Hz, 1H), 3.83 (s, 3H), 2.09 (s, 3H), 1.67 - 1.44 (m, 4H)

[0036] 3-5) Synthesis of other compounds via synthetic route C In step 3, the following compounds were also synthesized via synthetic route C by using a benzoic acid or pyridinecarboxylic acid derivative corresponding to each final synthesized compound instead of 3-methoxybenzene-5-(trifluoromethyl)benzoic acid: N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 2), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-fluoro-3-(trifluoromethyl)benzamide (compound 4), N-(3-(2'-amino-7'-oxo-5'H-spiro [Cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-chloro-3-(trifluoromethyl)benzamide (compound 5), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzamide (compound 6), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclo Pyropropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 7), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,4-difluorobenzamide (compound 9), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'( 7'H)-yl)-4-methylphenyl)-2,4-difluorobenzamide (compound 14), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,5-difluorobenzamide (compound 15), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-methoxybenzamide (compound 16),N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-chloro-2-fluoro-5-(trifluoromethyl)benzamide (compound 17), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-fluoro-5-(trifluoromethyl)benzamide (compound 18), N-(3-(2' -amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-methoxy-5-(trifluoromethyl)benzamide (compound 19), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4'-methoxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamide (compound 20), N-(3 -(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-6-(trifluoromethyl)picolinamide (compound 21), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (compound 22), N-(3-(2'-amino-7'-oxo-5'H-spiro[ Cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-hydroxy-5-(trifluoromethyl)benzamide (compound 23), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 24), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-chloro-5-(trifluoromethyl)benzamide (compound 25), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-chloro-5-(trifluoromethyl)benzamide (compound 26), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl )-4-methylphenyl)-3-morpholino-5-(trifluoromethyl)benzamide (compound 29), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-methoxyethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 31), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl) N-(3-(2'-methylphenyl)-3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 33), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(piperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 34), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl) N-(3-(2'-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 37), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound 61), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl)benzamide (compound 65), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclobutanecarboxamide (compound 75), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7' H)-yl)-4-methylphenyl)-3-oxocyclobutan-1-carboxamide (compound 76), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclohex-1-en-1-carboxamide (compound 77), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-methylthioph Benzo-2-carboxamide (compound 78), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl) isoxazole-5-carboxamide (compound 79), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl) benzo[d]thiazole-2-carboxamide (compound 80), N-(3-(2'-amino N-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4,4,4-trifluorobutanamide (compound 81), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)thiazole-5-carboxamide (compound 82), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclopentanecarboxamide (compound 83), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)tetrahydro-2H-pyran-4-carboxamide (compound 84).

[0037] <Example 4> Synthesis route D of compound 112 Compound 112 was synthesized via synthetic route D as shown in Scheme 4 below, and other compounds were also synthesized via synthetic route D in the same manner. The synthesis method will be described in detail based on compound 112. [Scheme 4] [ka] 4-1) Step 1 6′-(5-amino-2-methylphenyl)-2′-((4-methoxybenzyl)amino)-5′,6-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-7′-one (35.0 mg, 0.08 mmol) obtained in Step 2 of Example 3 was dissolved in tetrahydrofuran (1.5 mL), and 3-(trifluoromethyl)phenyl isocyanate (19.0 mg, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was diluted with acetonitrile. The insoluble solid was filtered using a Celite pad and washed with acetonitrile. The resulting solid was dried to obtain 12.6 mg of the target compound as a white solid in 25% yield. MS(m / z): 603.20[M+1]

[0038] 4-2) Step 2 The 1-(3-(2-((4-methoxybenzyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea (9.0 mg, 15 μmol) obtained in Step 1 was dissolved in trifluoroacetic acid (1.0 mL), anisole (3.0 μL, 30 μmol) was added, and the mixture was stirred under reflux at 75°C for 3 hours. After the reaction was complete, the reaction mixture was added dropwise to a saturated sodium bicarbonate aqueous solution at 0°C and stirred slowly for 15 minutes. The mixed solution was extracted with dichloromethane:methanol (9:1) solvent, and the collected organic layer was dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by HPLC (5:95 → 95:5 (v / v), 40 minutes) to obtain 1.5 mg of the target compound (compound 112) in a yield of 14%. MS(m / z): 483.15[M+1] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.84 (s, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.62-7.44 (m, J=6.6, 2.9, 1.2 Hz, 3H), 7.31 (d, J=7.1 Hz, 1H), 7.28-7.16 (m, 2H), 6.63 (s, 2H), 4.80 (d, J = 15.0 Hz, 1H), 4.58 (d, J = 15.5 Hz, 1H), 2.08 (s, 3H), 1.66-1.45 (m, 4H)

[0039] 4-3) Synthesis of other compounds via synthetic route D The following compounds were synthesized via synthetic route D: 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclopropylurea (compound 112), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclobutylurea (compound 113), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[ 4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclopentylurea (compound 114), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(cyclopropylmethyl)urea (compound 115), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(cy Chlohexylmethyl)urea (compound 116), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-benzylurea (compound 117), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-(trifluoromethoxy)phenyl)urea (compound 118), 1-(3-(2'-amino-7 '-Oxo-5'H-Spiro[Cyclopropane-1,8'-Pyrido[4,3-d]Pyrimidine]-6'(7'H)-yl)-4-Methylphenyl)-3-(3-Cyanophenyl)Urea (Compound 119), 1-(3-(2'-Amino-7'-Oxo-5'H-Spiro[Cyclopropane-1,8'-Pyrido[4,3-d]Pyrimidine]-6'(7'H)-yl)-4-Methylphenyl)-3-(3,4-Difluorophenyl)Urea (Compound 120), 1-(3-(2'-Amino-7'-Oxo-5'H-Spiro[Cyclopropane-1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(2-methoxyphenyl)urea (compound 121), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea (compound 122), 1-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(m-tolyl)urea (compound 125).

[0040] <Example 5> Synthesis route E of compound 123 Compound 123 is synthesized via synthetic route E, as shown in Scheme 5 below, and the synthesis method is described below. [Scheme 5] [ka] 5-1) Step 1 2,4-dichloro-5-(chloromethyl)pyrimidine (6.95 g, 35.20 mmol) and 2-methyl-5-nitro-3-pyridinamine (7.01 g, 45.76 mmol) obtained in Step 1 of Example 1 were dissolved in acetone (70 mL), sodium iodide (6.86 g, 45.76 mmol) and potassium carbonate (9.73 g, 70.40 mmol) were added, and the mixture was stirred under reflux at 50°C for 2 hours. After the reaction was complete, the mixed solution was cooled to room temperature, filtered through a Celite pad, and concentrated using a rotary evaporator. The concentrate was diluted with ethyl acetate and extracted with ethyl acetate and water. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (dichloromethane:ethyl acetate = 7:3 (v / v)), and the solution was concentrated under reduced pressure to obtain 3.4 g of the target compound as a yellow solid in 31% yield. MS(m / z): 313.9[M+1] 1H NMR (400 MHz, CDCl3) δ 8.79(d, J=2.2Hz, 1H), 8.52 (s, 1H), 7.45(d, J=2.2 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 4.40 (t, J = 5.6 Hz, 1H), 2.57 (s, 3H)

[0041] 5-2) Step 2 The N-((2,4-dichloropyrimidine-5-yl)methyl)-2-methyl-5-nitropyridine-3-amine (3.80 g, 12.10 mmol) obtained in Step 1 was dissolved in anhydrous tetrahydrofuran (100 mL), and dissolved gas was removed from the mixture by bubbling nitrogen gas through for 5 minutes. The reaction vessel was placed in an ice bath at 0°C, and 60% sodium hydride (0.51 g, 12.70 mmol) was added in installments, and the mixture was stirred at room temperature for 1 hour. The reaction vessel was placed in an ice bath at 0°C, and ethyl malonyl chloride (2.28 mL, 18.15 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was cooled in an ice bath at 0°C, and the reaction was quenched with saturated ammonium chloride solution. The remaining organic solvent was concentrated under reduced pressure using a rotary evaporator, the concentrate was diluted with water, and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (ethyl acetate:hexane = 3:7 (v / v)), and the solution was concentrated under reduced pressure to obtain 3.5 g of the target compound as a white solid in 68% yield. MS(m / z): 428.00[M+1] 1H NMR (400 MHz, CDC13) δ 9.40 (d, J = 2.4 Hz, 1H), 8.95 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 5.36 (d, J= 15.3 Hz, 1H), 4.52 (d, J =15.3 Hz, 1H), 4.13 (qd, / = 7.1, 2.0 Hz, 2H), 3.25 (d, J= 15.7 Hz, 1H), 3.09 (d, J= 15.7 Hz, 1H), 2.64 (s, 3H), 1.23 (t, J=7.2 Hz, 3H)

[0042] 5-3) Step 3 **ethyl 3-(((2,4-dichloropyrimidine-5-yl)methyl)(2-methyl-5-nitropyridine-3-yl)amino)-3-oxopropanoate ethyl** (1.66 g, 3.88 mmol) obtained in Step 2 was dissolved in dimethyl sulfoxide (30 mL), and nitrogen gas was passed through the mixture for 5 minutes to remove dissolved gases. The reaction vessel was cooled in an ice bath (0 °C), and cesium carbonate (1.51 g, 4.65 mmol) was added in small amounts. After the reaction was complete, the reaction mixture was added dropwise to 1N hydrochloric acid aqueous solution (200 mL) at 0 °C and stirred slowly for 15 minutes. The resulting mixture was extracted with dichloromethane, the organic layers were dried together over anhydrous sodium sulfate, and then concentrated under reduced pressure. MS(m / z): 392.00[M+l]

[0043] 5-4) Step 4 Ethyl 2-chloro-6-(2-methyl-5-nitropyridine-3-yl)-7-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-8-carboxylate (0.34 g, 0.87 mmol) obtained in Step 3 was dissolved in 1,4-dioxane (10 mL). 0.56 mL, 8.68 mmol, of 4N hydrochloric acid aqueous solution dissolved in 1,4-dioxane was added, and the mixture was stirred under reflux at 100°C for 2 hours. After the reaction was complete, the mixed solution was cooled to room temperature, and the remaining solvent was removed under reduced pressure. The remaining mixture was diluted with dichloromethane. The insoluble solid was filtered using a Celite pad, and the collected filtrate was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (ethyl acetate:dichloromethane = 6:4 (v / v)), and the solution was concentrated under reduced pressure to obtain 0.15 g of the target compound as a yellow solid in 53% yield. MS(m / z): 319.95 [M+1] 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J = 2.4 Hz, 1H), 8.55 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 4.95 (d, J = 15.9 Hz, 1H), 4.75 (d, J = 15.8 Hz, 1H), 4.04 (s, 2H), 2.55 (s, 3H)

[0044] 5-5) Step 5 2-chloro-6-(2-methyl-5-nitropyridine-3-yl)-5,8-dihydropyrido[4,3-d]pyrimidine-7(6H)-one (0.12 g, 0.37 mmol) obtained in Step 4 was dissolved in anhydrous dimethylformamide (3.0 mL) and nitrogen gas was blown in for 5 minutes. Next, (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (0.25 g, 0.56 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Triethylamine (0.16 mL, 0.56 mmol) was slowly added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (ethyl acetate:dichloromethane = 3:7 (v / v)), and the solution was concentrated under reduced pressure to obtain 87.0 mg of the target compound as a yellow solid in 67% yield. MS(m / z): 346.05[M+1] 1 H NMR (400 MHz, CDCl3) δ 9.36 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.5 Hz, 2H), 5.06 (d, J = 15.8 Hz, 1H), 4.82 (d, J = 15.8 Hz, 1H), 2.57 (s, 3H), 2.10 - 1.85 (m, 4H)

[0045] 5-6) Step 6 2'-chloro-6'-(2-methyl-5-nitropyridine-3-yl)-5',6'-dihydro-7'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-7'-one (0.08 g, 0.23 mmol) obtained in Step 5 was dissolved in tetrahydrofuran (4.0 mL), and methanol (2.0 mL) and water (1.0 mL) were added. Iron (0.06 g, 1.16 mmol) and ammonium chloride (0.06 g, 1.16 mmol) were added at room temperature, and the mixture was stirred under reflux at 80 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was diluted with water and extracted with dichloromethane. The collected organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 62.6 mg of the target compound as a pale yellow solid in 91% yield. MS(m / z): 316.10[M+1] 1 H NMR (400 MHz, CDC13) δ 8.36 (s, 1H), 8.06 (d, J = 2.6 Hz, 1H), 6.89 (d, J =2.6 Hz, 1H), 4.90 (d, J= 16.5 Hz, 1H), 4.79 (d, J= 16.4 Hz, 1H), 3.72 (s, 2H), 2.33 (s, 3H), 2.08 - 2.00 (m, 2H), 1.92 - 1.83 (m, 2H).

[0046] 5-7) Step 7 6′-(5-amino-2-methylpyridine-3-yl)-2′-chloro-5′,6′-dihydro-7′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-7′-one (0.07 g, 0.22 mmol) obtained in Step 6 was dissolved in dichloromethane (5.0 mL), and 3-(trifluoromethyl)benzoyl chloride (0.06 mL, 0.40 mmol) and potassium carbonate (0.06 g, 0.44 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (ethyl acetate:dichloromethane = 4:6 (v / v)), and the solution was concentrated under reduced pressure to obtain 62.6 mg of the target compound as a yellow solid in 58% yield. MS(m / z): 488.00[M+1] 1 H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.37 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.17 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 5.05 (d, J = 16.3 Hz, 1H), 4.80 (d, J = 16.6 Hz, 1H), 2.19 (s, 3H), 2.14-1.88 (m, 4H)

[0047] 5-8) Step 8 N-(5-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-6-methylpyridine-3-yl)-3-(trifluoromethyl)benzamide (0.06 g, 0.12 mmol) obtained in Step 7 was dissolved in dimethyl sulfoxide (3.0 mL), and 4-methoxybenzylamine (0.16 mL, 1.23 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate. The resulting organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:methanol = 95:5 (v / v)), and the solvent was removed under reduced pressure to obtain the target compound **(compound 123)** 65.8 mg in yield 91% as a yellow solid. MS(m / z): 589.20[M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 2.3 Hz, 1H), 8.33 (s, 1H), 8.29 (d, J = 7.9 Hz, 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.14 (s, 1H), 8.01 (d, J = 7.82 (t, J = 7.8 Hz, 1H), 6.90 - 6.84 (m, 4H), 4.85 (d, J = 15.1 Hz, 1H), 4.66 (d, J = 15.2 Hz, 1H), 3.73 (s, 3H), 3.66 (s, 2H), 2.28 (s, 3H), 1.68 - 1.45 (m, 4H)

[0048] 5-9) Step 9 The N-(5-(2'-((4-methoxybenzyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-6-methylpyridine-3-yl)-3-(trifluoromethyl)benzamide (0.65 mg, 0.11 mmol) obtained in Step 8 was dissolved in a solution of trifluoroacetic acid (3.0 mL), anisole (23.0 μL, 0.22 mmol) was added, and the mixture was stirred under reflux at 75°C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified with MPLC (dichloromethane:methanol = 95:5 (v / v)). The solution was concentrated under reduced pressure to obtain 32.0 mg of the target compound as a pale yellow solid (Compound 123, N-(5-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-6-methylpyridine-3-yl)-3-(trifluoromethyl)benzamide), yield 62%. MS(m / z): 469.10[M+1] 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.34 (s, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.82 (t, J=7.8 Hz, 1H), 6.68 (s, 2H), 4.85 (d, J=15.1 Hz, 1H), 4.67 (d, J=15.2 Hz, 1H), 2.30 (s, 3H), 1.68-1.50 (m, 4H).

[0049] <Example 6> Synthesis route F of compound 124 Compound 124 was synthesized via synthetic route F, as shown in Scheme 6 below. The synthesis method is described in detail based on compound 124. [Scheme 6] [ka] 6-1) Step 1 N,N-dimethylformamide (3 mL) was mixed with N-(3-(2′-chloro-7′-oxo-5′H-spiro[cyclopropane-1,8′-pyrido[4,3-d]pyrimidine]-6′(7′H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (250 mg, 0.51 mmol), methyl iodide (0.16 mL, 2.57 mmol), and potassium carbonate (213 mg, 1.54 mmol). The mixture was stirred under reflux at 120°C for 12 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and water was added dropwise. The resulting residue was purified by flash column chromatography (dichloromethane:methanol = 0-5%), and the solution was concentrated under reduced pressure to obtain 120 mg of the target compound as a solid in 47% yield. MS (m / z): 501 [M+1]

[0050] 6-2) Step 2 N-(3-(2-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-N-methyl-3-(trifluoromethyl)benzamide (0.12 g, 0.24 mmol) obtained in Step 1 was dissolved in 2-butanol (10.0 mL), and potassium carbonate (0.17 g, 1.23 mmol), 6-methylpyridine-3-amine (39 mg, 0.36 mmol), and tris(dibenzylideneacetone)dipalladium (0) (46 mg, 0.050 mmol) were added at room temperature. The reaction mixture was stirred at 100°C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered through a Celite pad, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (0-5% dichloromethane:methanol), and the solution was concentrated under reduced pressure to obtain 104 mg of the target compound as a brown solid (Compound 124, N-methyl-N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide), yield 76%. MS (m / z): 573 [M+1]

[0051] <Example 7> Synthesis route G of compound 134 Compound 134 is synthesized via synthetic route G, as shown in Scheme 7 below, and the synthesis method is described below. [Scheme 7] [ka] 7-1) Step 1 2,4-dichloro-5-(chloromethyl)pyrimidine (27.8 g, 140.80 mmol) and methyl 3-amino-4-methylbenzoate (30.24 g, 183.04 mmol) obtained in Step 1 of Example 1 were dissolved in acetone (300 mL), then sodium iodide (27.44 g, 183.04 mmol) and potassium carbonate (38.92 g, 281.60 mmol) were added, and the mixture was stirred at 50 °C with reflux for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through a Celite pad, and concentrated using a rotary evaporator. The resulting concentrate was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After removing the solvent, 36.3 g (79.0% yield) of the target compound was obtained as a yellow oily substance, which was used in the next reaction without purification. MS(m / z): 326 [M+1]

[0052] 7-2) Step 2 The methyl 3-(((2,4-dichloropyrimidine-5-yl)methyl)amino)-4-methylbenzoate (36.3 g, 111.13 mmol) obtained in Step 1 was dissolved in anhydrous tetrahydrofuran (300 mL), and nitrogen gas was passed through the mixture for 5 minutes to remove dissolved gases. The reaction vessel was cooled in an ice bath (0 °C), and 60% sodium hydride (5.78 g, 144.47 mmol) was added in small amounts, followed by stirring at room temperature for 1 hour. The reaction vessel was placed back in an ice bath (0 °C), and ethyl malonyl chloride (20.92 mL, 166.69 mmol) was added dropwise, followed by stirring at room temperature for 16 hours. After the reaction was complete, the reaction mixture was cooled in an ice bath (0 °C), and the reaction was stopped by adding saturated ammonium chloride aqueous solution. The remaining organic solvent was concentrated under reduced pressure using a rotary evaporator, and the residue was diluted with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated. The resulting residue was purified with MPLC (ethyl acetate:hexane = 3:7 (v / v)), and the solvent was removed under reduced pressure to obtain 20.2 g (41.2% yield) of the target compound as a yellow oily substance. MS(m / z): 440 [M+1]

[0053] 7-3) Step 3 The methyl 3-(N-((2,4-dichloropyrimidine-5-yl)methyl)-3-ethoxy-3-oxopropanamide)-4-methylbenzoate (0.3 g, 0.68 mmol) obtained in Step 2 was dissolved in tetrahydrofuran (6.0 mL), and nitrogen gas was passed through the mixture for 5 minutes to remove dissolved gases. The reaction vessel was placed in an ice bath (0 °C), and 60% sodium hydride (0.04 g, 1.02 mmol) was added in small amounts, followed by stirring at 30 °C for 12 hours. After the reaction was complete, water was added to stop the reaction, and the mixture was extracted with a dichloromethane:methanol (9:1) mixed solvent. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by MPLC (hexane:ethyl acetate = 4:6 (v / v)), and the solvent was removed under reduced pressure to obtain 0.25 g (yield 91%) of the target compound as a yellow solid. MS(m / z): 404 [M+1]

[0054] 7-4) Step 4 Ethyl 2-chloro-6-(5-(methoxycarbonyl)-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-8-carboxylate (0.3 g, 0.74 mmol) obtained in Step 3 was dissolved in 1,4-dioxane (15 mL). 0.3 mL, 7.4 mmol, of 4N hydrochloric acid aqueous solution dissolved in 1,4-dioxane was added, and the mixture was stirred under reflux at 80°C for 1 hour. After the reaction was complete, the mixed solution was cooled to room temperature, the residual solvent was removed under reduced pressure, and the residual mixture was diluted with dichloromethane. The insoluble solid was filtered using a Celite pad, and the recovered filtrate was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (hexane:ethyl acetate = 4:6 (v / v)), and the solution was concentrated under reduced pressure to obtain 0.1 g of the target compound as a yellow solid in 63% yield. MS (m / z): 331 [M+1]

[0055] 7-5) Step 5 3-(2-chloro-7-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)-4-methylbenzoate (0.03 g, 0.093 mmol) obtained in Step 4 was dissolved in anhydrous dimethylformamide (1.0 mL) and nitrogen gas was bubbling for 5 minutes. Then, (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (0.06 g, 0.14 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Triethylamine (0.04 mL, 0.28 mmol) was slowly added to the mixture and stirred at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (hexane:ethyl acetate = 4:6 (v / v)), and the solution was concentrated under reduced pressure to obtain 28.3 mg of the target compound as a pale yellow solid in 85% yield. MS (m / z): 358 [M+1]

[0056] 7-6) Step 6 3-(2-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylbenzoate methyl (0.03 g, 0.014 mmol) obtained in Step 5 was dissolved in tetrahydrofuran (0.5 mL) and water (0.5 mL) was added. Lithium hydroxide (0.06 g, 1.16 mmol) and ammonium chloride (18.0 mg, 0.42 mmol) were added at room temperature and the mixture was stirred under reflux at 30°C for 2 hours. After the reaction was complete, 1N hydrochloric acid aqueous solution was added dropwise to the reaction mixture to adjust the pH to 2-3, then diluted with water and extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to the next reaction without purification. The target compound was obtained as a pale yellow solid (17.0 mg, yield 60%). MS(m / z): 344[M+1]

[0057] 7-7) Step 7 3-(2-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (17.0 mg, 0.05 mol) obtained in Step 6 was dissolved in dimethylformamide (1 mL), and HATU (28.0 mg, 0.074 mmol), N,N-diisopropylethylamine (0.03 mL, 0.15 mmol) and 3-(trifluoromethyl)aniline (0.01 mL, 0.074 mmol) were added, and the mixture was stirred at 60°C for 3 hours. After the reaction was complete, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (hexane:ethyl acetate = 5:5 (v / v)), and the solution was concentrated under reduced pressure to obtain 7 mg of the target compound as a pale yellow solid in 29% yield. MS(m / z): 487[M+1]

[0058] 7-8) Step 8 3-(2-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (6.5 mg, 0.013 mmol) obtained in Step 7 was dissolved in dimethyl sulfoxide (0.5 mL), and 4-methoxybenzylamine (17.0 μL, 0.13 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 90°C for 2 hours. After the reaction was complete, the mixed solution was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with MPLC (hexane:ethyl acetate = 3:7 (v / v)), and the solution was concentrated under reduced pressure to obtain 4 mg of the target compound as a pale yellow solid in 52% yield. MS (m / z): 588 [M+1]

[0059] 7-9) Step 9 The N-(3-(2-amino-7'-oxo-5'H-spiro[cyclopropene-1,8-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (4 mg, 0.009 mmol) obtained in Step 8 was dissolved in a solution of trifluoroacetic acid (0.2 mL), then anisole (2.0 mL, 0.017 mmol) was added, and the mixture was stirred under reflux at 75°C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by Prep HPLC (water:acetonitrile = 10-95%). The solution was concentrated under reduced pressure to obtain 1 mg of the target compound as a white solid (Compound 134, 3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide), yield 23%. MS(m / z): 468 [M+1] 1H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.96 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.63-7.57 (m, 1H), 7.48 (dd, J = 17.5, 8.0 Hz, 2H), 6.67 (s, 2H), 4.91 (d, J = 15.3 Hz, 1H), 4.64 (d, J = 15.4 Hz, 1H), 2.19 (s, 3H), 1.65-1.49 (m, 4H).

[0060] Information on the example compounds synthesized in this invention is shown in Tables 1 to 6 below. [Table 1] JPEG2026519043000017.jpg247159JPEG2026519043000018.jpg244161JPEG2026519043000019.jpg244157JPEG2026519043000020.jpg248158JPEG2026519043000021.jpg244163JPEG2026519043000022.jpg244158JPEG2026519043000023.jpg245157JPEG2026519043000024.jpg244160JPEG2026519043000025.jpg248160JPEG2026519043000026.jpg227158JPEG2026519043000027.jpg228158JPEG2026519043000028.jpg222159JPEG2026519043000029.jpg249159JPEG2026519043000030.jpg249158JPEG2026519043000031.jpg246158JPEG2026519043000032.jpg248158JPEG2026519043000033.jpg247159JPEG2026519043000034.jpg248160JPEG2026519043000035.jpg248161JPEG2026519043000036.jpg248162JPEG2026519043000037.jpg247162JPEG2026519043000038.jpg239161JPEG2026519043000039.jpg248161JPEG2026519043000040.jpg247158JPEG2026519043000041.jpg249161JPEG2026519043000042.jpg248163JPEG2026519043000043.jpg248157JPEG2026519043000044.jpg166159

Table 2

[0061] <Experiment Example 1> Evaluation of enzyme activity inhibition Table 7 below shows the results of enzyme activity inhibition experiments against kinases ACK1, BMX, and Src, conducted by Reaction Biology (RBC) in the United States, for the selected example compounds. [* <10 nM: A, <100 nM: B, >100 nM: C]. [Table 7]

[0062] <Experiment Example 2> Cellular Inhibition Analysis C4-2B and 22Rv1 cells were purchased from ATCC and cultured according to the manufacturer's instructions. The cells were placed in 96-well plates in 7 × 10⁶ rows. 3 Cells were seeded at 100 μl / well and allowed to adhere for 1 day. After removing the culture medium, 90 μl / well of fresh culture medium was added, followed by 10 μl / well of culture medium containing compounds serially diluted 3-fold at 9 concentrations (0.076–500 μM) and DMSO control to a final concentration of 0–50 μM. The cells were incubated in a 37°C CO2 incubator for 72 hours. Cell proliferation after 72 hours was evaluated by adding 10 μl / well of CCK-8 solution, shaking for 30 seconds, then incubating in a 37°C CO2 incubator for 2 hours, and measuring the absorbance at 450 nm using a microplate reader. The measured absorbance values ​​were corrected by subtracting the absorbance of wells containing only culture medium and CCK-8 solution, and the GI50 value was calculated using GraphPad Prism 8 software. Meanwhile, in another 96-well plate, the cells were placed in a 7 × 10⁶ well. 3 Cells were seeded at 100 μl / well, allowed to adhere for 1 day, CCK-8 solution was added, and absorbance was measured to establish the "growth (%) = 0" value. The results are shown in Table 3 below. [* <1 μM: A, <5 μM: B, <10 μM: C, >10 μM: D]. [Table 8] Furthermore, experiments were conducted using the same method for the A172, A549, HCI-H460, AsPC-1, MIA-Paca-2, DLD-1, HCT-116, HT-29, SW480, SW620, MDA-MB-231, and SKOV3 cell lines, and the results are shown in Tables 9 and 10 below. [* <1 μM: A, <5 μM: B, <10 μM: C, >10 μM: D]. [Table 9] [Table 10]

[0063] <Experiment Example 3> Measurement of kinase inhibitory activity To measure the inhibitory activity of the compounds of the present invention against protein kinases, biochemical assays were performed using a full kinase panel. The inhibitory effect of Example compounds 8 and 51 on kinases was measured when treated with a single concentration of 1 μM, and the residual enzyme activity value was calculated. Kinases were identified when the calculated residual enzyme activity value was 40% or less, i.e., inhibited by 60% or more. The results are shown in Tables 11 to 14 below. The results for Example Compound 8 are shown in Tables 11 and 12 below. [Table 11] JPEG2026519043000075.jpg249151JPEG2026519043000076.jpg246161JPEG2026519043000077.jpg247107JPEG2026519043000078.jpg12597 [Table 12] JPEG2026519043000080.jpg244152

[0064] The results for Example Compound 51 are shown in Tables 13 and 14 below. [Table 13] JPEG2026519043000082.jpg244142JPEG2026519043000083.jpg247143JPEG2026519043000084.jpg247121JPEG2026519043000085.jpg15784 [Table 14] JPEG2026519043000087.jpg244146

[0065] The following are examples of formulations of compositions containing compound 8 according to the present invention, but the present invention is not limited to these examples and is intended merely to provide a specific explanation.

[0066] <Example of Formulation 1> Example of a pharmaceutical composition formulation <Formulation Example 1-1> Preparation of Powder Compound 8 (20 mg), lactose (100 mg), and talc (10 mg) were mixed and filled into an airtight bag to prepare a powder. <Prescription Example 1-2> Preparation of Tablets Compound 8 (10 mg), corn starch (100 mg), lactose (100 mg), and magnesium stearate (2 mg) were mixed and compressed into tablets using a standard tablet manufacturing method. <Prescription Examples 1-3> Capsule Preparation Compound 8 (10 mg), corn starch (100 mg), lactose (100 mg), and magnesium stearate (2 mg) were mixed according to a standard capsule preparation method, and the mixture was filled into gelatin capsules to prepare the capsules. <Prescription Examples 1-4> Preparation of Injectable Drugs Compound 8 (10 mg), an appropriate amount of sterile distilled water for injection, and an appropriate amount of pH adjusting agent were mixed and prepared according to the usual method for preparing injection solutions so that each ampoule (2 mL) contained the aforementioned components.

[0067] <Example of formulation 2> Health supplement <Formulation Example 2-1> Manufacturing of Health Foods Compound 8 (1 mg), an appropriate amount of vitamin mixture (vitamin A acetate 70 μg, vitamin E 1.0 mg, vitamin B1 0.13 mg, vitamin B2 0.15 mg, vitamin B6 0.5 mg, vitamin B12 0.2 μg, vitamin C 10 mg, biotin 10 μg, nicotinamide 1.7 mg, folic acid 50 μg, calcium pantothenate 0.5 mg), and an appropriate amount of mineral mixture (ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, monopotassium phosphate 15 mg, dicalcium phosphate 55 mg, potassium citrate 90 mg, calcium carbonate 100 mg, magnesium chloride 24.8 mg) were mixed, and then granules were prepared, and a health food was manufactured according to a conventional method. <Formulation Example 2-2> Manufacturing of Health Drinks Furthermore, Compound 8 (1 mg), citric acid (1000 mg), oligosaccharide (100 g), plum concentrate (2 g), taurine (1 g), and purified water were added to bring the total volume to 900 mL. The above components were mixed and stirred according to a conventional method for preparing health drinks, and heated at 85°C for about 1 hour. The resulting solution was filtered, collected in a sterilized 2 L container, sealed, sterilized, and stored in a refrigerator.

[0068] Specific embodiments of the present invention have been described in detail above. It will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Accordingly, the substantial scope of the invention should be defined by the appended claims and their equivalents.

Claims

1. A compound according to claim 1, having formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a solvate thereof: 【Chemistry 1】 In Equation 1, R １ and R ２ Each of these may be independently selected from hydrogen or (C1-C4) alkyl, or together form a 3- to 5-membered ring; X is selected from substituted or unsubstituted (C1-C4) alkyl, (C3-C6) cycloalkyl, (C4-C6) cycloalkenyl, phenyl, benzyl, or 5- or 6-membered single or bicyclic heterocyclic compounds, wherein the substituted compounds are (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C2) alkoxy, halo, hydroxy, imidazolyl, (C1- C2) alkylimidazolyl, (C1-C2) alkoxyphenyl, morpholino, cyano, oxo(=O), (C1-C2) alkoxy(C1-C2) alkylamino, piperazinyl, (C1-C2) alkylpiperazinyl, ((C1-C2) alkylpiperazine-1-yl)(C1-C2) alkyl and di(C1-C2) alkylamino(C1-C2) alkyl(C1-C2) alkylamino group, one or more selected from the group, A is selected from morpholino or NH-Y, and Y is selected from hydrogen, or substituted or unsubstituted phenyl, benzyl, (C1-C4) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, pyridinyl, pyrazolyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or azetidine group, wherein the substitution is (C1-C2) alkyl, (C1-C4) alkoxy, piperazinyl, (C1-C2) alkylpiperazinyl, acetylpiperazinyl, morpholino, morpholine-4-carbonyl, (C1-C2) alkylpiperazine-1-carbonyl, oxetanyl, ((C1-C2) One or more of the group selected from alkylpiperazine-1-yl)(C1-C2)alkyl, imidazolyl, pyrrolidinyl, di(C1-C2)alkylaminopyrrolidinyl, piperidinyl, acetylpiperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazine-1-yl)piperidinyl, halo, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino, pyridinyl, furanyl, hydroxy, and tert-butoxycarbonyl (BOC) groups. Z is either CH or N; L is CH ２ or NH; n 1 or n 2 is an integer between 0 and 1.

2. A compound according to claim 1, having formula 1-1: 【Chemistry 2】 In Equation 1-1, X is selected from substituted or unsubstituted (C1-C4) alkyl, (C3-C6) cycloalkyl, (C4-C6) cycloalkenyl, phenyl, benzyl, or 5- or 6-membered monocyclic or bicyclic heterocyclic compounds, wherein the substitution is (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C2) alkoxy, halo, hydroxy, imidazolyl, or (C1-C2) alkyl One or more selected from the group consisting of ruimidazolyl, (C1-C2)alkoxyphenyl, morpholino, cyano, oxo(=O), (C1-C2)alkoxy(C1-C2)alkyl(C1-C2)alkylamino, piperazinyl, (C1-C2)alkylpiperazinyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino groups, A is selected from morpholino or -NH-Y, Y is hydrogen, or selected from substituted or unsubstituted phenyl, benzyl, (C1-C4) alkyl, (C2-C3) alkenyl, (C3-C6) cycloalkyl, pyridinyl, pyrazolyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or azetidinyl, wherein the substitution is (C1-C2) alkyl, (C1-C4) alkoxy, piperazinyl, (C1-C2) alkylpiperazinyl, acetylpiperazinyl, morpholino, morpholine-4-carbonyl, (C1-C2) alkylpiperazine-1-carbonyl, oxetanyl, ((C1-C2) alkylpiperazine- One or more of the group selected from 1-yl)(C1-C2)alkyl, imidazolyl, pyrrolidinyl, di(C1-C2)alkylaminopyrrolidinyl, piperidinyl, acetylpiperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazine-1-yl)piperidinyl, halo, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino, pyridinyl, furanyl, hydroxy, and tert-butoxycarbonyl (BOC) groups, Z is either CH or N; L is CH 2 or NH; n is an integer between 0 and 1.

3. The compound according to claim 1, A compound in which the 5 or 6-membered monocyclic or bicyclic heterocyclic compound is selected from the group consisting of thiophene, furan, pyrazole, oxazole, thiazole, pyridine, pyran, tetrahydropyran, oxazine, thiazine, pyrimidine, piperazine, and benzothiazole.

4. A compound according to claim 1, having formula 1-2: 【Transformation 3】 In Equation 1-2, R ３ From R ５ Each of these can be the same or different, and is selected from the group consisting of hydrogen, (C1-C2)alkyl, (C1-C2)alkoxy, trifluoromethyl, halo, hydroxy, (C1-C2)alkylimidazolyl, (C1-C2)alkoxyphenyl, morpholino, (C1-C2)alkoxy(C1-C2)alkyl(C1-C2)alkylamino, piperazinyl, (C1-C2)alkylpiperazinyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino; A １ is selected from morpholino or NH-Y １ and Here, Y １ The phenyl or pyridinyl is selected from hydrogen, (C3-C4) cycloalkyl, benzyl, 1H-pyrazolyl, di(C1-C2) alkyl-1H-pyrazolyl, (oxetan-3-yl)-1H-pyrazolyl, trifluoro(C1-C2) alkyl-1H-pyrazolyl, pyridinyl(C1-C2) alkyl, hydroxy(C1-C2) alkyl, hydroxy(C2-C4) alkenyl, hydroxy(C3-C6) cycloalkyl, morpholino(C3-C4) alkyl, furanyl(C1-C2) alkyl, azetidine substituted with tert-butoxycarbonyl (BOC), tetrahydropyranyl, benzothiazolyl, benzofuranyl, and substituted or unsubstituted phenyl or pyridinyl, where the substitution is (C Selected from 1-C2) alkyl, (C1-C2) alkoxy, halo, trifluoro(C1-C2) alkoxy, piperazinyl, (C1-C2) alkylpiperazinyl, acetylpiperazinyl, morpholino, morpholine-4-carbonyl, (C1-C2) alkylpiperazine-1-carbonyl, ((C1-C2) alkylpiperazine-1-yl)(C1-C2) alkyl, imidazolyl, di(C1-C2) alkylaminopyrrolidinyl, piperidinyl, acetylpiperidinyl, di(C1-C2) alkylaminopiperidinyl, ((C1-C2) alkylpiperazine-1-yl)piperidinyl, and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino.

5. A compound according to claim 1, having formulas 1-3: 【Chemistry 4】 In Equation 1-3, X 1 This is selected from pyridinyl compounds substituted with substituents selected from the group consisting of (C3-C6) cycloalkyl, oxo(C3-C6) cycloalkyl, (C4-C6) cycloalkenyl, thiophene, (C1-C2) alkylthiophene, furan, thiazole, oxazole, benzothiazole, tetrahydropyran, trifluoro(C1-C3) alkyl; or (C1-C2) alkyl, (C1-C2) alkoxy, trifluoromethyl, halo, and hydroxy. A 2 This is Morpholino or NH-Y 2 Selected from, Here, Y 2 This is one or more selected from the group consisting of hydrogen, benzyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, (C1-C2)alkylpyridinyl, pyridinyl(C1-C2)alkyl, hydroxy(C1-C2)alkyl, hydroxy(C2-C4)alkenyl, hydroxy(C3-C6)cycloalkyl, morpholino(C3-C4)alkyl, furanyl(C1-C2)alkyl, ((C1-C2)alkylpiperazine-1-yl)piperidinyl-trifluoro(C1-C2)alkoxypyridinyl, and azetidine substituted with tert-butoxycarbonyl (BOC).

6. A compound according to claim 1, having formulas 1-4: 【Transformation 5】 In Equation 1-4, X 2 is selected from (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C2)alkyl, benzyl, or substituted or unsubstituted phenyl, wherein the substitution is one or more from the group selected from (C1-C2)alkyl, (C1-C2)alkoxy, halo, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, and cyano groups. A 3 This is Morpholino or NH-Y 3 Selected from, Here, Y 3 is one or more selected from hydrogen or (C1-C2) alkylpyridinyl.

7. A compound according to claim 1, having formulas 1-5: 【Transformation 6】 In Equation 1-5, X ３ is selected from substituted or unsubstituted phenyl, and the substitution is one or more selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, and halo groups. A ４ is Morpholino or NH-Y ４ Selected from, Y ４ is one or more selected from hydrogen, benzyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, morpholino(C3-C4)alkyl, furanyl(C1-C2)alkyl, or pyridinyl(C1-C2)alkyl.

8. A compound according to claim 1, having formulas 1-6: 【Transformation 7】 In Equation 1-6, X 4 The group is selected from substituted or unsubstituted phenyl groups, and the substitution is one or more from the group selected from (C1-C2)alkyl, (C1-C2)alkoxy, halo, and trifluoromethyl groups. A 5 is Morpholino or NH-Y 5 Selected from, here Y 5 is hydrogen, or one or more selected from (C1-C2) alkylpyridinyl compounds.

9. The compound according to claim 1, wherein the compound is N-(3-(2'-((1,3-dimethyl-1H-pyrazole-5-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 1), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl )benzamide (compound 2), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 3), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-fluoro-3-(trifluoromethyl)benzamide (compound 4), N-(3 -(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-chloro-3-(trifluoromethyl)benzamide (compound 5), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzamide (compound 6), N-(3-(2 '-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 7), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)benzamide (compound 8),N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,4-difluorobenzamide (compound 9), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,4-difluorobenzamide (compound 10), N-(3- (2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,5-difluorobenzamide (compound 11), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide Mido (compound 12), 3-bromo-N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)benzamide (compound 13), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2,4-diflu Olobenzuamide (compound 14), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3,5-difluorobenzamide (compound 15), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-methoxybenzamide (compound 16), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-chloro-2-fluoro-5-(trifluoromethyl)benzamide (compound 17), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-fluoro-5-(trifluoromethyl)benzamide (compound 18), N-(3-(2' -amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-methoxy-5-(trifluoromethyl)benzamide (compound 19), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4'-methoxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamide (compound 20), N-(3 -(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-6-(trifluoromethyl)picolinamide (compound 21), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (compound 22), N-(3-(2'-amino-7'-oxo-5'H-spiro[ Cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-hydroxy-5-(trifluoromethyl)benzamide (compound 23), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 24), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-chloro-5-(trifluoromethyl)benzamide (compound 25), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-chloro-5-(trifluoromethyl)benzamide (compound 26), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3- d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (compound 27), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-morpholino-5-(trifluoromethyl)benzamide (compound 28), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3 -d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-morpholino-5-(trifluoromethyl)benzamide (compound 29), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-methoxyethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 30), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclo Lopropan-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-methoxyethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 31), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropan-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 32), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 33), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(piperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 34) ), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(piperazine-1-yl)-5-(trifluoromethyl)benzamide (compound 35), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-(dimethylamino)ethyl)(methyl) Mino)-5-(trifluoromethyl)benzamide (compound 36), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 37), N-(4-methyl-3-(2'-((4-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3 -d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 38), N-(3-(2'-((4-(4-acetylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 39), N-(4-methyl-3-(2'-((4-morpholinophenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 40), N-(4-methyl-3-(2'-((4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 41), N-(3-(2'-((4-(4-ethylpiperazine-1-yl)-2-methoxyphen (Lu)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 42), N-(4-methyl-3-(2'-((4-((4-methylpiperazine-1-yl)methyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 43), N-(3-(2'-((4-(1H-imidazole-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 44), N-(4-methyl-3-(7'-oxo-2'-((4-(piperazine-1-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(tri Fluoromethyl)benzamide (compound 45), (S)-N-(3-(2'-((4-(3-(dimethylamino)pyrrolidine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 46), N-(4-methyl-3-(7'-oxo-2'-((4-(piperidine-4-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 47), N-(4-methyl-3-(2'-((3-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 48), N-(3-(2'-((4-(1-acetylpiperidine-4-yl)phenyl)amino)-7'-oxo- 5'H-Spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 49), N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-Spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound 50) N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 51), N-(4-methyl-3-(2'-((1-(oxetan-3-yl)-1H-pyrazole-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl )-3-(trifluoromethyl)benzamide (compound 52), N-(3-(2'-((2-methoxy-4-morpholinophenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 53), N-(3-(2'-((2-methoxy-4-(morpholin-4-carbonyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 54), N-(3-(2'-((3-methoxy-4-(4-methylpiperazine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 55), N-(3-(2'-((3-methoxy-4-morpholinophen N-(3-(2'-((4-(4-ethylpiperazine-1-yl)-3-(trifluoromethyl)benzamide (compound 56), N-(3-(2'-((4-(4-ethylpiperazine-1-yl)-3-fluorophenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide N-(3-(2'-((6-(4-ethylpiperazine-1-yl)-2-methoxypyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 58), N-(4-methyl-3-(7'-oxo-2'-(phenylamino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6 '(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 59), N-(3-(2'-((4-(4-(dimethylamino)piperidine-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 60), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound 61), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl)benzamide (compound 62), N-(3-(2'-((4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl) -4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 63), N-(4-methyl-3-(7'-oxo-2'-((1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 64), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]- 6'(7'H)-yl)-4-methylphenyl)-4-(4-methylpiperazine-1-yl)-3-(trifluoromethyl)benzamide (compound 65), N-(3-(2'-((4-(4-acetylpiperazine-1-yl)-2-methoxyphenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 66), N-(3-(2'-((3-methoxy-4-(piperazine-1- Il)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 67), N-(3-(2'-((1,3-dimethyl-1H-pyrazole-5-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 68),N-(3-(2'-((2-methoxy-6-(4-methylpiperazine-1-yl)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 69), N-(3-(2'-(hydroxyamino)-7'-oxo-5'H-spiro[cyclopropane-1, 8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 70), 1-(4-fluorophenyl)-3-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)urea (compound 71), 4-Chloro-N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)benzamide (compound 72), N-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)thiophene-2-carboxamide (compound 73), N-(4-methyl-3- (2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)furan-2-carboxamide (compound 74), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclobutanecarboxamide (compound 75), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'- Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-oxocyclobutan-1-carboxamide (compound 76), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclohex-1-en-1-carboxamide (compound 77), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4- Methylphenyl)-4-methylthiophene-2-carboxamide (compound 78), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl) isoxazole-5-carboxamide (compound 79), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl) benzo[d]thiazole-2-carboxamide (compound 80),N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-4,4,4-trifluorobutanamide (compound 81), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)thiazole-5-carboxamide (compound 82), N-(3-(2'-amino-7'-oxo-5'H-spiro[cycloprop Pyropropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)cyclopentanecarboxamide (compound 83), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)tetrahydro-2H-pyran-4-carboxamide (compound 84), N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine N-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 85), N-4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 86), N-4-methyl-3-(7'-oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d] Pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 87), N-(4-methyl-3-(7'-oxo-2'-((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 88), N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 89), N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 91), N-(4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cy Clopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 92), N-(4-methyl-3-(7'-oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 93), N-(4-methyl-3-(7'-oxo-2'-((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 94), N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 95), N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl (L)-5-(trifluoromethyl)nicotinamide (compound 96), N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(3,5-difluorophenyl)acetamide (compound 97), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-morpholino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrimidine] [4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 98), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(7'-oxo-2'-((tetrahydro-2H-pyran-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 99), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(7'-oxo-2' -((pyridine-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 100), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((3-morpholinopropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 101), 2-(3,5-difluorophenyl)-N-(3-(2'-((furan-2-ylmethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)acetamide (compound 102), N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 103), N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 104), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8' -Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 105), N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 106), N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane- 1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 107), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 108),N-(3-(2'-(benzo[d]thiazole-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-(3,5-difluorophenyl)acetamide (compound 109), 2-(3,5-difluorophenyl)-N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl Nyl)acetamide (compound 110), 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazine-1-yl)piperidine-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide (compound 111), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine] Limidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclopropylurea (compound 112), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclobutylurea (compound 113), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-cyclopentylurea (compound 114), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(cyclopropylmethyl)urea (compound 115), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(cyclohexylmethyl)urea (compound 116), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-Pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-benzylurea (compound 117), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-(trifluoromethoxy)phenyl)urea (compound 118), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl) -4-methylphenyl)-3-(3-cyanophenyl)urea (compound 119), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(3,4-difluorophenyl)urea (compound 120), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(2-methoxyphenyl)urea ( Compound 121), 1-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea (Compound 122), N-(5-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-6-methylpyridine-3-yl)-3-(trifluoromethyl)benzamide (Compound 123), N-methyl-N- (4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 124), 1-(4-methyl-3-(2'-((6-methylpyridine-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(m-tolyl)urea (compound 125),N-(3-(2'-((2-hydroxyethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 126), (S)-N-(3-(2'-((1-hydroxypropane-2-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 127), N-(3-(2'-(((1r,3r)-3-hydroxycyclobutyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 128), tert-butyl3-((6'-(2-methyl-5-(3-(trifluoromethyl)benzamide)phenyl)-7'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine [Zin]-2'-yl)amino)azetidine-1-carboxylate (compound 129), N-(3-(2'-((2-hydroxyethyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 130), (S)-N-(3-(2'-((1-hydroxypropane-2-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6 '(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 131), N-(3-(2'-(((1r,3r)-3-hydroxycyclobutyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 132), tert-butyl3-((6'-(2-methyl-5-(5-(trifluoromethyl)nicotinamide)phenyl)-7'-oxo-6',A compound characterized by comprising a group selected from 7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-2'-yl)amino)azetidine-1-carboxylate (compound 133) and 3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (compound 134).

10. The compounds described in claim 1 are ABL1, ABL2 / ARG, ACK1, ARAF, BLK, BMX / ETK, BRAF, BRK, BTK, C-KIT, C-SRC, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 / HER2, ERBB4 / HER4, FAK / PTK2, FER, FES / FPS, FGFR1, FGF R2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIPK4, HPK1 / MAP4K1, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / MAP4K5, LATS2, LCK, LIMK1, LIMK2, LOK / STK10, LRRK2, LYN, LYN B, MEK5, MEKK2, MEKK3, MINK / MINK1, MLCK2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MUSK, NEK4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, SIK2, SIK3, SLK / STK2 It inhibits one or more protein kinases selected from the group consisting of SRMS, STK32B / YANK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TEC, TESK2, TIE2 / TEK, TNIK, TNK1, TRKA, TRKB, TRKC, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, YES / YES1, YSK4 / MAP3K19, and ZAK / MLTK.

11. A pharmaceutical composition for treating or preventing the aforementioned protein kinase-related disease, comprising the compound of claim 1.

12. In claim 11, The protein kinases mentioned above are ABL1, ABL2 / ARG, ACK1, ARAF, BLK, BMX / ETK, BRAF, BRK, BTK, C-KIT, C-SRC, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 / HER2, ERBB4 / HER4, FAK / PTK2, FER, FES / FPS, FGFR1, and FGF. R2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIPK4, HPK1 / MAP4K1, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / MAP4K5, LATS2, LCK, LIMK1, LIMK2, LOK / STK10, LRRK2, LYN, LYN B, MEK5, MEKK2, MEKK3, MINK / MINK1, MLCK2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MUSK, NEK4, P38A / MA PK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, SIK2, SIK3, SLK / STK2, SR A pharmaceutical composition characterized by one or more protein kinases selected from the group consisting of MS, STK32B / YANK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TEC, TESK2, TIE2 / TEK, TNIK, TNK1, TRKA, TRKB, TRKC, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, YES / YES1, YSK4 / MAP3K19, and ZAK / MLTK.

13. The pharmaceutical composition according to claim 11, characterized in that the protein kinase-related disease is a cancerous disease.

14. A pharmaceutical composition according to claim 13, characterized in that the cancerous disease belongs to the group selected from prostate cancer, endometrial cancer, bladder cancer, gastric cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, urethral cancer, leukemia, multiple myeloma, hematological cancer, lymphoma, and fibroadenoma.

15. A pharmaceutical composition according to claim 13, characterized in that the pharmaceutical composition is administered as a combination therapy with one or more anticancer agents selected from the group consisting of cytotoxic anticancer agents, targeted anticancer agents, immunoanticancer agents, and metabolic anticancer agents.

16. The pharmaceutical composition according to claim 11, characterized in that the compound has a solubility of 60% or more when treated with a protein kinase at a single concentration of 1 μM.

17. A protein kinase-related health functional food for improving or preventing disease, containing the compound described in claim 1.

18. Claim 17, wherein the functional food contains protein kinases ABL1, ABL2 / ARG, ACK1, ARAF, BLK, BMX / ETK, BRAF, BRK, BTK, C-KIT, C-SRC, CSK, DDR1, DDR2, EGFR, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 / HER2, ERBB4 / HER4, FAK / PTK2, FER, FES / FP S, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, H IPK4, HPK1 / MAP4K1, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / MAP4K5, LATS2, LCK, LIMK1, LIMK2, LOK / STK10, LRRK2, LYN, LYN B, MEK5, MEKK2, MEKK3, MINK / MINK1, MLCK2 / MYLK2, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MUSK, NEK4, P38A / M APK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, SIK2, SIK3, SLK / STK2, It is one or more protein kinases selected from the group consisting of SRMS, STK32B / YANK2, SYK, TAK1, TAOK1, TAOK2 / TAO1, TAOK3 / JIK, TEC, TESK2, TIE2 / TEK, TNIK, TNK1, TRKA, TRKB, TRKC, TXK, TYK1 / LTK, TYK2, TYRO3 / SKY, YES / YES1, YSK4 / MAP3K19, and ZAK / MLTK.

19. A health functional food according to claim 17, wherein the protein kinase-related disease is...

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