Novel compound for inhibiting protein kinase and pharmaceutical composition comprising same

Abstract

The present invention relates to novel compounds for inhibiting protein kinases and pharmaceutical compositions comprising the same. More particularly, the compound according to the present invention can effectively inhibit various protein kinases, and thus can be effectively used for developing a therapeutic agent for protein kinase-related diseases, particularly cancer.

Description

Technical Field

[0001] This invention relates to novel compounds for protein kinase inhibition and pharmaceutical compositions comprising the compounds. More specifically, this invention relates to novel spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl compounds having protein kinase inhibitory activity, pharmaceutically acceptable salts thereof, hydrates thereof or stereoisomers thereof, methods for preparing said compounds, and pharmaceutical compositions comprising said compounds for the prevention, improvement or treatment of cancer. Background Technology

[0002] Cells contain various cell signaling systems that regulate cell proliferation, growth, metastasis, and apoptosis, and each component is intricately interconnected. When the regulatory functions within a cell are disrupted due to genetic or environmental factors, abnormal cell proliferation or disruption of cell signaling pathways can lead to the transformation of normal cells into malignant cells.

[0003] Protein tyrosine kinases (PTKs) play a crucial role in cellular signaling associated with cell growth, differentiation, and proliferation. Abnormal mutations or overexpression of specific protein tyrosine kinases disrupt normal intracellular signaling systems, leading to various diseases such as cancer, inflammation, metabolic disorders, and neurological disorders. PTKs catalyze the phosphorylation of tyrosine residues on substrate proteins, thereby mediating the transduction of extracellular growth factor signals into intracellular responses. Under normal circumstances, the interaction between growth factors and their receptors regulates cell proliferation, while mutations or overexpression of receptor proteins can lead to abnormal signal transduction, resulting in tumorigenesis.

[0004] Therefore, there remains an unmet medical need to develop more selective and effective protein tyrosine kinase inhibitors that demonstrate enhanced anticancer efficacy compared to existing kinase inhibitors. Summary of the Invention

[0005] Technical issues

[0006] The purpose of this invention is to provide compounds that have inhibitory activity against protein kinases.

[0007] Another object of the present invention is to provide pharmaceutical compositions comprising novel compounds that inhibit protein kinases for the prevention or treatment of protein kinase-mediated diseases.

[0008] Another object of the present invention is to provide health functional foods containing novel compounds for improving or preventing protein kinase-mediated diseases.

[0009] Technical means

[0010] This invention provides a compound selected from the group consisting of compounds represented by Formula 1, their stereoisomers, their pharmaceutically acceptable salts, their prodrugs, or their solvates:

[0011] [Formula 1]

[0012]

[0013] in:

[0014] R 1 and R 2 They can be the same or different, and are independently selected from hydrogen or (C1-C4) alkyl, or they can be linked together to form 3- to 5-membered rings;

[0015] 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 heterocycles, wherein the substituent is selected from one or more members of the group consisting of: (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C2)alkoxy, halogen, hydroxyl, Imidazolyl, (C1-C2)alkylimidazolyl, (C1-C2)alkoxyphenyl, morpholinyl, cyano, oxo (=O), (C1-C2)alkoxy(C1-C2)alkyl(C1-C2)alkylamino, piperazine, (C1-C2)alkylpiperazine, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino,

[0016] A is selected from morpholino or -NH-Y, wherein Y is hydrogen, or a substituted or unsubstituted group, wherein the substituted or unsubstituted group is selected from phenyl, benzyl, (C1-C4)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, pyridinyl, pyrazolyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or azircyclic butyl, wherein the substituent is selected from one or more members of the group consisting of: (C1-C2)alkyl, (C1-C4)alkoxy, piperazine, (C1-C2)alkylpiperazine, acetylpiperazine, morpholino, morpholino-4-carbonyl, (C1-C2)alkylpiperazine-1-carbonyl, oxocyclic Butyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl, imidazolyl, pyrrolyl, di(C1-C2)alkylaminopyrrolyl, piperidinyl, acetylpiperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazin-1-yl)piperidinyl, halogen, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino, pyridinyl, furanyl, hydroxyl, and tert-butoxycarbonyl (BOC); Z is CH or N; L is CH2 or NH; n1 or n2 can be an integer from 0 to 1.

[0017] This invention provides pharmaceutical compositions comprising novel compounds that inhibit protein kinases for the prevention or treatment of protein kinase-mediated diseases.

[0018] Furthermore, the present invention provides health functional foods containing novel compounds for improving or preventing protein kinase-mediated diseases.

[0019] Beneficial effects

[0020] The compounds according to the present invention effectively inhibit the activity of the following protein tyrosine kinases and various other 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, NE K4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, S IK2, SIK3, SLK / 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, ZAK / MLTK. Therefore, these compounds can be used to prevent, treat, or improve cancers or cancer-related diseases associated with abnormal cell growth.

[0021] The compounds, or pharmaceutically acceptable salts thereof, or hydrates thereof, according to the present invention, and pharmaceutical compositions comprising them as active ingredients for the prevention or treatment of cancer or cancer-related diseases, exhibit low cytotoxicity and high selectivity in terms of inhibitory activity and antiproliferative effects against cancer cells. Therefore, the compounds and compositions can be effectively used for the prevention or treatment of various cancers, such as gastric cancer, lung cancer, liver cancer, colorectal cancer, small bowel 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, hematologic malignancies (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphomas (including Hodgkin lymphoma, non-Hodgkin lymphoma), psoriasis, or fibromas. Detailed Implementation

[0022] The invention will be described in more detail below.

[0023] The inventors conducted in-depth research to develop more effective protein kinase inhibitors, and thus synthesized novel compounds based on the spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl group. The inventors demonstrated that these compounds effectively inhibited various protein kinases, thus completing this invention.

[0024] Therefore, the present invention provides compounds selected from the group consisting of compounds represented by Formula 1, their stereoisomers, their pharmaceutically acceptable salts, their prodrugs, or their solvates:

[0025] [Formula 1]

[0026]

[0027] in:

[0028] R 1 and R 2 They can be the same or different, and are independently selected from hydrogen or (C1-C4) alkyl, or they can be linked together to form 3- to 5-membered rings;

[0029] 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 heterocycles, wherein the substituent is selected from one or more members of the group consisting of: (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C2)alkoxy, halogen, hydroxyl, imidazolyl, (C1-C2)alkylimidazolyl, (C1-C2)alkoxyphenyl, morpholinyl, cyano. The heterocycle is selected from the group consisting of 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, wherein the 5- or 6-membered monocyclic or bicyclic heterocycle is selected from the group consisting of thiophene, furan, pyrazole, oxazole, thiazole, pyridine, pyran, tetrahydropyran, oxazine, thiazine, pyrimidine, piperazine and benzothiazole.

[0030] A is selected from morpholino or -NH-Y, wherein Y is selected from hydrogen, or a substituted or unsubstituted group, wherein the substituted or unsubstituted group is selected from phenyl, benzyl, (C1-C4)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, pyridinyl, pyrazolyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or azircyclic butyl, wherein the substituent is selected from one or more members of the group consisting of: (C1-C2)alkyl, (C1-C4)alkoxy, piperazine, (C1-C2)alkylpiperazine, acetylpiperazine, morpholino, morpholino-4-carbonyl, (C1-C2)alkylpiperazine-1-carbonyl, oxygen Heterocyclic butyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl, imidazolyl, pyrrolyl, di(C1-C2)alkylaminopyrrolyl, piperidinyl, acetylpiperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazin-1-yl)piperidinyl, halogen, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino, pyridinyl, furanyl, hydroxyl, and tert-butoxycarbonyl (BOC); Z is CH or N; L is CH2 or NH; and n1 or n2 is an integer from 0 to 1.

[0031] Preferably, the compound can be represented by Formula 1-1.

[0032] [Equation 1-1]

[0033]

[0034] in:

[0035] 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 heterocycles, wherein the substituent is selected from one or more members of the group consisting of: (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C2)alkoxy, halogen, hydroxyl, imidazolyl, (C1-C2)alkylimidazolyl, (C1-C2)alkoxyphenyl, morpholinyl, cyano The heterocyclic compounds are selected from the group consisting of thiophene, furan, pyrazole, oxazole, thiazole, pyridine, pyran, tetrahydropyran, oxazine, thiazine, pyridine, piperazine, benzothiazole, and di(C1-C2)alkylamino, wherein the 5- or 6-membered monocyclic or bicyclic heterocycle is selected from the group consisting of thiophene, furan, pyrazole, oxazole, thiazole, pyridine, pyran, tetrahydropyran, oxazine, thiazine, pyridine, piperazine, and benzothiazole.

[0036] A is selected from morpholino or -NH-Y, wherein Y is selected from hydrogen, or a substituted or unsubstituted group, wherein the substituted or unsubstituted group is selected from phenyl, benzyl, (C1-C4)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, pyridinyl, pyrazolyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or azircyclic butyl, wherein the substituent is selected from one or more members of the group consisting of: (C1-C2)alkyl, (C1-C4)alkoxy, piperazine, (C1-C2)alkylpiperazine, acetylpiperazine, morpholino, morpholino-4-carbonyl, (C1-C2)alkylpiperazine-1-carbonyl, Oxycyclic butyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl, imidazolyl, pyrrolyl, di(C1-C2)alkylaminopyrrolyl, piperidinyl, acetylpiperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazin-1-yl)piperidinyl, halogen, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino, pyridinyl, furanyl, hydroxyl, and tert-butoxycarbonyl (BOC); Z is CH or N; L is CH2 or NH; and n is an integer from 0 to 1.

[0037] More preferably, the compound may be represented by formula 1-2, 1-3, 1-4, 1-5 or 1-6:

[0038] [Equation 1-2]

[0039]

[0040] in:

[0041] R 3 To R 5 They may be the same or different from each other, and are selected from hydrogen, (C1-C2)alkyl, (C1-C2)alkoxy, trifluoromethyl, halogen, hydroxyl, (C1-C2)alkylimidazolyl, (C1-C2)alkoxyphenyl, morpholinyl, (C1-C2)alkoxy(C1-C2)alkyl(C1-C2)alkylamino, piperazine, (C1-C2)alkylpiperazine, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino;

[0042] A 1 Selected from morpholino or -NH-Y 1 , where Y 1 Selected from hydrogen, (C3-C4)cycloalkyl, benzyl, 1H-pyrazolyl, di(C1-C2)alkyl-1H-pyrazolyl, (oxacyclobut-3-yl)-1H-pyrazolyl, trifluoro(C1-C2)alkyl-1H-pyrazolyl, pyridyl(C1-C2)alkyl, hydroxy(C1-C2)alkyl, hydroxy(C2-C4)alkenyl, hydroxy(C3-C6)cycloalkyl, morpholinyl(C3-C4)alkyl, furanyl(C1-C2)alkyl, tert-butoxycarbonyl (BOC)-substituted azacyclobutyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or substituted or unsubstituted phenyl or pyridyl, wherein the substituent is selected from the group consisting of the following One or more members of: (C1-C2)alkyl, (C1-C2)alkoxy, halogen, trifluoro(C1-C2)alkoxy, piperazine, (C1-C2)alkylpiperazine, acetylpiperazine, morpholino, morpholino-4-carbonyl, (C1-C2)alkylpiperazine-1-carbonyl, ((C1-C2)alkylpiperazine-1-yl)(C1-C2)alkyl, imidazolyl, di(C1-C2)alkylaminopyrrolidinyl, piperidinyl, acetylpiperazine, di(C1-C2)alkylaminopiperazine, ((C1-C2)alkylpiperazine-1-yl)piperazine, and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino.

[0043] [Equation 1-3]

[0044]

[0045] in:

[0046] X 1The group is 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 pyridinyl, which is substituted by a substituent selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, trifluoromethyl, halogen and hydroxyl;

[0047] A 2 Selected from morpholino or -NH-Y 2 , where Y 2 Selected from one or more members of the group consisting of: hydrogen, benzyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, (C1-C2)alkylpyridyl, pyridyl(C1-C2)alkyl, hydroxy(C1-C2)alkyl, hydroxy(C2-C4)alkenyl, hydroxy(C3-C6)cycloalkyl, morpholinyl(C3-C4)alkyl, furanyl(C1-C2)alkyl, ((C1-C2)alkylpiperazin-1-yl)piperidinyl-trifluoro(C1-C2)alkoxypyridyl and tert-butoxycarbonyl (BOC) substituted nitrogen-containing heterocyclic butyl groups.

[0048] [Equations 1-4]

[0049]

[0050] in:

[0051] X 2 Selected from (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C2)alkyl, benzyl, or substituted or unsubstituted phenyl, wherein the substituent is selected from one or more members of the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, halogen, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy and cyano, A 3 Selected from morpholino or -NH-Y 3 And Y 3 It may be selected from one or more of hydrogen or (C1-C2) alkylpyridinyl groups.

[0052] [Equations 1-5]

[0053]

[0054] in:

[0055] X 3 Selected from substituted or unsubstituted phenyl groups, wherein the substituents are selected from one or more members of the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy and halogen;

[0056] A 4Selected from morpholino or -NH-Y 4 , where Y 4 It is selected from one or more members of the group consisting of hydrogen, benzyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, morpholinyl (C3-C4)alkyl, furanyl (C1-C2)alkyl or pyridyl (C1-C2)alkyl.

[0057] [Equations 1-6]

[0058]

[0059] in:

[0060] X 4 Selected from substituted or unsubstituted phenyl groups, wherein the substituents are selected from one or more of the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, halogen, and trifluoromethyl.

[0061] A 5 Selected from morpholino or -NH-Y 5 , where Y 5 It can be hydrogen, or one or more selected from (C1-C2) alkylpyridinyl groups.

[0062] In one example, the compound may be selected from the group consisting of: N-(3-(2'-((1,3-dimethyl-1H-pyrazol-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 2), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-1, 8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-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]pyrimidinyl]-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]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-4-chloro-3-(trifluoromethyl)benzamide -5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazol-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-imidazol-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)-3,4-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)-3,4-difluorobenzamide3-d]pyrimidinyl]-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]pyrimidinyl]-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]pyrimidinyl]-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-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-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-methoxybenzamide 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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-6-(trifluoromethyl)pyridineamide (compound 21), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-6-(trifluoromethyl)pyridineamide (compound 21), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-4,3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 24), N-(3-(2'-amino-7'-)-yl)-(4,3-d]pyrimidin]-6'(7'H)-yl ...4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 24), N-(3-(2'-amino-7'-)-(4,3-d]pyrimidin]-6'(7'H)-yl)-5-(trifluoromethyl)nicotinamide (compound 25), N-(3-(2'-amino-7'-)-(4,3-d]pyrimidin]-6'(7'H)-yl)-5-(trifluoromethyl)nicotinamide (compound 25), N-(3-(2'-amino-7'-)-(4,3-d]pyrimidin]-6'(7'H)-yl)-5-(trifluoromethyl)nico -Oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-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-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-morpholino-5-(trifluoromethyl)benzamide '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[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'-(cyclopropylamino) ...2-methoxyethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 31), N-(3-(2'-(cyclopropylamino)-7'-oxo-5'H-spiro[cyclopropane-[3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide (compound 32), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide (compound 33), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-3-(piperazin-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-(piperazin-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-(3 -(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 37), N-(4-methyl-3-(2'-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 38), N-(3-(2'-((4-(4-acetylpiperazin-1-yl)phenyl) N-(4-methyl-3-(2'-((4-morpholinylphenyl)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-morpholinylphenyl)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) ...3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 41), N-(3-(2'-((4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 42), N-(4-methyl-3-(2'-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl) (S)-N-(3-(2'-((4-(1H-imidazol-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), (S)-N-(3-)-(7'-oxo-2'-((4-(piperazin-1-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (Compound 45), (S)-N-(3-) (2'-((4-(3-(dimethylamino)pyrrolidone-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 46), N-(4-methyl-3-(7'-oxo-2'-((4-(piperidin-4-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 47), N-(4-methyl-3-(2'-((3-(4-methylpiperazin-1-yl)phenyl) N-(3-(2'-((4-(1-acetylpiperidin-4-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-acetylpiperidin-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-methylpyridin-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 49), N-(4-methyl-3-(2'-((6-methylpyridin-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[3-d]pyrimidin]-6'(7'H)-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound 50), N-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 51), N-(4-methyl-3-(2'-((1-(oxacyclobut-3-yl)-1H-pyrazol-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide 'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 52), N-(3-(2'-((2-methoxy-4-morpholinylphenyl)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-methylpiperazin-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 55), N-(3-(2'-((3-methoxy-4-morpholinylphenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 56), N-(3-(2'-((4-(4-ethylpiperazin-1-yl)-3-fluorobenzamide) N-(3-(2'-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-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 57), N-(4-methyl-3-(7'-oxo-2'-(phenylamino)-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)-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)-4-methylphenyl)-3-(trifluoromethyl)benzamide3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 59), N-(3-(2'-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoro) (Methyl)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-methylpiperazin-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-pyrazol-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-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide (compound 65), N-(3-(2'-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino) N-(3-(2'-((3-methoxy-4-(piperazin-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 66), N-(3-(2'-((3-methoxy-4-(piperazin-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-pyrazol-5-yl ...3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 68), N-(3-(2'-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 69), N-(3-(2'-((2-hydroxyamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methyl phenyl)-3-(trifluoromethyl)benzamide (compound 70), 1-(4-fluorophenyl)-3-(4-methyl-3-(2'-((6-methylpyridin-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-methylpyridin-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-Methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)thiophene-2-carboxamide (compound 73), N-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-oxocyclobutane-1-carboxamide (compound 76), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)cyclohexyl-1-en-1-carboxamide (compound 7 ...3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)benzo[d]thiazol-2-carboxamide (compound 80), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)benzo[d]thiazol-2-carboxamide (compound 80), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)benzo[d]thiazol-2-carboxamide ,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-4,4,4-trifluorobutamide (compound 81), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)thiazolyl-5-carboxamide (compound 82), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-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]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)cyclopentanecarboxamide ,8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 85), N-(4-methyl-3-(2'-morpholinyl-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 86), N-(4-methyl-3- (7'-oxo-2'-((tetrahydro-2H-pyridano-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyridano[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 87), N-(4-methyl-3-(7'-oxo-2'-((pyridano-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyridano[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 88), N-(4-methyl-3-(2'-((3-morpholinylpropyl)amino)-7'-oxo ...3-d]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 90), N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 93), N-(4-methyl-3-(7'-oxo-2'-((pyridin-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (Methyl)nicotinamide (compound 94), N-(4-methyl-3-(2'-((3-morpholinylpropyl)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 96), 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 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'-morpholinyl-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[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'-((pyridin-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-morpholinylpropyl)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]thiazolyl-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)-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 'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 104), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-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]thiazolyl-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 107), N-(4-methyl-3-(2'-((6-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 107), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 108), N-(3-(2'-(benzo[d]thiazolyl-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-6'(7'H)- 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-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]-6'(7'H)-yl)-4-methylphenyl)-3-cyclo Propylurea (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) 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 ...3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-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]pyrimidin]-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-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl)urea 1-(4-methyl-3-(2'-((6-methylpyridin-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-methylpyridin-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)amino) (S)-N-(3-(2'-((1-hydroxypropyl-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 126), (S)-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 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 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)benzamide3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 128), 3-((6'-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-7'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-2'-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester (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-hydroxypropyl-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), 3-((6'-(2-methyl-5-(5-(trifluoromethyl)nicotinamide)benzene) Compound 133 contains tert-butyl ester of 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).

[0063] The compounds according to the invention exhibit inhibitory activity against the following: 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 , FGFR2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIPK 4. 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 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, wherein the compounds are capable of inhibiting one or more protein kinases selected from the group consisting of the above.

[0064] [definition]

[0065] In this specification, the term "stereoisomer" refers to two compounds having the same molecular formula but different atomic spatial arrangements. Stereoisomers can be enantiomers that are mirror images of each other, or diastereomers that are not mirror images of each other (e.g., cis / trans isomers and conformational isomers). These can include R and S configurations for each asymmetry center, Z and E double bond isomers, and Z and E conformational isomers. Compositions containing not only single stereochemical isomers, but also enantiomers, diastereomers, and geometric (or conformational) mixtures of the compound are also within the scope of this invention.

[0066] In this specification, the term "pharmaceutically acceptable salt" refers to 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 amine, ammonium, triethylammonium, and pyridine salts.

[0067] Furthermore, acid addition salts formed from free acids can be prepared as pharmaceutically acceptable acid salts. Free acids can include inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid, etc. 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, methylene dihydroxynaphthyl acid, glutamic acid, citric acid, aspartic acid, etc. Preferably, hydrochloric acid is used as the inorganic acid, while methanesulfonic acid is used as the organic acid.

[0068] Furthermore, the compositions according to the invention may further comprise pharmaceutically acceptable salts, as well as all salts, hydrates or solvates that can be prepared by conventional methods.

[0069] The addition salts according to the invention can be prepared by conventional methods, for example, by dissolving the compound in a water-miscible organic solvent (e.g., acetone, methanol, ethanol, or acetonitrile) and then by adding an excess organic base or by adding an aqueous solution of an inorganic base, followed by precipitation or crystallization. Alternatively, the addition salts can be obtained by evaporating the solvent or excess base from the reaction mixture and then by drying or by filtering the precipitated salt.

[0070] As used herein, the term "prodrug" refers to a compound that, when administered to a subject or patient, can (directly or indirectly) provide the compounds of the present invention. Examples of prodrugs include esterified or hydroxylated compounds, wherein the ester or hydroxyl group is cleaved in vivo (e.g., in the intestine) to produce a compound according to Formula 1.

[0071] In this specification, the term "solvent" refers to an adduct formed by inert solvent molecules and a compound through intermolecular forces. When a compound is treated with water, the solvation product is called a hydrate; for example, the solvation product may be a monohydrate, a dihydrate, or an alkoxide.

[0072] Furthermore, the present invention provides pharmaceutical compositions for treating or preventing protein kinase-related diseases, comprising compounds of the present invention.

[0073] 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.

[0074] Protein kinases can be selected from one or more of the following groups: 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, FG FR1, FGFR2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIP K4, 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, NE K4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, S IK2, SIK3, SLK / 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.

[0075] Preferably, when tested at a single concentration of 1 μM, the compound exhibits an inhibition rate of 60% or higher against protein kinases.

[0076] Protein kinase-related diseases can be cancers, and can be selected from, but are not limited to, the group consisting of prostate cancer, endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small bowel 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, blood cancer, lymphoma, and fibroma.

[0077] 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, immunotumor agents, and metabolic anticancer agents.

[0078] According to conventional methods, pharmaceutical compositions may be provided in one or more dosage forms selected from, but not limited to, the group consisting of gels, emulsions, injections, powders, granules, aerosols, pastes, transdermal absorption preparations and patches.

[0079] In another embodiment of the invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, flow aids, flavoring agents, antioxidants, buffers, antibacterial agents, diluents, dispersants, surfactants, binders, and lubricants commonly used in the manufacture of pharmaceutical compositions.

[0080] Specifically, the carrier, excipients, and diluents may include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate / ester, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, and mineral oil. Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid dosage forms can be prepared by mixing the composition with at least one excipient (e.g., starch, calcium carbonate, sucrose or lactose, gelatin, etc.). In addition to simple excipients, lubricants (e.g., magnesium stearate and talc) may also be used. Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc., and may include various excipients (e.g., wetting agents, sweeteners, flavoring agents, preservatives, etc.) in addition to commonly used simple diluents (e.g., 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 (e.g., olive oil), injectable esters (e.g., ethyl oleate), etc. Suppository bases may include Witepsol, macrogol, Tween 61, cocoa butter, lauryl fat, glycerin gelatin, etc.

[0081] The pharmaceutical composition can be administered to the subject via conventional routes such as intravenous, intra-arterial, intraperitoneal, intramuscular, intrasternal, percutaneous, intranasal, inhalation, local, rectal, oral, intraocular, or intradermal.

[0082] The preferred dosage of the compound can vary depending on the subject's condition and weight, the type and severity of the disease, the form of the drug, the route of administration, and the duration of administration, and can be appropriately selected by those skilled in the art. According to one embodiment of the invention, the daily dose can be, but is not limited to, 0.01 mg / kg to 200 mg / kg, specifically 0.1 mg / kg to 200 mg / kg, and more specifically 0.1 mg / kg to 100 mg / kg. It can be administered once daily or divided into multiple doses, and the scope of the invention is not limited thereto.

[0083] In this invention, the “subject” can be a mammal, including humans, but is not limited to these examples.

[0084] Furthermore, the present invention provides a health functional food for improving or preventing protein kinase-related diseases, which contains the compounds of the present invention.

[0085] Protein kinases can be selected from one or more of the following groups: 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, FG FR1, FGFR2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIP K4, 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, NE K4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, S IK2, SIK3, SLK / 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, ZAK / MLTK.

[0086] Protein kinase-related diseases can be cancers, and the cancers can be selected from, but are not limited to, the group consisting of, but not limited to, prostate cancer, endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small bowel 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, blood cancer, lymphoma, and fibroma.

[0087] In this specification, the term "health functional food" as used herein refers to food manufactured and processed using raw materials or ingredients that have beneficial functions for the human body in accordance with the Health Functional Food Act, and the term "functional" refers to the intake of nutrients intended to regulate the structure and function of the human body or to obtain effects beneficial to health (e.g., physiological effects).

[0088] Health functional foods may contain conventional food additives. Unless otherwise specified, their suitability as "food additives" is determined according to the specifications and standards of the relevant items in the general rules and general test methods of the Food Additive Codex approved by the Ministry of Food and Drug Safety.

[0089] The items listed in the Codex Alimentarius include, for example, chemically synthesized compounds (e.g., ketones, glycine, potassium citrate, niacin, and cinnamic acid); natural additives (e.g., persimmon pigments, licorice extract, crystalline cellulose, sorghum pigments, and guar gum); and mixed preparations (e.g., monosodium glutamate preparations, alkali preparations for noodles, preservative preparations, and tar coloring preparations).

[0090] The effective dose of active ingredients in health functional foods can be used according to the effective dose of therapeutic agents; however, in cases of long-term intake for health and hygiene purposes or for health regulatory purposes, it can be below the above range, and it is certain that active ingredients can be used in amounts above the above range without safety concerns.

[0091] There are no particular restrictions on the types of health functional foods. Examples include meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, ramen, other noodles, chewing gum, dairy products (including ice cream), various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes.

[0092] Example

[0093] The invention will be described in more detail below by way of embodiments. These embodiments are provided only to illustrate the invention more specifically, and those skilled in the art will understand that the scope of the invention is not limited thereto without departing from its spirit and scope.

[0094] <Example 1> Synthetic route A of compound 51

[0095] As shown in Scheme 1, compound 51 was synthesized according to synthetic route A, and other compounds were synthesized similarly using the same method. The synthetic method is described in detail with reference to compound 51.

[0096] [Option 1]

[0097]

[0098] 1-1) Step 1

[0099] 5-(hydroxymethyl)pyrimidin-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 was bubbled into the mixture for 5 minutes. The reaction vessel was cooled in an ice-water bath (0 °C), and N,N-diisopropylethylamine (29.4 mL, 168.88 mmol) was added dropwise. The reaction mixture was then refluxed at 120 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and quenched dropwise with water. The resulting mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The 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 give 9.3 g of the target compound as a white solid, in 84% yield.

[0100]

[0101] 1-2) Step 2

[0102] The 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). Sodium iodide (27.4 g, 183.0 mmol) and potassium carbonate (38.9 g, 281.6 mmol) were then added, and the mixture was heated under reflux at 50 °C for 3 days. After the reaction was complete, the mixture was cooled to room temperature, filtered through a diatomaceous earth (Celite) mat, and concentrated under reduced pressure using a rotary evaporator. The residue was diluted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (ethyl acetate:hexane = 1:20 (v / v)) and the solvent was removed under reduced pressure to give 34.8 g of the target compound as a yellow solid, in a yield of 78%.

[0103]

[0104]

[0105] 1-3) Step 3

[0106] The N-((2,4-dichloropyrimidin-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 was bubbled into the mixture for 5 minutes to remove dissolved gases. The reaction vessel was then cooled in an ice-water bath (0 °C), and 60% sodium hydride (5.7 g, 144.4 mmol) was added in portions, followed by stirring at room temperature for 30 minutes. The reaction vessel was then cooled in an ice-water bath (0 °C), and ethylmalonyl 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 mixture was cooled to 0 °C and quenched with a saturated ammonium chloride solution. The remaining organic solvent was removed under reduced pressure using a rotary evaporator, the residue was diluted with water, and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (ethyl acetate: dichloromethane = 20:1 (v / v)) and the solvent was removed under reduced pressure to give 43.1 g of the target compound as a white solid, with a yield of 90%.

[0107]

[0108] Step 4 (1-4)

[0109] The 3-(((2,4-dichloropyrimidin-5-yl)methyl)(2-methyl-5-nitrophenyl)amino)-3-oxopropionate (39.2 g, 91.75 mmol) obtained in step 3 above was dissolved in dimethyl sulfoxide (500 mL), and nitrogen was bubbled into the mixture for 5 minutes. The reaction vessel was cooled in an ice-water bath (0 °C), and cesium carbonate (44.8 g, 137.6 mmol) was added in portions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was added dropwise to a 1N hydrochloric acid aqueous solution (500 mL) at 0 °C, and stirred slowly for 15 minutes. The yellow solid was filtered through a diatomaceous earth pad and washed with water to remove residual organic solvent. The obtained solid was dried to give 35.1 g of the target compound as a yellow solid, with a yield of 97%.

[0110]

[0111] Step 5 (1-5)

[0112] Ethyl 2-chloro-6-(2-methyl-5-nitrophenyl)-7-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-8-carboxylic acid (35.1 g, 89.8 mmol) obtained in step 4 above was dissolved in 1,4-dioxane (250 mL). Aqueous solution of 4N hydrochloric acid (222.5 mL, 890.1 mmol) in 1,4-dioxane was added, and the mixture was stirred under reflux at 100 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with dichloromethane. The insoluble solids were filtered off using a diatomaceous earth mat, and the combined filtrates were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (ethyl acetate:dichloromethane = 3:7 (v / v)), and the solvent was concentrated under reduced pressure to give 16.7 g of the target compound as a yellow solid, in a yield of 58%.

[0113]

[0114] Step 6 (1-6)

[0115] The 2-chloro-6-(2-methyl-5-nitrophenyl)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one (10.0 g, 31.3 mmol) obtained in step 5 above was dissolved in anhydrous dimethylformamide (150 mL), and nitrogen was bubbled into the mixture for 5 minutes. The reaction vessel was cooled in an ice-water bath (0 °C), and 1-bromo-2-chloroethane (4.6 mL, 37.6 mmol) was added, followed by fractional 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 1N hydrochloric acid aqueous solution (150 mL) at 0 °C, and stirred slowly for 15 minutes. The resulting yellow solid was filtered and washed with water to remove residual organic solvent. The resulting solid was dried to give 9.23 g of the target compound as a yellow solid, with a yield of 85%.

[0116]

[0117] Step 7 (1-7)

[0118] The 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 above was dissolved in tetrahydrofuran (10.0 mL), and methanol (5.0 mL) and water (3.0 mL) were added dropwise. At room temperature, iron (0.81 g, 14.50 mmol) and ammonium chloride (0.77 g, 14.50 mmol) were added, and the mixture was refluxed and stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The filtrate was neutralized by adding a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 0.87 g of the target compound as a yellow solid, with a yield of 95%.

[0119]

[0120] Step 8 (1-8)

[0121] The 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 above was dissolved in dichloromethane (10.0 mL), followed by the addition of 3-(trifluoromethyl)benzoyl chloride (0.42 mL, 2.77 mmol) and potassium carbonate (0.76 g, 5.55 mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was diluted with dichloromethane and extracted with water. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by MPLC (ethyl acetate:hexane = 3:7 (v / v)) and the solution was concentrated under reduced pressure to give 0.87 g of the target compound as a yellow solid, with a yield of 64%.

[0122]

[0123] Step 9 (1-9)

[0124] The N-(3-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (0.12 g, 0.24 mmol) obtained in step 8 above was dissolved in 2-butanol (10.0 mL), and potassium carbonate (0.17 g, 1.23 mmol), 6-methylpyridin-3-amine (39 mg, 0.36 mmol), and tris(dibenzylideneacetone)dipalladium(O) (46 mg, 0.050 mmol) were added dropwise 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 diatomaceous earth mat, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (0-10% dichloromethane:methanol), and the solution was concentrated under reduced pressure to give 95.0 mg of the target compound (compound 51) as a brown solid, with a yield of 71%.

[0125]

[0126]

[0127] 1-10) Synthesize other compounds via synthetic route A

[0128] In step 9 above, the following compounds were synthesized via synthetic route A by replacing 6-methylpyridin-3-amine with pyrazolamine, aniline, or pyrimidineamine derivatives corresponding to each final synthesized compound:

[0129] Compound 1 [N-(3-(2'-((1,3-dimethyl-1H-pyrazol-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 38 [N-(4-methyl-3-(2'-((4-(4-methylpiperazin-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 39 [N-(3-(2'-((4-(4-acetylpiperazin-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 40 [N-(4-methyl-3-(2'-((4-morpholinylphenyl)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-(4-methyl-3-(2'-((4-(4-(4-methylpiperazin-1-carbonyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide], Compound 42 [N-(3-(2'-((4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide], Compound 43 [N-(4-methyl-3-(2'-((4-(((4-methylpiperazin-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 44 [N-(3-(2'-((4-(1H-imidazol-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 45 [N-(4-methyl-3-(7'-oxo-2'-((4-(piperazin-1-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,[3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide], compound 46 [(S)-N-(3-(2'-((4-(3-(dimethylamino)pyrrolidone-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 47 [N-(4-methyl-3-(7'-oxo-2'-((4-(piperidin-4-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide], compound 48 [N-(4-methyl-3-(2'-((3-(4-methylpiperazin-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 49 [N-(3-(2'-((4-(1-acetylpiperidin-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 51 [N-(4-methyl-3-(2'-((6-methylpyridin-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 52 [N-(4-methyl-3-(2'-((1-(oxacyclobut-3-yl)-1H-pyrazol-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 53 [N-(3-(2'-((2-methoxy-4-morpholinylphenyl)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'-((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 55 [N-(3-(2'-((3-methoxy-4-(4-methylpiperazin-1- ...Compound 56 [N-(3-(2'-((3-methoxy-4-morpholinylphenyl)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'-((4-(4-ethylpiperazin-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 58 [N-(3-(2'-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-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 59 [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 60 [N-(3-(2'-((4-(4-(dimethylamino)piperidin-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 63 [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 64 [N-(4-methyl-3-(7'-oxo-2'-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide], Compound 66 [N-(3-(2'-((4-(4-acetylpiperazin-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 67 [N-(3-(2'-((3-methoxy-4-(piperazin-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 68 [N-(3-(2'-((1,3-dimethyl-1H-pyrazol-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 69 [N-(3-(2'-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-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 71 [1-(4-fluorophenyl)-3-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)urea], Compound 72 [4-Chloro-N-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)benzamide], compound 73 [N-(4-methyl-3-(2'-((6-methylpyridin-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 74 [N-(4-methyl-3-(2'-((6-methylpyridin-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 103 [N-(3-(2'-(benzo[d]thiazolyl-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 104 [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 105 [N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3 ...[3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide], Compound 106 [N-(3-(2'-(benzo[d]thiazolyl-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide], Compound 107 [N-(3-(2'-((2,3-dihydrobenzofuran-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide], Compound 108 [N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide], Compound 109 [N-(3-(2'-(benzo[d]thiazolyl-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-2-(3,5-difluorophenyl)acetamide], Compound 110 [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] and compound 111 [2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide].

[0130] <Example 2> Synthetic route B of compound 8

[0131] As shown in Scheme 2 below, compound 8 was synthesized via synthetic route B, and other compounds were also synthesized via synthetic route B using the same method. The synthetic method is described in detail based on compound 8.

[0132] [Option 2]

[0133]

[0134] 2-1) Step 1

[0135] The 2-chloro-6-(2-methyl-5-nitrophenyl)-5,8-dihydropyrido[4,3-d]pyrimidin-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 refluxed and stirred 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 combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (dichloromethane:ethyl acetate = 7:3 (v / v)) and concentrated to give 97 mg of the target compound in 46% yield.

[0136]

[0137] 2-2) Step 2

[0138] The 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 refluxed and stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The filtrate was neutralized by adding a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 73 mg of the target compound as a yellow solid, with a yield of 99%.

[0139]

[0140] 2-3) Step 3

[0141] The 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 above was dissolved in dichloromethane (2.0 mL), and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (60 mg, 0.224 mmol), azobenzotriazole tetramethylurea hexafluorophosphate (111 mg, 0.298 mmol), and N,N-diisopropylethylamine (77.8 μL, 0.447 mmol) were added. The mixture was then 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 combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by HPLC (5:95 → 95:5 (v / v), 40 min) and concentrated to give 21 mg of the target compound (compound 8) in 23% yield.

[0142]

[0143]

[0144] 2-4) Synthesizing other compounds via synthetic route B

[0145] In step 3 above, benzoic acid or pyridine carboxylic acid derivatives corresponding to each final synthesized compound were used instead of 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid to synthesize the following compounds via synthetic route B:

[0146] 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-(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-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide], 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)-3,4-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)-3,5-difluorobenzamide], Compound 12 [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 13 [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 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-fluoro-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-morpholino-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-((2-methoxyethyl)(methyl)amino)-5-(trifluoromethyl)benzamide], compound 32 ...[3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazin-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-(piperazin-1-yl)-5-(trifluoromethyl)benzamide], compound 36 [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 50 [N-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide], Compound 62 [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-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide], Compound 70 [N-(3-(2'-((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 85 [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 86 [N-(4-methyl-3-(2'-morpholinyl-7'-oxo-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'-((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 88 [N-(4-methyl-3-(7'-oxo-2'-((pyridin-3-ylmethyl ...]-3-(trifluoromethyl)benzamide], compound 88[3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide], Compound 89 [N-(4-methyl-3-(2'-((3-morpholinylpropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide], Compound 90 [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], Compound 91 [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 92 [N-(4-methyl-3-(2'-morpholinyl-7'-oxo-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'-((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 94 [N-(4-methyl-3-(7'-oxo-2'-((pyrido-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide], Compound 95 [N-(4-methyl-3-(2'-((3-morpholinylpropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide], Compound 96 [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 97 [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 98 [2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-morpholinyl-7'-oxo-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'-((tetrahydro-2H-pyran-4-yl)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-(7'-oxo-2'-((pyridin-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide], Compound 101 [2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((3-morpholinylpropyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)acetamide], Compound 102 [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 126 [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 127 [(S)-N-(3-(2'-((1-hydroxypropyl-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 128 [N-(3-(2'-(((1r,3r)-3-hydroxycyclobutyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide], Compound 129 [3-((6'-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-7'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-2'-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester], Compound 130 [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 131 [(S)-N-(3-(2'-((1-hydroxypropyl-2-yl ...]-5-(trifluoromethyl)nicotinamide],[3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide], compound 132 [N-(3-(2'-(((1r,3r)-3-hydroxycyclobutyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide] and compound 133 [3-((6'-(2-methyl-5-(5-(trifluoromethyl)nicotinamido)phenyl)-7'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-2'-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester].

[0147] <Example 3> Synthetic route C of compound 20

[0148] As shown in Scheme 3 below, compound 20 was synthesized via synthetic route C, and other compounds were also synthesized via synthetic route C using the same method. The synthetic method based on compound 20 is described in detail.

[0149] [Option 3]

[0150]

[0151] 3-1) Step 1

[0152] 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. The mixture was then refluxed at 90 °C for 16 hours. After the reaction was complete, the mixture was diluted with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane:ethyl acetate = 7:3 (v / v)) and the solvent was concentrated under reduced pressure to give 45.0 mg of the target compound as a yellow solid, in a yield of 45%.

[0153]

[0154]

[0155] 3-2) Step 2

[0156] The 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 above 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 refluxed and stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The filtrate was neutralized by adding a saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 4.65 g of the target compound as a yellow solid, with a yield of 99%.

[0157]

[0158] 3-3) Step 3

[0159] The 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 above was dissolved in dimethylformamide (1.2 mL), followed by the addition of 3-methoxy-5-(trifluoromethyl)benzoic acid (42.8 mg, 0.14 mmol), O-(7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (73.2 mg, 0.19 mmol), and N,N-diisopropylethylamine (50.0 μL, 0.29 mmol). The mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was diluted with ethyl acetate and extracted with water. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (dichloromethane:ethyl acetate = 6:4 (v / v)) and the solution was concentrated under reduced pressure to give 40 mg of the target compound as a yellow solid, with a yield of 60%.

[0160]

[0161]

[0162] 3-4) Step 4

[0163] The 4'-methoxy-N-(3-(2'-((4-methoxybenzyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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 the mixture was refluxed and stirred at 65 °C for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by HPLC (5:95 → 95:5 (v / v), 40 min) to give 8.5 mg of the target compound (compound 20) in 14% yield.

[0164]

[0165] 3-5) Synthesize other compounds via synthetic route C

[0166] In step 3 above, benzoic acid or pyridine carboxylic acid derivatives corresponding to each final synthesized compound were used instead of 3-methoxybenzyl-5-(trifluoromethyl)benzoic acid to synthesize the following compounds via synthetic route C:

[0167] 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)-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-fluoro-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)-4-chloro-3-(trifluoromethyl)benzamide], Compound 6 [N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide], Compound 7 [N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide], 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)-3,4-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)-2,4-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)-3,5-difluorobenzamide], 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-methoxybenzamide], 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)-3-chloro-2-fluoro-5-(trifluoromethyl)benzamide], compound 18 ...9 [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-[3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-2-fluoro-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)-3-methoxy-5-(trifluoromethyl)benzamide], 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)-4'-methoxy-5-(trifluoromethyl)-[1,1'-biphenyl]-3-carboxamide], 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)-6-(trifluoromethyl)pyridineamide], 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)-2-(trifluoromethyl)isonicotinamide], 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)-3-hydroxy-5-(trifluoromethyl)benzamide], Compound 24 [N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide], Compound 25 [N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-2-chloro-5-(trifluoromethyl)benzamide], Compound 26 [N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-chloro-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-morpholino-5-(trifluoromethyl)benzamide], compound 31 ...[3-d]pyrimidine]-6'(7'H)-yl)-4-methylphenyl)-3-((2-methoxyethyl)(methyl)amino)-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-(4-methylpiperazin-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)-4-methylphenyl)-3-(piperazin-1-yl)-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)-3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(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-methylpiperazin-1-yl)methyl)-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)-4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide], 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)cyclobutaneformamide], 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)-3-oxocyclobutane-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)cyclohex-1-en-1-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)-4-methylthiophene-2-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)isoxazole-5-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)benzo[d]thiazol-2-carboxamide], 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)-4,4,4-trifluorobutamide], 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)thiazolyl-5-carboxamide], 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)cyclopentanecarboxamide] and compound 84 [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].

[0168] <Example 4> Synthetic route D of compound 112

[0169] As shown in Scheme 4 below, compound 112 was synthesized via synthetic route D, and other compounds were also synthesized via synthetic route D using the same method. The synthetic method based on compound 112 is described in detail.

[0170] [Option 4]

[0171]

[0172] 4-1) Step 1

[0173] The 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), followed by the addition of 3-(trifluoromethyl)phenyl isocyanate (19.0 mg, 0.10 mmol), and 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 through a diatomaceous earth pad and washed with acetonitrile. The obtained solid was dried to give 12.6 mg of the target compound as a white solid, in a yield of 25%.

[0174]

[0175] 4-2) Step 2

[0176] 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), and anisole (3.0 μL, 30 μmol) was added. The mixture was refluxed and stirred at 75 °C for 3 hours. After the reaction was complete, the mixture was slowly added dropwise to a saturated sodium bicarbonate aqueous solution at 0 °C and stirred slowly for 15 minutes. The reaction mixture was extracted with dichloromethane:methanol (9:1) solvent, and the collected organic layer was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by HPLC (5:95→95:5 (v / v), 40 min) to give 1.5 mg of the target compound (compound 112) in 14% yield.

[0177]

[0178] 4-3) Synthesize other compounds via synthetic route D

[0179] The following compounds were synthesized via synthetic route D:

[0180] 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-cyclopropylurea], 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-cyclobutylurea], 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-cyclopentylurea], 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-(cyclopropylmethyl)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-(cyclohexylmethyl)urea], 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-benzylurea], 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-(4-(trifluoromethoxy)phenyl)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-cyanophenyl)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-(3,4-difluorophenyl)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-(2-methoxyphenyl)urea], compound 12 ...[3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(3-(trifluoromethyl)phenyl)urea] and compound 125 [1-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(m-tolyl)urea].

[0181] <Example 5> Synthetic route of compound 123 E

[0182] As shown in Scheme 5 below, compound 123 is synthesized via synthetic route E, and the synthetic method is described below.

[0183] [Option 5]

[0184]

[0185] 5-1) Step 1

[0186] The 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), followed by the addition of sodium iodide (6.86 g, 45.76 mmol) and potassium carbonate (9.73 g, 70.40 mmol). The mixture was refluxed and stirred at 50 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, filtered through a diatomaceous earth mat, and concentrated under reduced pressure using a rotary evaporator. The concentrate was diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by MPLC (dichloromethane:ethyl acetate = 7:3 (v / v)) and the solvent was concentrated under reduced pressure to give 3.4 g of the target compound as a yellow solid, in a yield of 31%.

[0187]

[0188] 5-2) Step 2

[0189] The N-((2,4-dichloropyrimidin-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 nitrogen was bubbled into the mixture for 5 minutes to remove dissolved gases from the solution. The reaction vessel was then cooled in an ice-water bath (0 °C), and 60% sodium hydride (0.51 g, 12.70 mmol) was added in portions, followed by stirring at room temperature for 1 hour. The reaction vessel was then cooled in an ice-water bath (0 °C), and ethylmalonyl chloride (2.28 mL, 18.15 mmol) was added dropwise, with the mixture stirred at room temperature for 16 hours. After the reaction was complete, the mixture was cooled in an ice-water bath (0 °C), and the reaction was quenched using a 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 residue was purified by MPLC (ethyl acetate:hexane = 3:7 (v / v)) and the solution was concentrated under reduced pressure to give 3.5 g of the target compound as a white solid, with a yield of 68%.

[0190]

[0191] 5-3) Step 3

[0192] Ethyl 3-(((2,4-dichloropyrimidin-5-yl)methyl)(2-methyl-5-nitropyridin-3-yl)amino)-3-oxopropionate (1.66 g, 3.88 mmol) obtained in step 2 was dissolved in dimethyl sulfoxide (30 mL), and nitrogen was bubbled into the mixture for 5 minutes. The reaction vessel was cooled in an ice-water bath (0 °C), and cesium carbonate (1.51 g, 4.65 mmol) was added in portions, followed by stirring at 30 °C for 2 hours. After the reaction was complete, the mixture was quenched at 0 °C to 200 mL of 1 N hydrochloric acid solution and stirred slowly for 15 minutes. The mixture was extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by MPLC (dichloromethane:ethyl acetate = 7:3 (v / v)) and the solution was concentrated under reduced pressure to give 0.45 g of the target compound as a yellow solid, in a yield of 30%.

[0193]

[0194] 5-4) Step 4

[0195] Ethyl 2-chloro-6-(2-methyl-5-nitropyridin-3-yl)-7-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-8-carboxylic acid (0.34 g, 0.87 mmol) obtained in step 3 above was dissolved in 1,4-dioxane (10 mL). Aqueous solution of 4N hydrochloric acid (0.56 mL, 8.68 mmol) dissolved in 1,4-dioxane was added, and the mixture was refluxed and stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and the residue was removed under reduced pressure. The residue was diluted with dichloromethane. The insoluble solids were filtered through a diatomaceous earth mat, and the collected filtrate was dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (ethyl acetate:dichloromethane = 6:4 (v / v)), and the solvent was concentrated under reduced pressure to give 0.15 g of the target compound as a yellow solid, in a yield of 53%.

[0196]

[0197] 5-5) Step 5

[0198] The 2-chloro-6-(2-methyl-5-nitropyridin-3-yl)-5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one (0.12 g, 0.37 mmol) obtained in step 4 was dissolved in anhydrous dimethylformamide (3.0 mL), and nitrogen was bubbled into the mixture for 5 minutes. Then, (2-bromoethyl)diphenylsulfonium trifluoromethane sulfonate (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 mixture was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (ethyl acetate: dichloromethane = 3:7 (v / v)) and the solvent was concentrated under reduced pressure to give 87.0 mg of the target compound as a yellow solid, with a yield of 67%.

[0199]

[0200] 5-6) Step 6

[0201] The 2'-chloro-6'-(2-methyl-5-nitropyridin-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 above 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 refluxed and stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The filtrate was diluted with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give 62.6 mg of the target compound as a pale yellow solid, with a yield of 91%.

[0202]

[0203] 5-7) Step 7

[0204] The 6'-(5-amino-2-methylpyridin-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), followed by the addition of 3-(trifluoromethyl)benzoyl chloride (0.06 mL, 0.40 mmol) and potassium carbonate (0.06 g, 0.44 mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by MPLC (ethyl acetate:dichloromethane = 4:6 (v / v)) and the solvent was concentrated under reduced pressure to give 62.6 mg of the target compound as a yellow solid, in a yield of 58%.

[0205]

[0206] 5-8) Step 8

[0207] The N-(5-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (0.06 g, 0.12 mmol) obtained in step 7 above 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 mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by MPLC (dichloromethane:methanol = 95:5 (v / v)) and the solvent was concentrated under reduced pressure to give 65.8 mg of the target compound (compound 123) as a yellow solid, with a yield of 91%.

[0208]

[0209] 5-9) Step 9

[0210] The N-(5-(2'-((4-methoxybenzyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (0.65 mg, 0.11 mmol) obtained in step 8 above was dissolved in trifluoroacetic acid solution (3.0 mL), and anisole (23.0 μL, 0.22 mmol) was added. The mixture was refluxed and stirred at 75 °C for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by MPLC (dichloromethane:methanol = 95:5 (v / v)). The solvent was concentrated under reduced pressure to give 32.0 mg of the target compound (compound 123, N-(5-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide as a pale yellow solid, in 62% yield.

[0211]

[0212] <Example 6> Synthetic route of compound 124 F

[0213] Compound 124 was synthesized via synthetic route F, as shown in Scheme 6 below. The synthetic method is described in detail based on compound 124.

[0214] [Option 6]

[0215]

[0216] 6-1) Step 1

[0217] N-(3-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (250 mg, 0.51 mmol), iodomethane (0.16 mL, 2.57 mmol), and potassium carbonate (213 mg, 1.54 mmol) were added to N,N-dimethylformamide (3 mL), and the mixture was refluxed and stirred at 120 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and water was added dropwise. The residue obtained was purified by rapid column chromatography (0-5% dichloromethane:methanol), and the solvent was concentrated under reduced pressure to give 120 mg of the target compound as a solid, with a yield of 47%.

[0218]

[0219] 6-2) Step 2

[0220] The N-(3-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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-methylpyridin-3-amine (39 mg, 0.36 mmol), and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.050 mmol) were added dropwise 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 diatomaceous earth mat, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (0-5% dichloromethane:methanol), and the solvent was concentrated under reduced pressure to give 104 mg of the target compound (compound 124, N-methyl-N-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide as a brown solid, in 76% yield.

[0221]

[0222] <Example 7> Synthetic route of compound 134 G

[0223] As shown in Scheme 7 below, compound 134 was synthesized via synthetic route G, and the synthetic method is described below.

[0224] [Option 7]

[0225]

[0226] 7-1) Step 1

[0227] The 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), followed by the addition of sodium iodide (27.44 g, 183.04 mmol) and potassium carbonate (38.92 g, 281.60 mmol). The mixture was refluxed and stirred at 50 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered through a diatomaceous earth mat, and concentrated using a rotary evaporator. The concentrate was diluted with ethyl acetate and water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The solvent was concentrated under reduced pressure to give 36.3 g of the target compound as a yellow oil, with a yield of 79.0%, which could be used for the next reaction without purification.

[0228]

[0229] 7-2) Step 2

[0230] Methyl 3-(((2,4-dichloropyrimidin-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 was bubbled into the mixture for 5 minutes to remove dissolved gases from the solution. The reaction vessel was then cooled in an ice-water bath (0 °C), and 60% sodium hydride (5.78 g, 144.47 mmol) was added in portions, followed by stirring at room temperature for 1 hour. The reaction vessel was then placed in an ice-water bath at 0 °C, and ethylmalonyl chloride (20.92 mL, 166.69 mmol) was added dropwise, with the mixture stirred at room temperature for 16 hours. After the reaction was complete, the reaction vessel was cooled in an ice-water bath (0 °C), and the reaction was quenched with a 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 residue obtained was purified by MPLC (ethyl acetate:hexane = 3:7 (v / v)) and the solution was concentrated under reduced pressure to give 20.2 g of the target compound as a yellow oil, with a yield of 41.2%.

[0231]

[0232] 7-3) Step 3

[0233] Methyl 3-(N-((2,4-dichloropyrimidin-5-yl)methyl)-3-ethoxy-3-oxopropionamido)-4-methylbenzoate (0.3 g, 0.68 mmol) obtained in step 2 above was dissolved in tetrahydrofuran (6.0 mL), and nitrogen was bubbled into the mixture for 5 minutes. The reaction vessel was cooled in an ice-water bath (0 °C), and 60% sodium hydride (0.04 g, 1.02 mmol) was added in portions, followed by stirring at 30 °C for 12 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with a dichloromethane:methanol (9:1) solution. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by MPLC (hexane:ethyl acetate = 4:6 (v / v)), and the solvent was concentrated under reduced pressure to give 0.25 g of the target compound as a yellow solid, with a yield of 91%.

[0234]

[0235] 7-4) Step 4

[0236] Ethyl 2-chloro-6-(5-(methoxycarbonyl)-2-methylphenyl)-7-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-8-carboxylic acid (0.3 g, 0.74 mmol) obtained in step 3 above was dissolved in 1,4-dioxane (15 mL). A 4N hydrochloric acid aqueous solution (0.3 mL, 7.4 mmol) dissolved in 1,4-dioxane was added, and the mixture was refluxed and stirred at 80 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, and the residue was removed under reduced pressure. The residue was then diluted with dichloromethane. The insoluble solids were filtered through a diatomaceous earth mat, and the collected filtrate was dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by MPLC (hexane:ethyl acetate = 4:6 (v / v)), and the solution was concentrated under reduced pressure to give 0.1 g of the target compound as a yellow solid, with a yield of 63%.

[0237]

[0238] 7-5) Step 5

[0239] Methyl 3-(2-chloro-7-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylbenzoate (0.03 g, 0.093 mmol) obtained in step 4 above was dissolved in anhydrous dimethylformamide (1.0 mL), and nitrogen was bubbled into the mixture for 5 minutes. Then (2-bromoethyl)diphenylsulfonium trifluoromethane sulfonate (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 reaction mixture, 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 layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (hexane:ethyl acetate = 4:6 (v / v)) and the solvent was concentrated under reduced pressure to give 28.3 mg of the target compound as a pale yellow solid, with a yield of 85%.

[0240]

[0241] 7-6) Step 6

[0242] Methyl 3-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylbenzoate (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 refluxed and stirred 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, and the mixture was then diluted with water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated, and the mixture was ready for the next reaction without purification. The target compound (17.0 mg, 60% yield) was obtained as a pale yellow solid.

[0243]

[0244] 7-7) Step 7

[0245] The 3-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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), followed by the addition of 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). The mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by MPLC (hexane:ethyl acetate = 5:5 (v / v)) and the solution was concentrated under reduced pressure to give 7 mg of the target compound as a pale yellow solid, with a yield of 29%.

[0246]

[0247] 7-8) Step 8

[0248] The 3-(2'-chloro-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (6.5 mg, 0.013 mmol) obtained in step 7 above 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 mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by MPLC (hexane:ethyl acetate = 3:7 (v / v)) and the solution was concentrated under reduced pressure to give 4 mg of the target compound as a pale yellow solid, in a yield of 52%.

[0249]

[0250] 7-9) Step 9

[0251] The N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (4 mg, 0.009 mmol) obtained in step 8 above was dissolved in trifluoroacetic acid solution (0.2 mL), and then anisole (2.0 µL, 0.017 mmol) was added. The mixture was refluxed and stirred at 75 °C for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by Prep HPLC (water:acetonitrile = 10% to 95%). The solvent was concentrated under reduced pressure to give 1 mg of the target compound (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) as a white solid in 23% yield.

[0252]

[0253] Tables 1 to 6 below provide information on example compounds synthesized in this invention.

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292] <Experimental Example 1> Evaluation of Enzyme Activity Inhibition

[0293] Table 7 below shows the results of enzyme activity inhibition experiments of selected example compounds by Reaction Biology (RBC) on kinases ACK1, BMX, and Src.

[0294] [*<10 nM: A, <100 nM: B, >100 nM: C].

[0295] [Table 7]

[0296]

[0297] <Experimental Example 2> Cell Line Inhibition Analysis

[0298] C4-2B and 22Rv1 cells were purchased from ATCC and cultured according to the manufacturer's instructions. Cells were cultured at 7 × 10⁶ cells / year. 3 Cells were seeded at 100 μL / well in 96-well plates and allowed to adhere for one day. After removing the culture medium, 90 μL / well of fresh culture medium was added, followed by 10 μL / well of culture medium containing nine compounds (0.076–500 μM, 3-fold serial dilutions) and DMSO control to achieve a final concentration of 0–50 μM. Cells were then incubated at 37°C in a CO2 incubator for 72 hours. Cell proliferation after 72 hours was assessed by adding 10 μL / well of CCK-8 solution, oscillating for 30 seconds, incubating at 37°C in a 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 GI value was calculated using GraphPad Prism 8 software. 50 The value of .

[0299] Meanwhile, in a separate 96-well plate, at 7×10 3 Seed cells at 100 μL / well, allowed to attach for one day, then CCK-8 solution was added, and absorbance was measured to determine the value of "growth (%) = 0".

[0300] The results are shown in Table 8 below [* <1 μM: A, <5 μM: B, <10 μM: C, >10 μM: D].

[0301] [Table 8]

[0302]

[0303] In addition, the same method was used to experiment with 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].

[0304] [Table 9]

[0305]

[0306] [Table 10]

[0307]

[0308] <Experimental Example 3> Measurement of Kinase Inhibitory Activity

[0309] To measure the inhibitory activity of protein kinases against the compounds of the present invention, a whole-kinase panel was used for biochemical assays. When Example Compound 8 and Example Compound 51 were treated at a single concentration of 1 μM, the inhibitory efficacy of the kinases was measured, and the residual enzyme activity was calculated. Kinases were identified when the calculated residual enzyme activity was below 40% (i.e., inhibition of more than 60%). The results are shown in Tables 11 to 14 below.

[0310] Tables 11 and 12 below show the results for example compound 8.

[0311] [Table 11]

[0312]

[0313] [Table 12]

[0314]

[0315] Tables 13 and 14 below show the results for example compound 51.

[0316] [Table 13]

[0317]

[0318] [Table 14]

[0319]

[0320] In the following, formulation examples comprising the composition of compound 8 according to the invention are described; however, the invention is not intended to be limited thereto, but only to provide a specific description.

[0321] <Formulation Example 1> Formulation Example of Pharmaceutical Composition

[0322] <Formulation Example 1-1> Preparation of Powder

[0323] Compound 8 (20 mg), lactose (100 mg), and talc (10 mg) were mixed and placed in a sealed bag to prepare a powder.

[0324] <Formulation Examples 1-2> Tablet Preparation

[0325] According to conventional tablet manufacturing methods, compound 8 (10 mg), corn starch (100 mg), lactose (100 mg) and magnesium stearate (2 mg) are mixed and then compressed into tablets.

[0326] <Formulation Examples 1-3> Preparation of Capsules

[0327] According to conventional capsule manufacturing methods, compound 8 (10 mg), corn starch (100 mg), lactose (100 mg) and magnesium stearate (2 mg) were mixed, and then the mixture was filled into gelatin capsules to prepare capsules.

[0328] <Formulation Examples 1-4> Preparation of Injectables

[0329] Compound 8 (10 mg), an appropriate amount of sterile distilled water for injection, and an appropriate amount of pH adjuster were mixed and then prepared according to conventional methods for preparing injections, so that each ampoule (2 mL) contains the above-mentioned components.

[0330] <Formulation Example 2> Health Supplements

[0331] <Formulation Example 2-1> Preparation of Health Food

[0332] Compound 8 (1 mg), an appropriate amount of a vitamin mixture (70 μg vitamin A acetate, 1.0 mg vitamin E, 0.13 mg vitamin B1, 0.15 mg vitamin B2, 0.5 mg vitamin B6, 0.2 μg vitamin B12, 10 mg vitamin C, 10 μg biotin, 1.7 mg nicotinamide, 50 μg folic acid, 0.5 mg calcium pantothenate) and an appropriate amount of a mineral mixture (1.75 mg ferrous sulfate, 0.82 mg zinc oxide, 25.3 mg magnesium carbonate, 15 mg potassium dihydrogen phosphate, 55 mg dicalcium phosphate, 90 mg potassium citrate, 100 mg calcium carbonate, 24.8 mg magnesium chloride) were mixed, and then granules were prepared according to conventional methods to prepare a health food product.

[0333] <Formulation Example 2-2> Preparation of Health Beverage

[0334] Compound 8 (1 mg), citric acid (1000 mg), oligosaccharides (100 g), apricot concentrate (2 g), taurine (1 g), and purified water were added to a total volume of 900 mL. The above ingredients were mixed according to standard health beverage preparation methods, and then stirred and heated at 85°C for approximately 1 hour. The resulting solution was filtered, collected in a sterile 2 L container, sealed, sterilized, and refrigerated.

[0335] The specific aspects of the present invention have been described in detail above. Those skilled in the art will understand that such detailed description is merely a preferred embodiment and does not limit the scope of the invention. Therefore, the essential scope of the invention should be defined by the appended claims and their equivalents.

Claims

1. A compound selected from compounds having Formula 1, their stereoisomers, their pharmaceutically acceptable salts, their prodrugs, or their solvates: [Formula 1] in: R 1 and R 2 may each be the same or different and are independently selected from hydrogen or (Ci-C4)alkyl, or can be linked together to 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 monocyclic or bicyclic heterocycles, wherein the substituent is selected from one or more members of the group consisting of: (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C2)alkoxy, halogen, hydroxyl, Imidazolyl, (C1-C2)alkylimidazolyl, (C1-C2)alkoxyphenyl, morpholinyl, cyano, oxo (=O), (C1-C2)alkoxy(C1-C2)alkyl(C1-C2)alkylamino, piperazine, (C1-C2)alkylpiperazine, ((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, wherein Y is hydrogen, or a substituted or unsubstituted group, wherein the substituted or unsubstituted group is selected from phenyl, benzyl, (C1-C4)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, pyridinyl, pyrazolyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or azircyclic butyl, wherein the substituent is selected from one or more members of the group consisting of: (C1-C2)alkyl, (C1-C4)alkoxy, piperazine, (C1-C2)alkylpiperazine, acetylpiperazine, morpholino, morpholino-4-carbonyl, (C1- C2)alkylpiperazin-1-carbonyl, oxetyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl, imidazolyl, pyrrolyl, di(C1-C2)alkylaminopyrrolyl, piperidinyl, acetylpiperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazin-1-yl)piperidinyl, halogen, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino, pyridinyl, furanyl, hydroxyl and tert-butoxycarbonyl (BOC); Z is CH or N; L is CH2 or NH; n1 or n2 is an integer between 0 and 1.

2. The compound according to claim 1, wherein the compound has formula 1-1: [Equation 1-1] in: 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 heterocycles, wherein the substituent is selected from one or more members of the group consisting of: (C1-C4)alkyl, (C1-C4)alkoxy, (C3-C6)cycloalkyl, trifluoromethyl, trifluoromethyl(C1-C2)alkoxy, halogen, hydroxyl, Imidazolyl, (C1-C2)alkylimidazolyl, (C1-C2)alkoxyphenyl, morpholinyl, cyano, oxo (=O), (C1-C2)alkoxy(C1-C2)alkyl(C1-C2)alkylamino, piperazine, (C1-C2)alkylpiperazine, ((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. Wherein, Y is selected from hydrogen, or substituted or unsubstituted phenyl, benzyl, (C1-C4)alkyl, (C2-C3)alkenyl, (C3-C6)cycloalkyl, pyridyl, pyrazolyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, or azircyclic butyl, wherein the substituent is selected from one or more members of the group consisting of: (C1-C2)alkyl, (C1-C4)alkoxy, piperazine, (C1-C2)alkylpiperazine, acetylpiperazine, morpholinyl, morpholin-4-carbonyl, (C1-C2)alkylpiperazine-1-carbonyl, oxygen Heterocyclic butyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl, imidazolyl, pyrrolyl, di(C1-C2)alkylaminopyrrolyl, piperidinyl, acetylpiperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazin-1-yl)piperidinyl, halogen, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino, pyridinyl, furanyl, hydroxyl and tert-butoxycarbonyl (BOC); Z is CH or N; L is CH2 or NH; n is an integer between 0 and 1.

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

4. The compound according to claim 1, wherein the compound has formula 1-2: [Equation 1-2] in: R 3 to R 5 may each be the same or different and are selected from the group consisting of hydrogen, (Ci-C2)alkyl, (Ci-C2)alkoxy, trifluoromethyl, halogen, hydroxy, (Ci-C2)alkylimidazolyl, (Ci-C2)alkoxyphenyl, morpholinyl, (Ci-C2)alkoxy(Ci-C2)alkyl(Ci-C2)alkylamino, piperazinyl, (Ci-C2)alkylpiperazinyl, ((Ci-C2)alkylpiperazin-1-yl)(Ci-C2)alkyl, and di(Ci-C2)alkylamino(Ci-C2)alkyl(Ci-C2)alkylamino; A 1 selected from morpholinyl or -NH-Y 1 , wherein Y is selected from the group consisting of hydrogen, (C3-C4)cycloalkyl, benzyl, 1H-pyrazolyl, di(C1-C2)alkyl-1H-pyrazolyl, (oxetan-3-yl)-1H-pyrazolyl, trifluoro(C1-C2)alkyl-1H-pyrazolyl, pyridyl(C1-C2)alkyl, hydroxy(C1-C2)alkyl, hydroxy(C2-C4)alkenyl, hydroxy(C3-C6)cycloalkyl, morpholinyl(C3-C4)alkyl, furanyl(C1-C2)alkyl, tert-butoxycarbonyl (BOC) substituted azetidinyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, and substituted or unsubstituted phenyl or pyridyl, wherein the substituents are selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, halogen, trifluoro(C1-C2)alkoxy, piperazinyl, (C1-C2)alkylpiperazinyl, acetyl piperazinyl, morpholinyl, morpholine-4-carbonyl, (C1-C2)alkylpiperazine-1-carbonyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl, imidazolyl, di(C1-C2)alkylaminopyrrolidinyl, piperidinyl, acetyl piperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazin-1-yl)piperidinyl, and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino. 1 wherein Y is selected from the group consisting of hydrogen, (C3-C4)cycloalkyl, benzyl, 1H-pyrazolyl, di(C1-C2)alkyl-1H-pyrazolyl, (oxetan-3-yl)-1H-pyrazolyl, trifluoro(C1-C2)alkyl-1H-pyrazolyl, pyridyl(C1-C2)alkyl, hydroxy(C1-C2)alkyl, hydroxy(C2-C4)alkenyl, hydroxy(C3-C6)cycloalkyl, morpholinyl(C3-C4)alkyl, furanyl(C1-C2)alkyl, tert-butoxycarbonyl (BOC) substituted azetidinyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, and substituted or unsubstituted phenyl or pyridyl, wherein the substituents are selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, halogen, trifluoro(C1-C2)alkoxy, piperazinyl, (C1-C2)alkylpiperazinyl, acetyl piperazinyl, morpholinyl, morpholine-4-carbonyl, (C1-C2)alkylpiperazine-1-carbonyl, ((C1-C2)alkylpiperazin-1-yl)(C1-C2)alkyl, imidazolyl, di(C1-C2)alkylaminopyrrolidinyl, piperidinyl, acetyl piperidinyl, di(C1-C2)alkylaminopiperidinyl, ((C1-C2)alkylpiperazin-1-yl)piperidinyl, and di(C1-C2)alkylamino(C1-C2)alkyl(C1-C2)alkylamino.

5. The compound according to claim 1, wherein the compound has formulas 1-3: [Equation 1-3] in: X 1 (C3-C6)cycloalkyl, oxo(C3-C6)cycloalkyl, (C4-C6)cycloalkenyl, thienyl, (C1-C2)alkylthienyl, furanyl, thiazolyl, oxazolyl, benzothiazolyl, tetrahydropyranyl, trifluoro(C1-C3)alkyl; or pyridinyl substituted with one or more substituents selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, trifluoromethyl, halogen and hydroxy; A 2 selected from morpholinyl or -NH-Y 2 , wherein Y 2 one or more selected from the group consisting of hydrogen, benzyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, (Ci-C2)alkylpyridinyl, pyridinyl(Ci-C2)alkyl, hydroxy(Ci-C2)alkyl, hydroxy(C2-C4)alkenyl, hydroxy(C3-C6)cycloalkyl, morpholinyl(C3-C4)alkyl, furanyl(Ci-C2)alkyl, ((Ci-C2)alkylpiperazin-1-yl)piperidinyl-trifluoro(Ci-C2)alkyloxy pyridinyl, and tert-butoxycarbonyl (BOC)-substituted azetidinyl.

6. The compound according to claim 1, wherein the compound has formulas 1-4: [Equations 1-4] in: X 2 selected from the group consisting of (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C2)alkyl, benzyl, or substituted or unsubstituted phenyl, wherein the substituents are selected from one or more of (C1-C2)alkyl, (C1-C2)alkoxy, halogen, trifluoro(C1-C2)alkyl, trifluoro(C1-C2)alkoxy, and cyano, A 3 selected from morpholinyl or -NH-Y 3 , wherein Y 3 one or more selected from the group consisting of hydrogen or (C1-C2)alkylpyridyl.

7. The compound according to claim 1, wherein the compound has formulas 1-5: [Equations 1-5] in: X 3 selected from substituted or unsubstituted phenyl, wherein the substituents are selected from one or more members consisting of (Ci-C2)alkyl, (Ci-C2)alkoxy, and halogen; A 4 selected from morpholinyl or -NH-Y 4 wherein Y 4 is selected from one or more of hydrogen, benzyl, tetrahydropyranyl, benzothiazolyl, benzofuranyl, morpholinyl(C3-C4)alkyl, furanyl(C1-C2)alkyl, or pyridinyl(C1-C2)alkyl.

8. The compound according to claim 1, wherein the compound has formulas 1-6: [Equations 1-6] in: X 4 selected from the group consisting of (C1-C2)alkyl, (C1-C2)alkoxy, halogen, and trifluoromethyl, A 5 selected from morpholinyl or -NH-Y 5 wherein Y 5 is hydrogen, or one or more selected from (Ci-C2)alkylpyridinyl.

9. The compound according to claim 1, wherein the compound is selected from the group consisting of: N-(3-(2'-((1,3-dimethyl-1H-pyrazol-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide (compound 6), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4- (Methylphenyl)-3-(4-methyl-1H-imidazol-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)-3,4-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)-3,4-difluorobenzamide8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-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]pyrimidinyl]-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-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]pyrimidin]-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]pyrimidin]-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]pyrimidin]-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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-6-(trifluoromethyl)pyridineamide (compound 21 ...8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-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]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 24 ...5-(trifluoromethyl)nicotinamide (compound 24), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8' '-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-methyl 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-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-morpholino-5-(trifluoromethyl)benzamide 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'-(cyclopropylamino) ...[3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide (compound 32), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamide (compound 33), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-3-(piperazin-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-(piperazin-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-(3 -(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-((2-(dimethylamino)ethyl)(methyl)amino)-5-(trifluoromethyl)benzamide (compound 37), N-(4-methyl-3-(2'-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 38), N-(3-(2'-((4-(4-acetylpiperazin-1-yl)phenyl) N-(4-methyl-3-(2'-((4-morpholinylphenyl)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-morpholinylphenyl)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) ...3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 41), N-(3-(2'-((4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 42), N-(4-methyl-3-(2'-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl) (S)-N-(3-(2'-((4-(1H-imidazol-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), (S)-N-(3-)-(7'-oxo-2'-((4-(piperazin-1-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidine]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (Compound 45), (S)-N-(3-) (2'-((4-(3-(dimethylamino)pyrrolidone-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 46), N-(4-methyl-3-(7'-oxo-2'-((4-(piperidin-4-yl)phenyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 47), N-(4-methyl-3-(2'-((3-(4-methylpiperazin-1-yl)phenyl) N-(3-(2'-((4-(1-acetylpiperidin-4-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-acetylpiperidin-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-methylpyridin-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 49), N-(4-methyl-3-(2'-((6-methylpyridin-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[3-d]pyrimidin]-6'(7'H)-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (compound 50), N-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 51), N-(4-methyl-3-(2'-((1-(oxacyclobut-3-yl)-1H-pyrazol-4-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide 'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 52), N-(3-(2'-((2-methoxy-4-morpholinylphenyl)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-methylpiperazin-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 55), N-(3-(2'-((3-methoxy-4-morpholinylphenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 56), N-(3-(2'-((4-(4-ethylpiperazin-1-yl)-3-fluorobenzamide) N-(3-(2'-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-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 57), N-(4-methyl-3-(7'-oxo-2'-(phenylamino)-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)-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)-4-methylphenyl)-3-(trifluoromethyl)benzamide3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 59), N-(3-(2'-((4-(4-(dimethylamino)piperidin-1-yl)phenyl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoro) (Methyl)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-methylpiperazin-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-pyrazol-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-methylpiperazin-1-yl)-3-(trifluoromethyl)benzamide (compound 65), N-(3-(2'-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino) N-(3-(2'-((3-methoxy-4-(piperazin-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 66), N-(3-(2'-((3-methoxy-4-(piperazin-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-pyrazol-5-yl ...3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 68), N-(3-(2'-((2-methoxy-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 69), N-(3-(2'-((2-hydroxyamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methyl phenyl)-3-(trifluoromethyl)benzamide (compound 70), 1-(4-fluorophenyl)-3-(4-methyl-3-(2'-((6-methylpyridin-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-methylpyridin-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-Methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)thiophene-2-carboxamide (compound 73), N-(4-methyl-3-(2'-((6-methylpyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-oxocyclobutane-1-carboxamide (compound 76), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)cyclohexyl-1-en-1-carboxamide (compound 7 ...3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)benzo[d]thiazol-2-carboxamide (compound 80), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)benzo[d]thiazol-2-carboxamide (compound 80), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)benzo[d]thiazol-2-carboxamide ,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-4,4,4-trifluorobutamide (compound 81), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)thiazolyl-5-carboxamide (compound 82), N-(3-(2'-amino-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-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]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)cyclopentanecarboxamide ,8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 85), N-(4-methyl-3-(2'-morpholinyl-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 86), N-(4-methyl-3- (7'-oxo-2'-((tetrahydro-2H-pyridano-4-yl)amino)-5'H-spiro[cyclopropane-1,8'-pyridano[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 87), N-(4-methyl-3-(7'-oxo-2'-((pyridano-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyridano[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-3-(trifluoromethyl)benzamide (compound 88), N-(4-methyl-3-(2'-((3-morpholinylpropyl)amino)-7'-oxo ...3-d]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 90), N-(3-(2'-(benzylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 93), N-(4-methyl-3-(7'-oxo-2'-((pyridin-3-ylmethyl)amino)-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (Methyl)nicotinamide (compound 94), N-(4-methyl-3-(2'-((3-morpholinylpropyl)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 96), 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 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'-morpholinyl-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[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'-((pyridin-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-morpholinylpropyl)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]thiazolyl-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)-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 'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 104), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-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]thiazolyl-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]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 107), N-(4-methyl-3-(2'-((6-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-5-(trifluoromethyl)nicotinamide (compound 107), N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-6'(7'H)-yl)phenyl)-5-(trifluoromethyl)nicotinamide (compound 108), N-(3-(2'-(benzo[d]thiazolyl-5-ylamino)-7'-oxo-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidinyl]-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]pyrimidinyl]-6'(7'H)- 2-(3,5-difluorophenyl)-N-(4-methyl-3-(2'-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-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]-6'(7'H)-yl)-4-methylphenyl)-3-cyclo Propylurea (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) 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 ...3-d]pyrimidin]-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]pyrimidin]-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]pyrimidin]-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]pyrimidin]-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-methylpyridin-3-yl)-3-(trifluoromethyl)phenyl)urea 1-(4-methyl-3-(2'-((6-methylpyridin-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-methylpyridin-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)amino) (S)-N-(3-(2'-((1-hydroxypropyl-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 126), (S)-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 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 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)benzamide3-d]pyrimidin]-6'(7'H)-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (compound 128), 3-((6'-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)-7'-oxo-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-pyrido[4,3-d]pyrimidin]-2'-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester (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-hydroxypropyl-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), 3-((6'-(2-methyl-5-(5-(trifluoromethyl)nicotinamide)benzene) Compound 133 contains tert-butyl ester of 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 compound of claim 1, wherein the compound inhibits one or more protein kinases selected from the group consisting of: 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, FGFR2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K 4. 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, NE K4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, S IK2, SIK3, SLK / 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.

11. A pharmaceutical composition for treating or preventing protein kinase-related diseases, comprising the compound according to claim 1.

12. The pharmaceutical composition according to claim 11, wherein, The protein kinase is selected from one or more protein kinases from the group consisting of: 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, FGFR2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, GCK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HI PK4, 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, NE K4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, RIPK3, ROS / ROS1, RSK1, SIK1, S IK2, SIK3, SLK / 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.

13. The pharmaceutical composition according to claim 11, wherein, The protein kinase-related diseases are characterized by being cancerous.

14. The pharmaceutical composition according to claim 13, wherein, The cancerous diseases mentioned are selected from the group consisting of prostate cancer, endometrial cancer, bladder cancer, gastric cancer, lung cancer, liver cancer, colorectal cancer, small bowel 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, blood cancer, lymphoma, and fibroma.

15. The pharmaceutical composition according to claim 13, wherein, The pharmaceutical composition is characterized in that it is administered in combination with one or more anticancer agents selected from the group consisting of cytotoxic anticancer agents, targeted anticancer agents, immunomodulatory anticancer agents, and metabolic anticancer agents.

16. The pharmaceutical composition according to claim 11, wherein, The compound is characterized in that when the protein kinase is treated with a single concentration of 1 μM, the inhibitory effect of the compound is greater than 60%.

17. A health functional food for improving or preventing protein kinase-related diseases, comprising the compound according to claim 1.

18. The health functional food according to claim 17, wherein, The protein kinase is selected from one or more protein kinases from the group consisting of: 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 / H ER4, FAK / PTK2, FER, FES / FPS, FGFR1, FGFR2, FGFR3, FGFR4, FGR, FLT1 / VEGFR1, FLT3, FLT4 / VEGFR3, FMS, FRK / PTK5, FYN, G CK / MAP4K2, GLK / MAP4K3, HCK, HGK / MAP4K4, HIPK4, HPK1 / MAP4K1, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KDR / VEGFR2, KHS / M AP4K5, LATS2, LCK, LIMK1, LIMK2, LOK / STK10, LRRK2, LYN, LYNB, MEK5, MEKK2, MEKK3, MINK / MINK1, MLCK2 / MYLK2, MLK1 / MA P3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MUSK, NEK4, P38A / MAPK14, P38B / MAPK11, PDGFRA, PDGFRB, PKAcg, PYK2, RAF1, RET, R IPK3, ROS / ROS1, RSK1, SIK1, SIK2, SIK3, SLK / 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.

19. The health functional food according to claim 17, wherein, The aforementioned protein kinase-related diseases are cancers.

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