TW202304908A - Tetrahydropyridopyrimidine compound - Google Patents

Abstract

Provided is a tetrahydropyridopyrimidine compound which has Axl inhibitory activity and selectively inhibits Axl over Mer.

Description

Tetrahydropyridopyrimidine compounds

The present invention relates to a tetrahydropyridopyrimidine compound with Axl inhibitory effect or its pharmaceutically acceptable salt and its medical application.

The documents cited in this specification are incorporated in this specification by reference.

Axl is a receptor-type tyrosine kinase belonging to the TAM (Tyro3-Axl-Mer) family, and Gas6 (growth arrest-specific protein 6, growth arrest-specific protein 6) is known as a ligand. Axl controls various physiological functions such as cell proliferation, cell survival, cell chemotaxis, immune response, autophagy, angiogenesis, EMT (epithelial-mesenchymal transition) (non-patent document 1). Axl activated by binding to Gas6 is mainly through the MAPK (mitogen-activated protein kinase) pathway, PI3K (phosphatidylinositol 3-kinase, phosphatidylinositol 3-kinase)/Akt pathway, and JAK/STAT (Janus kinase-signal transducer and activator of transcription, Janus kinase-signal transducer and activator of transcription) pathway transmits intracellular signals, so Axl signal abnormalities are related to cancer or immune diseases (Non-Patent Document 1).

Furthermore, it has been reported that Axl is expressed in breast cancer (Non-Patent Document 2), non-small cell lung cancer (Non-Patent Document 3), squamous cell carcinoma of the head and neck (Non-Patent Document 4), and esophageal cancer (Non-Patent Document 5). , Ovarian Cancer (Non-Patent Document 9), Pancreatic Cancer (Non-Patent Document 10), Acute Myelogenous Leukemia (Non-Patent Document 6), Chronic Myeloid Leukemia (Non-Patent Document 7), Malignant Melanoma (Non-Patent Document 8) etc. are related to resistance to anticancer agents, and function as a resistance factor to radiation therapy (Non-Patent Document 11).

On the other hand, regarding Mer, which belongs to the same TAM family as Axl, it is known that Mer knockout mice cause abnormalities in the retina (Non-Patent Document 12). In addition, in a long-term administration test in mice by administering a compound having Mer-inhibiting activity, it was suggested that an irreversible modification of retinal photoreceptors was induced due to Mer-inhibition (Patent Document 5).

Therefore, Axl inhibitors are expected to inhibit proliferation, relieve resistance to treatment with anticancer agents and radiation therapy, and enhance sensitivity in cancers accompanied by Axl signaling abnormalities or cancers that depend on Axl signaling. Enhancement of healing effects. In addition, Axl inhibitors that selectively inhibit Axl with respect to Mer are expected to avoid the above-mentioned side effects on the retina in addition to enhancing the therapeutic effect.

As compounds having Axl inhibitory activity, compounds having a quinoline ring (Patent Documents 1 and 2), compounds having a pyridine ring or a trioxane ring (Patent Documents 3 and 10), and diaminoheterocyclic carboxamides have been reported. compounds (Patent Document 9), compounds having a triazole ring (Patent Documents 6, 7, 8), etc., but did not reveal the inhibitory activity on Mer or the effect on the retina.

On the other hand, Patent Document 5 reports a compound having a pyridone ring that has a high inhibitory specificity to Axl and a low inhibitory activity to Mer. However, Patent Document 5 does not disclose the compound of the present invention. [Prior art literature] [Patent Document]

[Patent Document 1] International Publication No. 2015/012298 [Patent Document 2] International Publication No. 2013/074633 [Patent Document 3] International Publication No. 2016/097918 [Patent Document 4] International Publication No. 2013/115280 [Patent Document 5] International Publication No. 2016/006706 [Patent Document 6] International Publication No. 2008/083367 [Patent Document 7] International Publication No. 2010/005876 [Patent Document 8] International Publication No. 2010/083465 [Patent Document 9] International Publication No. 2015/119122 [Patent Document 10] International Publication No. 2012/135800 [Non-patent literature]

[Non-Patent Document 1] Carl M. Gay et al., Br J Cancer 2017;116:415-423 [Non-Patent Document 2] Catherine Wilson et al., Cancer Res. 2014;74(20):5878-5890 [Non-Patent Document 3] Zhenfeng Zhang et al., Nat. Genet. 2012;44(8):852-860 [Non-Patent Document 4] Keith M Giles et al., Mol. Cancer Therapeutics 2013;12(11):2541-2558 [Non-Patent Document 5] Jun Hong et al., Cancer Res. 2013;73(1):331-340 [Non-Patent Document 6] Chih-Chen Hong, et al., Cancer letters 2008;268(2):314-324 [Non-Patent Document 7] Maeva Dufies et al., Oncotarget 2011;2(11):874-885 [Non-Patent Document 8] William D Tap et al., Neoplasia 2010;12(8):637-649 [Non-Patent Document 9] Mihalis S Kariolis et al., J. Clin. Invest. 2017;127(1):183-198 [Non-Patent Document 10] Ozhan Ocal et al., Dis. Model Mech. 2015;8:1201-1211 [Non-Patent Document 11] Toni M Brabd et al., Clin. Cancer Res. 2015;21(11):2601-2612 [Non-Patent Document 12] Heather M. Seitz et al, J Immunol 2007;178(9):5635-5642

[Problem to be solved by the invention]

The object of the present invention is to provide a novel compound or a pharmaceutically acceptable salt thereof which has Axl inhibitory activity and selectively inhibits Axl with respect to Mer, and a pharmaceutical composition containing the same. [Technical means to solve the problem]

。 [4]一種化合物或其藥學上容許之鹽，該化合物係以下述式表示之N-(3-氟-4-((7-甲基-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)氧基)苯基)-3-(4-氟苯基)-1-異丙基-2,4-二側氧基-1,2,3,4-四氫嘧啶-5-甲醯胺： [化2]

。 [5]一種化合物或其藥學上容許之鹽，該化合物係以下述式表示之N-(3-氟-4-((7-((1-甲基哌啶-4-基)甲基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)氧基)苯基)-3-(4-氟苯基)-1-異丙基-2,4-二側氧基-1,2,3,4-四氫嘧啶-5-甲醯胺： [化3]

。 [6]一種化合物或其藥學上容許之鹽，該化合物係以下述式表示之N-(3-氟-4-((7-((1-甲基四氫吖唉-3-基)甲基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)氧基)苯基)-3-(4-氟苯基)-1-異丙基-2,4-二側氧基-1,2,3,4-四氫嘧啶-5-甲醯胺： [化4]

。 [7]一種化合物或其藥學上容許之鹽，該化合物係以下述式表示之1-(環丙基甲基)-N-(3-氟-4-((7-(1-甲基四氫吖唉-3-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)氧基)苯基)-3-(4-氟苯基)-2,4-二側氧基-1,2,3,4-四氫嘧啶-5-甲醯胺： [化5]

。 [8]一種化合物或其藥學上容許之鹽，該化合物係以下述式表示之1-(環丙基甲基)-3-(4-氟苯基)-N-(4-((7-(1-甲基哌啶-4-基)-5,6,7,8-四氫吡啶并[3,4-d]嘧啶-4-基)氧基)苯基)-2,4-二側氧基-1,2,3,4-四氫嘧啶-5-甲醯胺： [化6]

。 [9]一種醫藥組合物，其包含如上述[1]至上述[8]中任一項所記載之化合物或其藥學上容許之鹽。 [10]一種Axl抑制劑，其含有如上述[1]至上述[8]中任一項所記載之化合物或其藥學上容許之鹽。 [11]如上述[10]所記載之Axl抑制劑，其為抗腫瘤劑。 [12]一種哺乳動物中之腫瘤之預防或治療方法，其包括將如上述[1]至上述[8]中任一項所記載之化合物或其藥學上容許之鹽之有效量投與至該哺乳動物。 [13]一種哺乳動物中之Axl之阻礙化方法，其包括將如上述[1]至上述[8]中任一項所記載之化合物或其藥學上容許之鹽之有效量投與至該哺乳動物。 [14]一種腫瘤之預防或治療方法，其包括將如上述[1]至上述[8]中任一項所記載之化合物或其藥學上容許之鹽投與至對象。 [15]一種如上述[1]至上述[8]中任一項所記載之化合物或其藥學上容許之鹽之用途，其係用於製造用以預防或治療腫瘤之醫藥組合物。 [16]如上述[1]至上述[8]中任一項所記載之化合物或其藥學上容許之鹽，其係用於腫瘤之預防或治療。 [發明之效果] That is, the present invention relates to the following [1] to [16]. [1] A compound or a pharmaceutically acceptable salt thereof, which is selected from one of the following compound groups: (1) 1-cyclopentyl-N-(3-fluoro-4-((7-(( 1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-( 5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (2) N-(3-fluoro-4- ((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1 -Isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (3) N-(3-fluoro-4-((7-(( 1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-( 4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (4)N-(3-fluoro- 4-((7-((1-Methyltetrahydroazil-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (5) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-formamide, (6) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methylpiperidine- 4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2, [ 3,4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy -1,2,3,4-tetrahydropyrimidine-5-formamide, (8)N-(4-((7-(tetrahydroacridine-1-carbonyl)-5,6,7,8- Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-2,5-difluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (9) 1-cyclopentyl-N-(3-fluoro-4-((7- (1-methylpiperidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4- Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (10)N-(3-fluoro-4-((7-(2 -(1-methylpiperidin-4-yl)acetyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)- 3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (11)N-(4 -((7-(2-(Tetrahydroacri-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- Base) oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-formamide, (12) N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxamide, (13) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(( 1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4 -Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (14) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7- Methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-di Oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (15) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(( 1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-( 4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (16)N-(4-((7-(2-( Tetrahydroazine-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluoro Phenyl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide , (17) N-(4-((7-(1-ethyltetrahydroazil-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine -5-formamide, (18) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methyltetrahydroazine-3 -yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3 , 4-tetrahydropyrimidine-5-formamide, (19) 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-(1-methyltetrahydroazine -3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2 ,3,4-tetrahydropyrimidine-5-carboxamide, (20)1-(cyclopropylmethyl)-N-(2-fluoro-4-((7-(1-methyltetrahydroacridine -3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl )-2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (21)1-cyclopentyl-3-(4-fluorophenyl)-N- (4-((7-(1-Methyltetrahydroazidin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy) Phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (22)N-(3-fluoro-4-((7-(3- (Pyrrolidin-1-yl)propionyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4- Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (23)(S)-N-(3- Fluoro-4-((7-(2-(1-methylpyrrolidin-2-yl)acetyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-methyl Amide, (24) N-(3-fluoro-4-((7-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-5,6,7,8-tetrahydro Pyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2 ,3,4-tetrahydropyrimidine-5-formamide, (25)N-(3-fluoro-4-((7-(2-(4-methylpiper-1-yl)-2-side Oxyethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-iso Propyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (26)N-(4-((7-(cyclopentylcarbonyl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (27)N-(4-((7-(2-cyclopropylacetyl) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-iso Propyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (28)N-(4-((7-(3,3-difluorocyclo Butylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl) -1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (29)N-(4-((7-(2,2 -Difluorocyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4- Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (30)N-(3-fluoro-4- ((7-(1-methylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3 -(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (31)N-(4- ((7-(cyclobutylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-( 4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (32)N-(3-fluoro- 4-((7-(2-(4-Methylpiper-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl )oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide , (33) N-(3-fluoro-4-((7-((1-methylpiperidin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetra Hydropyrimidine-5-carboxamide, (34)N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)oxy)-3-fluorophenyl)-1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4 -tetrahydropyrimidine-5-formamide, (35)N-(3-fluoro-4-((7-(2-((1-methylpiperidin-4-yl)amino)-2-side Oxyethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-iso Propyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (36)N-(3-fluoro-4-((7-(3-( 1-methylpiperidin-4-yl)propionyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3- (4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (37)N-(4-( (7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-cyclopropane Base-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (38)N-(3-fluoro-4 -((7-(oxetane-3-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3 -(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (39)N-cyclopropyl -4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Formamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-formamide, (40)N-(4-((7-cyclobutyl -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-iso Propyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (41)N-(3-fluoro-4-((7-(4-( 4-methylpiperidine-1-yl)piperidine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl) -3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (42)N-( 2,5-Difluoro-4-((7-(2-(1-methylpiperidin-4-yl)acetyl)-5,6,7,8-tetrahydropyrido[3,4- d] pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydro Pyrimidine-5-carboxamide, (43)N-(2-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxamide, (44)N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (45)N-(2,5-difluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two sides Oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (46)1-cyclopentyl-N-(3-fluoro-4-((7-((1-methylpiper Pyridin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl )-2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (47)3-(4-fluorophenyl)-1-isopropyl-N- (4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy Base) phenyl) -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (48) 1-(cyclopropylmethyl)-N-(2 -Fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl )Oxy)phenyl)-3-(4-Fluorophenyl)-2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (49)1- (Cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine -4-yl)oxy)phenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-formamide, (50)3-(4-fluorophenyl )-1-isopropyl-N-(4-((7-((1-methyltetrahydroazine-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (51)1- Cyclopentyl-N-(2-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl )-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (52)N-(4-((7 -(2-(tetrahydroazil-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-oxygen Base)-2-fluorophenyl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-formamide, (53) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)ethyl) )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two sides Oxygen-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (54)N-(4-((7-(tetrahydroacridine-1-carbonyl)-5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl)- 2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (55)N-4-((7-(cyclopropylcarbonyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (56)N-4-((7-(2-(1-Ethylpiperidine- 4-yl)ethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluoro Phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (57)N-cyclopropyl-4-(( 6-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide) Pyridin-3-yl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide, (58)1-(cyclopropylmethyl)-3 -(4-fluorophenyl)-N-(5-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (59) 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-methyl Amide, (60) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(2-(1-methylpiperidin-4-yl) Ethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3 , 4-tetrahydropyrimidine-5-formamide, (61) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methyltetrahydroazine- 3-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)- 2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (62) 1-cyclopentyl-N-(3-fluoro-4-((7-( 1-Methyltetrahydroazin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4 -Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (63)1-cyclopentyl-N-(3-fluoro-4 -((7-((1-methyltetrahydroazine-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxygen Base) phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (64) 1-cyclopentyl Base-N-(2-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine -4-base) oxy)phenyl)-3-(4-fluorophenyl)-2,4-two side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, ( 65) 1-cyclopentyl-3-(4-fluorophenyl)-N-(4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine -4-yl)oxy)phenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-formamide, (66)1-(cyclopropylmethyl )-N-(3-fluoro-4-((7-(2-(4-methylpiper-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5- Formamide, (67) N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )Phenyl)-1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-formamide, (68) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-di Oxy-1,2,3,4-tetrahydropyrimidine-5-formamide, (69) 1-cyclopentyl-N-(3-fluoro-4-((7-(1-methyltetra Hydroazepine-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridine- 2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (70)1-(cyclopropylmethyl)-N-(3- Fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )Phenyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (71)N -(4-((7-(tetrahydroazine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3- Fluorophenyl)-1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-formamide, (72) 1-(cyclopropylmethyl)-N-(4-((7-((1-ethylpiperidin-4-yl)methyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-two-side oxy- 1,2,3,4-tetrahydropyrimidine-5-carboxamide, (73) 1-(cyclobutylmethyl)-N-(3-fluoro-4-((7-((1-methyltetrahydro Acridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorobenzene Base)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (74)N-(3-fluoro-4-((7-(6-form Base-2,6-diazaspiro[3.3]heptane-2-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)benzene Base)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (75) 1 -Cyclopentyl-N-(2,5-difluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetra Hydropyrimidine-5-formamide, and (76) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(4-(4-methyl piperidine-1-yl)piperidine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4 -Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide. [2] A compound or a pharmaceutically acceptable salt thereof, which is selected from one of the following compound groups: (1) 1-cyclopentyl-N-(3-fluoro-4-((7-(( 1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-( 5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (2) N-(3-fluoro-4- ((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1 -Isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (3) N-(3-fluoro-4-((7-(( 1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-( 4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (4)N-(3-fluoro- 4-((7-((1-Methyltetrahydroazil-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (5) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-formamide, (6) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methylpiperidine- 4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2, [ 3,4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy -1,2,3,4-tetrahydropyrimidine-5-formamide, (8)N-(4-((7-(tetrahydroacridine-1-carbonyl)-5,6,7,8- Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-2,5-difluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (9) 1-cyclopentyl-N-(3-fluoro-4-((7- (1-methylpiperidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4- Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (10)N-(3-fluoro-4-((7-(2 -(1-methylpiperidin-4-yl)acetyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)- 3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (11)N-(4 -((7-(2-(Tetrahydroacri-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- Base) oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-formamide, (12) N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxamide, (13) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(( 1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4 -Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide, (14) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7- Methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-di Oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (15) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(( 1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-( 4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (16)N-(4-((7-(2-( Tetrahydroazine-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluoro Phenyl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide , (17) N-(4-((7-(1-ethyltetrahydroazil-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine -5-formamide, (18) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methyltetrahydroazine-3 -yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidine-5-formamide, and (19)3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-(1-methyltetrahydroacridine Alas-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-two-side oxy-1, 2,3,4-tetrahydropyrimidine-5-carboxamide. [2] A compound or a pharmaceutically acceptable salt thereof, which is 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methylpiperidine-4 -yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridine-2- Base)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chemical 1]

. [4] A compound or a pharmaceutically acceptable salt thereof, which is N-(3-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-carboxamide: [Chem. 2]

. [5] A compound or a pharmaceutically acceptable salt thereof, which is N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl) represented by the following formula: -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2 ,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-formamide: [Chemical 3]

. [6] A compound or a pharmaceutically acceptable salt thereof, which is N-(3-fluoro-4-((7-((1-methyltetrahydroazil-3-yl)methanol) represented by the following formula: Base)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chemical 4]

. [7] A compound or a pharmaceutically acceptable salt thereof, which is 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrafluoroethylene) represented by the following formula Hydroazepine-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl) -2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chemical 5]

. [8] A compound or a pharmaceutically acceptable salt thereof, which is 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7- (1-Methylpiperidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-di Oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chem. 6]

. [9] A pharmaceutical composition comprising the compound described in any one of the above [1] to [8] or a pharmaceutically acceptable salt thereof. [10] An Axl inhibitor comprising the compound described in any one of the above [1] to the above [8] or a pharmaceutically acceptable salt thereof. [11] The Axl inhibitor according to the above [10], which is an antitumor agent. [12] A method for preventing or treating tumors in mammals, comprising administering to the mammal an effective amount of the compound or a pharmaceutically acceptable salt thereof as described in any one of the above [1] to the above [8]. mammal. [13] A method for inhibiting Ax1 in a mammal, comprising administering to the mammal an effective amount of the compound or a pharmaceutically acceptable salt thereof as described in any one of the above [1] to the above [8] animal. [14] A method for preventing or treating tumors, comprising administering the compound or a pharmaceutically acceptable salt thereof as described in any one of the above [1] to [8] to a subject. [15] Use of the compound described in any one of the above [1] to the above [8] or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing or treating tumors. [16] The compound described in any one of the above [1] to the above [8] or a pharmaceutically acceptable salt thereof, which is used for the prevention or treatment of tumors. [Effect of Invention]

According to the present invention, there can be provided a compound which has an Axl inhibitory effect and selectively inhibits Axl compared with Mer. That is, the compounds of the present invention have utility as Axl inhibitors.

Hereinafter, the content of the present invention will be described in detail.

The compound of the present invention shows the structure as indicated for the part where the stereostructure is clearly defined, and the other parts where the stereostructure is not clearly defined may include stereoisomers, may be one isomer, or Can be a mixture. On the other hand, there are also cases of polymorphism, which are not limited to a specific crystal form, but can be a single substance of any crystal form, or a mixture, and the compounds of the present invention also include amorphous bodies. , and also include solvates such as anhydrates and hydrates.

The "pharmaceutically acceptable salt" in this specification is not particularly limited as long as it forms a salt with the compound of the present invention and is pharmaceutically acceptable. Examples include: inorganic acid salts, organic acid salts, inorganic alkali salts, organic Alkali salts, acidic or basic amino acid salts, etc.

Preferable examples of inorganic acid salts include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc. Preferable examples of organic acid salts include acetate, succinate, Fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, mandelate and other carboxylates; methanesulfonate, ethanesulfonate, p- Sulfonates such as toluenesulfonate and benzenesulfonate.

Preferable examples of inorganic alkali salts include: alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts and ammonium salts; : Diethylamine salt, diethanolamine salt, meglumine salt, N,N'-dibenzylethylenediamine salt, etc.

Preferred examples of acidic amino acid salts include: aspartic acid salts, glutamic acid salts, etc. Preferred examples of basic amino acid salts include arginine salts and lysine salts , Ornithine etc.

The raw material compounds and various reagents in the production of the compound of the present invention may form salts or solvates such as hydrates, which can be changed according to the starting materials, solvents used, etc., and there are no special restrictions as long as the reaction is not hindered. limited. The solvent to be used also varies depending on the starting materials, reagents, etc., and is not particularly limited as long as it dissolves the starting materials to some extent without hindering the reaction. When the compound of the present invention is obtained in the form of a free body, it can be converted into a salt that the compound of the present invention can form or such a solvate according to a conventional method.

When the compound of the present invention is obtained in the form of a salt or a solvate, it can be converted into a free form of the compound of the present invention according to a conventional method.

Also, various isomers (such as geometric isomers, optical isomers, rotational isomers, stereoisomers, tautomers, etc.) obtained with respect to the compounds of the present invention or intermediates thereof can be obtained by using Usual separation methods, such as crystallization, diastereomer salt method, enzyme fractionation method, various chromatography methods (such as thin layer chromatography, column chromatography, gas chromatography, etc.) for purification and simple Leave.

The pharmaceutical composition of the present invention can be produced by mixing a pharmaceutically acceptable additive with the compound of the present invention or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention can be produced, for example, in accordance with known methods such as the method described in the Japanese Pharmacopoeia Sixteenth Revised Edition General Regulations for Preparations.

The pharmaceutical composition of the present invention can be appropriately administered to patients according to its dosage form.

The dose of the medicine of the present invention usually varies depending on symptoms, age, sex, body weight, etc., and may be a sufficient amount to exert the desired effect. For example, in the case of an adult, about 0.1-5000 mg (preferably 0.5-1000 mg) per day is used once a day or several days or divided into 2-6 times a day.

The compounds of the present invention also include isotope-labeled compounds of the compounds of the present invention, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature , which is the same as the compound of the present invention. Isotopes that can be incorporated into the compounds of the present invention are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine or chlorine, including ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²³ I and ¹²⁵ I etc.

Compounds of the present invention containing the above isotopes and/or other isotopes or pharmaceutically acceptable derivatives (eg, salts) thereof are included in the compounds of the present invention. The isotope-labeled compounds of the present invention, such as compounds doped with ³ H, ¹⁴ C and other radioactive isotopes, can be used for tissue distribution analysis of medicine or matrix. The ^{isotopes3H and14C} are believed to be useful due to the ease of their preparation and detection. It is believed that isotopes ¹¹ C and ¹⁸ F can be used in PET (Positron Emission Tomography, positron emission tomography), that isotope ¹²⁵ I can be used in SPECT (single photon emission computed tomography, single photon emission computed tomography), and that all of them can be used in brain imaging. Substitution with a heavier isotope such as ² H would yield certain therapeutic advantages such as increased in vivo half-life through higher metabolic stability or reduced required dosage, and therefore, are considered useful in certain situations. Isotopically-labeled compounds of the compounds of the present invention can be similarly prepared by carrying out the procedures disclosed in the Examples below, using readily available isotopically-labeled reagents instead of non-isotopically-labeled reagents.

The compounds of the present invention can be made into chemical probes for capturing target proteins of physiologically active low-molecular compounds. That is, the compound of the present invention can be reacted with the compound by the method described in J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5 2003, p492-498 or International Publication No. 2007/139149 etc Different structural parts necessary for activity expression are introduced into labeling groups, linking groups, etc., and converted into affinity chromatography, photoaffinity probes, etc.

Examples of labeling groups, linking groups and the like used in chemical probes include groups represented by the group consisting of the following (1) to (5). (1) Photoaffinity labeling groups (such as benzoyl, benzophenone, azido, carbonyl azido, diaziridinyl, enone, diazo and nitro, etc.) and chemical Affinity group (such as ketone group, carbamate group, ester group, alkylthio group, myco-acceptor group (such as α, β-unsaturated keto group, α, β-unsaturated ester group, α-carbon atom replaced by halogen atom) (2) -SS-, -O-Si-O-, monosaccharides (glucosyl, galactosyl, etc.) or disaccharides (lactose, etc.), etc. A linker that can break a bond, and an oligopeptide linker that can break a bond by an enzyme reaction; (3) biotin, 3-(4,4-difluoro-5,7-dimethyl-4H-3a, 4a-diaza-4-bora-s-benzodiinden-3-yl) propionyl and other fishing tag groups; (4) ¹²⁵ I, ³² P, ³ H, ¹⁴ C, etc. Radioactive labeling group; fluorescent yellow (fluorescein), rhodamine, dansyl, umbelliferone, 7-nitrofuracryl, 3-(4,4-difluoro-5,7-dimethyl- Fluorescent labeling groups such as 4H-3a, 4a-diaza-4-bora-s-benzobisinden-3-yl) propionyl; chemiluminescent groups such as luciferin and luminescent amine; lanthanide metal ions , radium ions and other heavy metal ions that can be detected; or (5) with glass beads, glass beds, microtiter plates, agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads, nylon bed and other solid-phase carrier binding base, etc.

Probes prepared by introducing labeling groups selected from the group consisting of the above (1) to (5) into the compounds of the present invention according to the methods described in the above documents can be used as chemical probes to identify new Useful marker protein for the exploration of drug development targets, etc. [Example]

The compounds of the present invention can be produced, for example, by the methods described in the following Production Examples and Examples. However, these are merely illustrative, and the compound of the present invention is not limited to the following specific examples in any case.

In the production examples and examples, unless otherwise specified, YMC GEL SILICA (YMC Co., Ltd, catalog code: SL06I52W) and Silica gel 60 were used as silica gel for purification in silica gel column chromatography. (Kanto Chemicals), Silica gel spherical (Fuji Silysia Chemical LTD., catalog code: PSQ60B), Silica gel 60 (Merck KGaA, catalog code: 1.07734), CHROMATOREX BW (Fuji Silysia Chemical LTD., catalog code: BW-300 ), Hi-Flash Column (YAMAZEN CORPORATION) or Presep Silica Gel (WAKO), the purification silica gel used in NH silica gel column chromatography is NH silica gel (Fuji Silysia Chemical LTD., catalog code: NH-DM2035), Hi-Flash Column Amino (YAMAZEN CORPORATION) or Presep NH2 HC (WAKO). In addition, the TLC (Thin Layer Chromatography, thin layer chromatography) plate used for the purification of silica gel thin layer chromatography uses TLC Silica gel 60F ₂₅₄ (Merck KGaA, catalog code: 1.05715 or 1.05744), NH silica gel thin layer chromatography The PLC plate for purification used in the method is CHROMATOREX NH-PLC05 plate (Fuji Silysia Chemical LTD., catalog code: NH-PLC05). Also, Presep (Wako Pure Chemical Industries, diatomaceous earth, granular) was used as a solid phase extraction column.

The measurement of proton nuclear magnetic resonance spectrum uses Varian Mercury 400, Varian Mercury Plus 400, JEOL 400 or JEOL 500. Chemical shifts in proton NMR spectra are reported in δ units (ppm) relative to tetramethylsilane, and coupling constants are reported in Hertz (Hz). The abbreviations for split modes are as follows. s: singlet, d: doublet, t: triplet, q: quartet, quin: quintet, spt: septet, m: multiplet, brs: broad singlet.

Mass spectrometry was performed using Waters UPLC ^™ . As the ionization method, electrospray ionization (ESI: Electrospray ionization) was used for measurement.

In Production Examples and Examples, commercially available compounds were used as appropriate.

The described abbreviations mean the following. HATU: N,N,N',N'-tetramethyl-O-(7-azobenzotriazol-1-yl)uronium hexafluorophosphate n-heptane: n-heptane CDCl ₃ : deuterium Chloroform DMSO-d ₆ : deuterated dimethylsulfide DMF: N,N-dimethylformamide THF: tetrahydrofuran

[Example 1] 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide [Chem. 7]

To 4-((4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-two-side oxygen) as described in Production Example 1-11 at room temperature Base-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) Trifluoroacetic acid (2 mL) was added to a solution of tertiary-butyl piperidine-1-carboxylate (33 mg) in dichloromethane (2 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. To a solution of the residue in THF (2 mL) was added 35-37% aqueous formaldehyde (35.5 mg) at room temperature, and stirred at room temperature for 10 minutes. Sodium triacetyloxyborohydride (18.5 mg, 0.087 mmol) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 20 minutes. Sodium bicarbonate and water were added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (18 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.20-1.50 (2H, m), 1.50-2.00 (11H, m), 2.05-2.60 (10H, m), 2.70-2.80 (2H, m), 2.85-3.15 (4H, m), 3.61 (2H, s), 4.90-5.05 (1H, m), 7.05-7.15 (1H, m), 7.20-7.35 (2H, m), 7.70-7.85 ( 2H, m), 8.46 (1H, s), 8.52 (1H, d, J = 2.0 Hz), 8.64 (1H, s), 10.84 (1H, s). ESI-MS (m/z): 669.54 [M+H] ⁺ .

[Production Example 1-1] 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one [Chem. 8]

Add formamidine acetate (20.2 g , 194 mmol), about 20% sodium ethoxide-ethanol solution (171 mL), stirred under reflux under nitrogen atmosphere for 76 hours and 40 minutes. After cooling the reaction mixture to room temperature, it was filtered using celite, and this was washed with ethyl acetate and methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=7:3) to obtain the title compound (26.3 g). ¹ H-NMR spectrum (400 MHz, DMSO-d ₆ ) δ (ppm): 2.25-2.65 (4H, m), 3.22 (2H, brs), 3.60 (2H, s), 7.15-7.35 (5H, m) , 7.92 (1H, s), 12.30 (1H, brs).

[Production Example 1-2] tertiary butyl 4-oxo-3,4,5,6-tetrahydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate [Chem. 9]

To 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (23.4 g) described in Production Example 1-1 at room temperature Add 10% palladium-carbon (50% water-containing product) (10.3 g) to the methanol (500 mL) and THF (200 mL) solution, and stir at normal pressure and room temperature for 7 hours and 10 minutes under hydrogen atmosphere. After setting the reaction mixture under a nitrogen atmosphere, it was filtered using celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (17.2 g). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.48 (9H, s), 2.55-2.68 (2H, m), 3.55-3.70 (2H, m), 4.35-4.48 (2H, m) , 8.01 (1H, s), 11.38 (1H, brs). ESI-MS (m/z): 252.02 [M+H] ⁺ .

[Production Example 1-3] tertiary butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate [Chem. 10]

The 4-oxo-3,4,5,6-tetrahydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (13.3 g, 52.9 mmol), triphenylphosphine (27.8 g, 106 mmol), and carbon tetrachloride (20.6 mL, 212 mmol) in 1,2-dichloroethane (200 mL) were stirred at 50°C for 4 hours. The reaction solution was returned to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (11.2 g). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.48 (9H, s), 2.86 (2H, t, J = 5.6 Hz), 3.73 (2H, t, J = 5.9 Hz), 4.63 ( 2H, s), 8.77 (1H, s).

[Production Example 1-4] tertiary butyl 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate [chemical 11]

Add 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (6.2 g, 23.0 mmol ), 4-amino-2-fluorophenol (3.51 g, 27.6 mmol) in DMF (100 mL) was added potassium carbonate (6.35 g, 46.0 mmol), and stirred at 60°C for 4 hours. The reaction mixture was returned to room temperature, added with water, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1) to obtain the title compound (7.25 g). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (9H, s), 2.82-2.94 (2H, m), 3.71-3.78 (4H, m), 4.60 (2H, s), 6.39 -6.54 (2H, m), 6.94 (1H, t, J = 8.6 Hz), 8.52 (1H, s).

[Production Example 1-5] Phenyl N-(5-methylpyridin-2-yl)carbamate and N-(5-methylpyridin-2-yl)-N-(phenoxycarbonyl)amino Mixture of phenyl formate [Chem. 12]

Add 2-amino-5-picoline (20 g, 185 mmol) in THF (400 mL) and N,N-diisopropylethylamine (64.6 mL, 370 mmol) at 0°C Phenyl chloroformate (35.0 mL, 277 mmol), stirred at room temperature for 1 hour and 15 minutes. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. The precipitate in the organic layer was collected by filtration to obtain a crude product (3.2 g) of phenyl N-(5-methylpyridin-2-yl)carbamate. The filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the precipitate was collected by filtration, and washed with diethyl ether to obtain N-(5-methylpyridin-2-yl)phenylcarbamate and N-(5 -Mixture of phenyl-methylpyridin-2-yl)-N-(phenoxycarbonyl)carbamate (32.0 g). N-(5-methylpyridin-2-yl)phenylcarbamate: ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 2.29 (3H, s), 7.15-7.30 (3H, m ), 7.35-7.44 (2H, m), 7.52 (1H, d, J = 8.5 Hz), 7.76 (1H, brs), 7.86 (1H, d, J = 8.8 Hz), 8.08-8.13 (1H, m) . Mixture of phenyl N-(5-methylpyridin-2-yl)carbamate and N-(5-methylpyridin-2-yl)-N-(phenoxycarbonyl)phenylcarbamate: ESI -MS (m/z): 228.95 [M＋H] ⁺ , 349.11 [M＋H] ⁺

[Production Example 1-6] Ethyl 3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylate [Chem. 13 ]

N-(5-methylpyridin-2-yl)phenyl carbamate and N-(5-methylpyridin-2-yl)-N-(phenoxycarbonyl) described in Production Example 1-5 A 2 N ammonia-ethanol solution (129 mL, 258 mmol) was added to the phenylcarbamate mixture (19.6 g), and stirred at 80°C for 1 hour and 20 minutes. 1,4-Dioxane (130 mL) was added to the reaction mixture, and stirred at 80°C for 2 hours. After the reaction mixture was brought to room temperature, it was concentrated under reduced pressure. Add ethanol (400 mL), 1,3-diethyl 2-(ethoxymethylene)malonate (26.1 mL, 129 mmol), about 20% sodium ethoxide-ethanol solution (67.4 mL) to the residue , stirred at 70° C. for 2 hours. After the reaction mixture was brought to room temperature, a 2 N hydrogen chloride-ethanol solution (86 to 90 mL) was added to adjust the pH to 6, and the mixture was concentrated under reduced pressure. After the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate:methanol = 9:1), the obtained solid was washed with dichloromethane (about 20 mL), and collected by filtration. This afforded the title compound (14.4 g). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.23-1.38 (3H, m), 2.40 (3H, s), 4.20-4.38 (2H, m), 7.13-7.23 (1H, m) , 7.64-7.73 (1H, m), 8.18-8.32 (1H, m), 8.43-8.53 (1H, m), 10.26 (1H, brs). ESI-MS (m/z): 276.02 [M+H] ⁺ .

[Production Example 1-7] 1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5- Ethyl formate [Chem. 14]

To 3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5- as described in Production Example 1-6 at room temperature Add iodocyclopentane (2.99 g, 15.3 mmol) and potassium carbonate (2.11 g, 15.3 mmol) to a mixture of ethyl formate (1.5 g, 5.45 mmol) and DMF (10 mL), and stir at 70°C for 24 hours . After cooling the reaction mixture to room temperature, water was added and extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The solvent was distilled off, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:4) to obtain the title compound (840 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.33 (3H, t, J = 7.0 Hz), 1.67-1.78 (4H, m), 1.83-1.94 (2H, m), 2.12-2.23 (2H, m), 2.39 (3H, s), 4.32 (2H, q, J = 7.3 Hz), 4.84-5.00 (1H, m), 7.14-7.20 (1H, m), 7.66 (1H, dd, J = 8.0, 2.5 Hz), 8.34 (1H, s), 8.44-8.47 (1H, m).

[Production Example 1-8] 1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5- Formic acid [Chem. 15]

To 1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4- Add water (705 μL) to a mixture of ethyl tetrahydropyrimidine-5-carboxylate (840 mg, 2.45 mmol) and 4 M hydrogen chloride-1,4-dioxane solution (4.53 mL), and stir at 70°C for 13 hours . Add 4 M hydrogen chloride-1,4-dioxane solution (2 mL) and water (350 μL) at the same temperature, and stir for 6 hours and 30 minutes. After cooling the reaction mixture to room temperature, it was concentrated under reduced pressure. Water was added to the residue, followed by extraction with dichloromethane 6 times. The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (480 mg). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 1.51-1.63 (2H, m), 1.72-1.88 (4H, m), 1.94-2.07 (2H, m), 2.33 (3H, s), 4.66-4.82 (1H, m), 7.30-7.34 (1H, m), 7.75-7.80 (1H, m), 8.36-8.39 (1H, m), 8.47 (1H, s), 12.57 (1H, brs).

[Production Example 1-9] 4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 16]

To 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) described in Production Example 1-4 at room temperature -Tertiary butyl formate (100 mg, 0.277 mmol) and 1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-diendoxy as described in Production Example 1-8 - Add N,N-diisopropylethylamine (97 μL, 0.555 mmol) to a solution of 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (96 mg, 0.305 mmol) in DMF (3 mL) and HATU (158 mg, 0.416 mmol), stirred at 60°C for 2 hours and 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 3: 2 ~ ethyl acetate) to obtain the title compound (165 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (9H, s), 1.70-1.85 (4H, m), 1.88-1.98 (2H, m), 2.15-2.27 (2H, m) , 2.44 (3H, s), 2.85-2.93 (2H, m), 3.68-3.78 (2H, m), 4.55-4.65 (2H, m), 4.93-5.03 (1H, m), 7.08-7.15 (1H, m), 7.20-7.30 (2H, m), 7.70-7.80 (1H, m), 7.80-7.85 (1H, m), 8.50-8.55 (2H, m), 8.64 (1H, s), 10.85 (1H, s). ESI-MS (m/z): 658.62 [M+H] ⁺ .

[Production Example 1-10] 1-cyclopentyl-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy Base) phenyl) -3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 17]

To 4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1, 2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary Trifluoroacetic acid (3 mL) was added to a solution of butyl ester (165 mg, 0.251 mmol) in dichloromethane (3 mL), and stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. Sodium bicarbonate and water were added to the residue, and extraction was performed with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (132 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.65-1.85 (4H, m), 1.85-1.98 (2H, m), 2.15-2.25 (2H, m), 2.44 (3H, s) , 2.80-2.88 (2H, m), 3.18-3.27 (2H, m), 4.03-4.08 (2H, m), 4.95-5.03 (1H, m), 7.10-7.17 (1H, m), 7.23-7.38 ( 2H, m), 7.73-7.78 (1H, m), 7.78-7.85 (1H, m), 8.48 (1H, s), 8.50-8.55 (1H, m), 8.64 (1H, s), 10.84 (1H, s). ESI-MS (m/z): 558.41 [M+H] ⁺ .

[Production Example 1-11] 4-((4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl) tertiary butyl piperidine-1-carboxylate[Chem. 18]

To 1-cyclopentyl-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 1-10 at room temperature -4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-methyl Add tertiary butyl 4-formylpiperidine-1-carboxylate (15.3 mg, 0.072 mmol) to a solution of amide (20 mg, 0.036 mmol) in THF (2 mL) and acetic acid (0.1 mL), at room temperature Stirring was continued for 13 hours and 10 minutes. Sodium triacetoxyborohydride (15.2 mg, 0.072 mmol) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 4 hours and 35 minutes. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH column chromatography (n-heptane: ethyl acetate = 3:2 to 1:4) to obtain the title compound quantitatively. ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.05-1.18 (2H, m), 1.18-1.35 (1H, m), 1.45 (9H, s), 1.58-1.85 (6H, m) , 1.85-1.98 (2H, m), 2.15-2.25 (2H, m), 2.35-2.45 (5H, m), 2.60-2.83 (4H, m), 2.85-2.93 (2H, m), 3.58-3.68 ( 2H, m), 3.98-4.23 (2H, m), 4.93-5.03 (1H, m), 7.08-7.15 (1H, m), 7.20-7.32 (2H, m), 7.72-7.77 (1H, m), 7.78-7.84 (1H, m), 8.44-8.48 (1H, m), 8.50-8.56 (1H, m), 8.64 (1H, s), 10.84 (1H, s). ESI-MS (m/z): 755.71 [M+H] ⁺ .

[Example 2] N-(3-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)benzene Base)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 19]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (200 mg) in THF (7 mL) solution was added 35-37% formaldehyde aqueous solution (0.276 mL) and sodium triacetyloxyborohydride (238 mg, 1.12 mmol), and stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (171 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.7 Hz), 2.50 (3H, s), 2.73-2.83 (2H, m), 2.89-3.00 (2H , m), 3.60 (2H, s), 4.90-5.00 (1H, m), 7.12-7.19 (1H, m), 7.20-7.28 (5H, m), 7.82 (1H, dd, J = 12.2, 2.5 Hz ), 8.48 (1H, s), 8.66 (1H, s), 10.88 (1H, brs).

[Production Example 2-1] 4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 20]

4-(4-Amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) described in Production Example 1-4 was prepared at room temperature -Tertiary butyl formate (419 mg, 1.16 mmol), 3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3 described in WO 2013074633 A1 , 4-tetrahydropyrimidine-5-carboxylic acid (408 mg, 1.40 mmol), N,N-diisopropylethylamine (0.395 mL, 2.33 mmol), HATU (575 mg, 1.51 mmol) in DMF (5 mL ) solution was stirred overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=5:1～3:1～2:1～1:1) to obtain the title compound (583 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.45-1.53 (15H, m), 2.85-2.92 (2H, m), 3.75 (2H, t, J = 5.8 Hz), 4.62 (2H , s), 4.90-5.00 (1H, m), 7.09-7.18 (1H, m), 7.22-7.29 (5H, m), 7.83 (1H, dd, J = 12.2, 2.5 Hz), 8.51 (1H, s ), 8.67 (1H, s), 10.90 (1H, brs).

[Production Example 2-2] N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)- 3-(4-Fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chem. 21]

To 4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1) described in Production Example 2-1 at room temperature, 2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (583 mg, 0.919 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL), and stirred at room temperature for 45 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound quantitatively. ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (6H, d, J = 6.7 Hz), 2.98 (2H, t, J = 5.5 Hz), 3.35 (2H, t, J = 5.8 Hz), 4.15 (2H, s), 4.90-5.00 (1H, m), 7.11-7.18 (1H, m), 7.22-7.27 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz) , 8.51 (1H, s), 8.67 (1H, s), 10.90 (1H, brs).

[Example 3] N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-formamide [Chem. 22]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.5 g, 2.81 mmol ) and THF (25 mL) were added tertiary-butyl 4-formylpiperidine-1-carboxylate (1.2 g, 5.63 mmol) and sodium triacetyloxyborohydride (1.78 g, 8.42 mmol), Stir at room temperature for 4 hours 20 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 9: 1 to 1: 1) to obtain a crude product. Trifluoroacetic acid (13 mL) was added to a mixture of the obtained crude product and dichloromethane (40 mL), followed by stirring at room temperature for 30 minutes. Toluene (40 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Toluene (40 mL) was added to the obtained residue, and the solvent was distilled off under reduced pressure. THF (40 mL), 35-37% formaldehyde aqueous solution (2.1 mL) and sodium triacetyloxyborohydride (1.85 g, 8.73 mmol) were sequentially added to the obtained residue, and stirred at room temperature for 1 hour and 35 minutes . Saturated aqueous sodium bicarbonate solution and water were added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:4～0:1). Diethyl ether was added to the obtained residue, followed by ultrasonic pulverization, and the solid was collected by filtration to obtain the title compound (903 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.30 (2H, qd, J = 12.2, 3.7 Hz), 1.51 (6H, d, J = 6.7 Hz), 1.53-1.67 (1H, m ), 1.80 (2H, dd, J = 12.2, 1.2 Hz), 1.89-2.00 (2H, m), 2.28 (3H, s), 2.43 (2H, d, J = 6.7 Hz), 2.73-2.83 (2H, m), 2.83-2.96 (4H, m), 3.63 (2H, s), 4.89-5.07 (1H, m), 7.14 (1H, t, J = 8.6 Hz), 7.23-7.29 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.49 (1H, s), 8.68 (1H, s), 10.90 (1H, s). ESI-MS (m/z): 646.49 [M+H] ⁺ .

[Example 4] N-(3-fluoro-4-((7-((1-methyltetrahydroazil-3-yl)methyl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide [Chem. 23]

To 3-((4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxygen) described in Production Example 4-1 at room temperature Base-1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanol Trifluoroacetic acid (10 mL) was added to a solution of tertiary-butyl tetrahydroacridine-1-carboxylate (2.08 g, 2.95 mmol) in dichloromethane (10 mL), and stirred at room temperature for 80 minutes. The reaction mixture was concentrated under reduced pressure. THF (20 mL), 35-37% formaldehyde aqueous solution (2.39 g), and sodium triacetyloxyborohydride (1.25 g, 5.90 mmol) were added to the residue at room temperature, and stirred at room temperature for 3 hours and 30 minutes . Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (1.21 g). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.8 Hz), 2.30 (3H, s), 2.68-2.83 (5H, m), 2.83-2.98 (4H , m), 3.40-3.53 (2H, m), 3.53-3.67 (2H, m), 4.90-5.03 (1H, m), 7.08-7.15 (1H, m), 7.18-7.33 (5H, m), 7.78 -7.87 (1H, m), 8.46 (1H, s), 8.66 (1H, s), 10.88 (1H, brs). ESI-MS (m/z): 618.49 [M+H] ⁺ .

[Production Example 4-1] 3-((4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2, 3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl)tetrahydroazepine -1-Tertiary butyl carboxylate [Chem. 24]

To N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxygen as described in Production Example 2-2 at room temperature Base) phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.85 g, 3.46 mmol) in THF (20 mL) and acetic acid (2 mL) was added with tertiary butyl 3-formyl tetrahydroazine-1-carboxylate (1.28 g, 6.92 mmol), and stirred for 10 minutes. Sodium triacetyloxyborohydride (2.20 g, 10.4 mmol) was added to the reaction mixture at room temperature, followed by stirring for 2 hours and 25 minutes. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified twice by NH silica gel column chromatography to obtain the title compound (2.08 g). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.43 (9H, s), 1.49 (6H, d, J = 4.0 Hz), 2.75-2.93 (7H, m), 3.58-3.70 (4H , m), 4.00-4.08 (2H, m), 4.93-5.00 (1H, m), 7.08-7.15 (1H, m), 7.18-7.33 (5H, m), 7.78-7.85 (1H, m), 8.47 (1H, s), 8.66 (1H, s), 10.89 (1H, s). ESI-MS (m/z): 704.55 [M+H] ⁺ .

[Example 5] 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrahydroazin-3-yl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-formamide [Chem. 25]

1-(cyclopropylmethyl)-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 5-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (4.31 g, 7.89 mmol) and dichloromethane (100 mL) were added with tertiary-butyl 3-oxotetrahydroazia-1-carboxylate (2.70 g, 15.8 mmol), and stirred for 2 hours. Sodium triacetyloxyborohydride (3.35 g, 15.8 mmol) was added to the reaction mixture, followed by stirring for 6 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with dichloromethane. After the organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. A mixture of ethyl acetate and n-heptane was added to the residue, and the solid was collected by filtration to obtain a crude product. Trifluoroacetic acid (18.2 mL) was added to a mixture of the obtained crude product and dichloromethane (80 mL), followed by stirring for 3 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, added with saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The organic layer was concentrated under reduced pressure to obtain a crude product. A 35-37% aqueous formaldehyde solution (1.60 g) and sodium triacetyloxyborohydride (4.18 g, 19.7 mmol) were added to a mixture of the obtained crude product and THF (200 mL), and stirred for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1:5 to 0:1) to obtain the title compound (3.75 g). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 0.36-0.44 (2H, m), 0.49-0.56 (2H, m), 1.17-1.27 (1H, m), 2.20 (3H, s), 2.59 (2H, t, J = 5.0 Hz), 2.76 (2H, t, J = 5.0 Hz), 2.80 (2H, t, J = 5.0 Hz), 3.06 (1H, quin, J = 5.0 Hz) , 3.39-3.46 (4H, m), 3.82 (2H, d, J = 7.3 Hz), 7.25-7.35 (3H, m), 7.37-7.44 (3H, m), 7.84-7.89 (1H, m), 8.43 (1H, s), 8.87 (1H, s), 10.95 (1H, s).

[Production Example 5-1] 4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 26]

To 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) described in Production Example 1-4 at room temperature - Add 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2 described in WO 2013074633 A1 to a solution of tertiary butyl formate (60 mg, 0.166 mmol) in DMF (2 mL), 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (55.7 mg, 0.183 mmol), N,N-diisopropylethylamine (0.058 mL, 0.333 mmol), HATU (82 mg, 0.216 mmol), stirred at room temperature for 63 hours and 40 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1～ethyl acetate) to obtain the title compound (108 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.42-0.49 (2H, m), 0.69-0.77 (2H, m), 1.15-1.33 (1H, m), 1.49 (9H, s) , 2.86-2.93 (2H, m), 3.71-3.78 (2H, m), 3.81 (2H, d, J = 7.3 Hz), 4.59-4.64 (2H, m), 7.09-7.16 (1H, m), 7.19 -7.30 (5H, m), 7.79-7.88 (1H, m), 8.51 (1H, s), 8.71 (1H, s), 10.88 (1H, brs). ESI-MS (m/z): 647.49 [M+H] ⁺ .

[Production Example 5-2] 1-(cyclopropylmethyl)-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-formamide [Chemical 27]

4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (108 mg, 0.167 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), and stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with dichloromethane. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure to obtain the title compound (78 mg). ESI-MS (m/z): 547.28 [M+H] ⁺ .

[Example 6] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methylpiperidin-4-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-Formamide [Chem. 28]

1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-diendoxy-N-(4-((5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (2.3 g, 4.35 mmol ) and dichloromethane (30 mL) was added tertiary-butyl 4-oxopiperidine-1-carboxylate (1.30 g, 6.53 mmol), and stirred at room temperature for 2 hours. Sodium triacetyloxyborohydride (1.38 g, 6.53 mmol) was added to the mixture, followed by stirring overnight at room temperature. Saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. After adding dichloromethane to the residue and cooling to 0°C, n-heptane was added. The suspension was stirred at 0°C for 20 minutes. The solid was collected by filtration to obtain crude product. Trifluoroacetic acid (6 mL) was added to a mixture of the obtained crude product and dichloromethane (18 mL), followed by stirring at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. THF (45 mL), 35-37% formaldehyde aqueous solution (0.956 mL) and sodium triacetyloxyborohydride (1.30 g, 6.13 mmol) were added to the obtained crude product, and stirred at room temperature for 20 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (1.87 g). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.44-0.48 (2H, m), 0.69-0.77 (2H, m), 1.21-1.31 (1H, m), 1.66-1.77 (2H, m), 1.84-1.90 (2H, m), 1.96-2.04 (2H, m), 2.28 (3H, s), 2.46-2.54 (1H, m), 2.83-2.93 (4H, m), 2.93-2.99 ( 2H, m), 3.72-3.86 (4H, m), 7.06-7.10 (2H, m), 7.20-7.30 (4H, m), 7.67-7.72 (2H, m), 8.47 (1H, s), 8.71 ( 1H, s), 10.79 (1H, brs). ESI-MS (m/z): 626.59 [M+H] ⁺ .

[Production Example 6-1] tertiary butyl 4-(4-aminophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate [Chem. 29]

To a mixture of 4-aminophenol (1.11 g, 10.2 mmol) and DMF (30 mL) was added 50-72% sodium hydride oil (250 mg) at 0°C, and stirred at 0°C for 10 minutes. To this reaction solution was added tertiary butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (2.5 g, 9.27 mmol), stirred at 0°C for 30 minutes. Water was added to the reaction liquid, and the temperature was raised to room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:1) to obtain the title compound (1.54 g). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.50 (9H, s), 2.87 (2H, t, J = 4.9 Hz), 3.58-3.83 (4H, m), 4.61 (2H, s ), 6.68-6.76 (2H, m), 6.85-6.96 (2H, m), 8.53 (1H, s). ESI-MS (m/z): 343.36 [M+H] ⁺ .

[Production Example 6-2] 4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 30]

To 4-(4-aminophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary as described in Production Example 6-1 at room temperature Butyl ester (500 mg, 1.46 mmol), 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3 described in WO 2013074633 A1 , To a mixture of 4-tetrahydropyrimidine-5-carboxylic acid (533 mg, 1.75 mmol), HATU (833 mg, 2.19 mmol) and DMF (20 mL) was added N,N-diisopropylethylamine (0.497 mL , 2.92 mmol), stirred at room temperature for 1 hour. Water was added to the reaction liquid, and extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7:3 to 3:7) to obtain the title compound (880 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.43-0.54 (2H, m), 0.68-0.81 (2H, m), 1.22-1.36 (1H, m), 1.50 (9H, s) , 2.85-2.90 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 3.82 (2H, d, J = 7.3 Hz), 4.62 (2H, s), 7.07-7.17 (2H, m), 7.19-7.34 (4H, m), 7.66-7.79 (2H, m), 8.53 (1H, s), 8.73 (1H, s), 10.82 (1H, s). ESI-MS (m/z): 629.48 [M+H] ⁺ .

[Production Example 6-3] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-N-(4-((5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 31]

4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (880 mg, 1.40 mmol ) and dichloromethane (15 mL) was added trifluoroacetic acid (5 mL), and stirred at room temperature for 1 hour and 5 minutes. Toluene (15 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Dichloromethane and saturated aqueous sodium bicarbonate solution were added to the obtained residue to adjust the pH to 8-9. Water was added to the mixture, and extraction was performed with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (692 mg). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 0.40-0.47 (2H, m), 0.51-0.63 (2H, m), 1.15-1.32 (1H, m), 2.65-2.71 ( 2H, m), 3.02 (2H, t, J = 5.8 Hz), 3.81 (2H, s), 3.86 (2H, d, J = 6.7 Hz), 7.12-7.23 (2H, m), 7.30-7.40 (2H , m), 7.41-7.50 (2H, m), 7.67-7.80 (2H, m), 8.42 (1H, s), 8.89 (1H, s), 10.88 (1H, s). ESI-MS (m/z): 529.44 [M+H] ⁺ .

[Example 7] N-(5-((7-(tetrahydroazil-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)pyridin-2-yl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-Formamide [Chemical 32]

To 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-N-(5-((5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-formyl Add pyridine (18 μL, 0.223 mmol) and 4-nitrophenyl chloroformate (26.2 mg, 0.13 mmol) to a solution of amine (29.6 mg, 0.056 mmol) in dichloromethane (1.0 mL), and carry out the adjustment at room temperature. Stir overnight. Ethyl acetate and water were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered with a short pad of NH silica gel. The solvent was distilled off under reduced pressure to obtain a crude product. To a DMF (1.0 mL) solution of the obtained crude product was added tetrahydroacridine (15.0 mg, 0.263 mmol) at room temperature, followed by stirring for 2 hours. The reaction mixture was diluted with dichloromethane, and purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1～1:1～1:4) to obtain the title compound (14.4 mg) . ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.47 (2H, q, J = 5.5 Hz), 0.75 (2H, q, J = 8.0 Hz), 1.24-1.33 (1H, m), 2.29 (2H, quin, J = 7.6 Hz), 2.90 (2H, t, J = 5.8 Hz), 3.67 (2H, t, J = 5.8 Hz), 3.82 (2H, d, J = 7.3 Hz), 4.09 ( 4H, t, J = 7.6 Hz), 4.50 (2H, brs), 7.20-7.28 (4H, m), 7.54 (1H, dd, J = 9.2, 3.1 Hz), 8.16 (1H, d, J = 3.1 Hz ), 8.35 (1H, d, J = 9.2 Hz), 8.51 (1H, s), 8.72 (1H, s), 11.29 (1H, s). ESI-MS (m/z): 613 [M+H] ⁺ .

[Production Example 7-1] 4-((6-aminopyridin-3-yl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary Butyl ester [Chem. 33]

To a solution of 2-amino-5-hydroxypyridine hydrochloride (818 mg, 5.58 mmol) in DMF (30 mL) was added potassium tertiary butoxide (1.50 g, 13.4 mmol) and Preparation Example 1- 4-Chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (1.00 g, 3.71 mmol) described in 3, under nitrogen atmosphere at the same temperature Stir for 40 minutes. Ethyl acetate and water were added and partitioned, and the obtained aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7: 3 to 1: 9) to obtain the title compound (963 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.50 (9H, s), 2.84-2.94 (2H, m), 3.76 (2H, t, J = 5.5 Hz), 4.44 (2H, brs ), 4.62 (2H, brs), 6.56 (1H, d, J = 8.6 Hz), 7.24-7.31 (1H, m), 7.93 (1H, d, J = 2.5 Hz), 8.53 (1H, s).

[Production Example 7-2] 4-((6-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4 -tetrahydropyrimidine-5-carboxamido)pyridin-3-yl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester[Ch 34]

4-((6-aminopyridin-3-yl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid as described in Production Example 7-1 Tertiary butyl ester (180 mg, 0.524 mmol), 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2 described in WO 2013074633 A1 , 3,4-tetrahydropyrimidine-5-carboxylic acid (175 mg, 0.577 mmol), HATU (301 mg, 0.792 mmol), N,N-diisopropylethylamine (178 μL, 1.05 mmol), DMF ( 6.0 mL) of the mixed solution was stirred at 60°C for 3 hours under nitrogen atmosphere. After cooling to room temperature, ethyl acetate and water were added and partitioned. The obtained organic layer was washed with water and saturated brine, dried over sodium sulfate, and filtered. The filtrate was distilled off under reduced pressure, and the obtained residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1～3:7) to obtain the title compound (276 mg ). ESI-MS (m/z): 630 [M＋H] ⁺

[Production Example 7-3] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-N-(5-((5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chem35]

To 4-((6-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-diendoxy-1) described in Production Example 7-2 at 0°C ,2,3,4-tetrahydropyrimidine-5-carboxamido)pyridin-3-yl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid Trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl ester (276 mg, 0.438 mmol) in dichloromethane (6.0 mL), and stirred at room temperature for 2 hours. The reaction mixture was diluted with toluene, and distilled off under reduced pressure. The residue was diluted with ethyl acetate, saturated aqueous sodium bicarbonate, and water, and partitioned. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was distilled off under reduced pressure to obtain the title compound (210 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.47 (2H, q, J = 4.9 Hz), 0.72-0.78 (2H, m), 1.23-1.33 (1H, m), 2.83 (2H , t, J = 5.9 Hz), 3.22 (2H, t, J = 5.9 Hz), 3.82 (2H, d, J = 7.3 Hz), 4.04 (2H, s), 7.18-7.31 (4H, m), 7.55 (1H, dd, J = 9.3, 2.9 Hz), 8.17 (1H, d, J = 2.4 Hz), 8.35 (1H, d, J = 8.8 Hz), 8.49 (1H, s), 8.72 (1H, s) , 11.29 (1H, brs).

[Example 8] N-(4-((7-(tetrahydroazil-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)-2,5-difluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-difluorooxy-1,2,3,4 -tetrahydropyrimidine-5-formamide [Chem. 36]

4-(2,5-difluoro-4-(1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-diendoxyl) as described in Production Example 8-6 -1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4-nitro To a mixture of phenyl phenyl ester (28.7 mg, 0.04 mmol) and DMF (2 mL) was added N,N-diisopropylethylamine (0.015 mL, 0.086 mmol) and tetrahydroacridine (0.005 mL, 0.074 mmol) , stirred at room temperature for 67 hours and 50 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7: 3 to 1: 9) to obtain a crude product. Diethyl ether was added to the obtained crude product, followed by ultrasonic pulverization, and the solid was collected by filtration to obtain the title compound (11.9 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.46-1.52 (6H, m), 2.18-2.34 (2H, m), 2.44 (3H, s), 2.85-2.94 (2H, m) , 3.67 (2H, t, J = 5.8 Hz), 4.03-4.11 (4H, m), 4.51 (2H, s), 4.85-5.08 (1H, m), 7.01 (1H, dd, J = 10.4, 6.7 Hz ), 7.22-7.32 (1H, m), 7.75 (1H, dd, J = 8.0, 2.5 Hz), 8.48 (1H, dd, J = 11.9, 7.0 Hz), 8.51-8.57 (2H, m), 8.65 ( 1H, s), 11.08 (1H, d, J = 1.8 Hz). ESI-MS (m/z): 633.83 [M+H] ⁺ .

[Production Example 8-1] 4-Amino-2,5-difluorophenol mesylate [Chem. 37]

Add methanesulfonic acid (2.72 mL, 41.9 mmol), 10 % palladium-carbon (50% water-containing product) (1.36 g), stirred at room temperature under atmospheric pressure for 5.5 hours under hydrogen atmosphere. After setting the reaction mixture under a nitrogen atmosphere, it was filtered using celite, and the filtrate was concentrated under reduced pressure. Tertiary butyl methyl ether was added to the residue, and the precipitate was collected by filtration to obtain the title compound (9.89 g). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 2.33 (3H, s), 6.87 (1H, dd, J = 11.7, 7.8 Hz), 7.05 (1H, dd, J = 11.2, 7.8 Hz), 9.67-10.60 (1H, m).

[Production Example 8-2] 4-(4-Amino-2,5-difluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tris Grade butyl ester [Chem. 38]

Add 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (500 mg, 1.85 mmol ), 4-amino-2,5-difluorophenol mesylate (447 mg, 1.85 mmol) described in Production Example 8-1 in dimethylsulfoxide (15 mL) was added with tertiary butanol Potassium (458 mg, 4.08 mmol), and stirred for 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with water. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (458 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.49 (9H, s), 2.87 (2H, t, J = 5.6 Hz), 3.70-3.83 (4H, m), 4.61 (2H, s ), 6.60 (1H, dd, J = 11.0, 8.1 Hz), 6.88 (1H, dd, J = 10.7, 6.8 Hz), 8.53 (1H, s).

[Production Example 8-3] 1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5- Ethyl formate [Chem. 39]

3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester described in Production Example 1-6 ( 238 mg, 0.864 mmol) and DMF (1 mL) were added with 2-iodopropane (242 μL, 2.42 mmol) and potassium carbonate (334 mg, 2.42 mmol), and stirred at 70°C for 14 hours. After cooling the reaction mixture to room temperature, water was added and extracted 3 times with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered. The solvent was distilled off, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1 to 1:4) to obtain the title compound (207 mg). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 1.21 (3H, t, J = 5.0 Hz), 1.34 (6H, d, J = 6.7 Hz), 2.33 (3H, s), 4.18 (2H, q, J = 5.0 Hz), 4.58-4.71 (1H, m), 7.25-7.30 (1H, m), 7.71-7.78 (1H, m), 8.33-8.37 (1H, m), 8.43 ( 1H, s).

[Production Example 8-4] 1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5- Formic acid [Chem. 40]

1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine- Add water (190 μL, 10.5 mmol) to a mixture of ethyl 5-formate (207 mg, 0.653 mmol) and 4 M hydrogen chloride-1,4-dioxane solution (1.2 mL, 4.80 mmol), and stir at 70°C 19 hours and 30 minutes. After cooling the reaction mixture to room temperature, the solvent was distilled off. Tertiary butyl methyl ether was added to the obtained crude product, and the precipitate was collected by filtration to obtain the title compound (142 mg). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 1.35 (6H, d, J = 6.7 Hz), 2.33 (3H, s), 4.60-4.74 (1H, m), 7.32 (1H , d, J = 10 Hz), 7.74-7.81 (1H, m), 8.34-8.40 (1H, m), 8.54 (1H, s), 12.55 (1H, brs).

[Production Example 8-5] 4-(2,5-Difluoro-4-(1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester[ Chemical 41]

4-(4-Amino-2,5-difluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- as described in Production Example 8-2 Tertiary butyl formate (75 mg, 0.198 mmol), 1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (168 mg, 0.436 mmol), HATU (188 mg, 0.496 mmol) and DMF (2 mL) were added amine (0.104 mL, 0.595 mmol), stirred at room temperature for 16 hours and 30 minutes. The reaction was stirred at 60°C for 1 hour. The reaction was stirred at 70°C for 3 hours. After cooling the reaction mixture to room temperature, water was added, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:3) to obtain the title compound (52 mg). ESI-MS (m/z): 650.49 [M+H] ⁺ .

[Production Example 8-6] 4-(2,5-Difluoro-4-(1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4-nitrobenzene Ester [42]

4-(2,5-difluoro-4-(1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-diendoxyl) described in Production Example 8-5 -1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl Trifluoroacetic acid (1 mL) was added to a mixture of ester (52 mg, 0.08 mmol) and dichloromethane (3 mL), and stirred at room temperature for 30 minutes. Toluene (2 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the obtained residue, followed by extraction with dichloromethane. The organic layer was dried with magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure to obtain a crude product (45.7 mg). 4-Nitrophenyl chloroformate (15.4 mg, 0.076 mmol) and pyridine (0.012 mL, 0.153 mmol) were successively added to a mixture of a part of the obtained crude product (28 mg) and dichloromethane (2 mL), Stir at room temperature for 14 hours 10 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7:3 to 1:4) to obtain the title compound (28.7 mg). ESI-MS (m/z): 715.45 [M+H] ⁺ .

[Example 9] 1-cyclopentyl-N-(3-fluoro-4-((7-(1-methylpiperidin-4-yl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-Formamide [Chem. 43]

1-cyclopentyl-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) as described in Production Example 9-1 )oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.071 mmol ), 4-oxopiperidine-1-carboxylic acid tertiary butyl ester (28.4 mg, 0.143 mmol) and THF (3 mL) in the mixture of Tainijia sodium triacetyloxyborohydride (30.2 mg, 0.143 mmol ), stirred for 21 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate), whereby a crude product was obtained. Trifluoroacetic acid (550 μL) was added to a mixture of the obtained crude product and dichloromethane (2 mL), followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and toluene was added to the residue to carry out azeotropy. A 35-37% aqueous formaldehyde solution (11.6 mg) and sodium triacetyloxyborohydride (30.2 mg, 0.143 mmol) were added to a mixture of the obtained residue and THF (1 mL), followed by stirring for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1～0:1), and a mixture of ethyl acetate and n-heptane was added to the obtained solid, The precipitate was collected by filtration to obtain the title compound (17.5 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.64-2.06 (12H, m), 2.17-2.25 (2H, m), 2.28 (3H, s), 2.46-2.56 (1H, m) , 2.84-3.00 (6H, m), 3.80 (2H, s), 4.93-5.02 (1H, m), 7.11 (1H, t, J = 10.0 Hz), 7.22-7.25 (5H, m), 7.77-7.85 (1H, m), 8.46 (1H, s), 8.65 (1H, s), 10.87 (1H, s).

[Production Example 9-1] 1-cyclopentyl-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy Base) phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 44]

1-cyclopentyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (74.2 mg , 0.233 mmol), 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) as described in Production Example 1-4 - Add HATU (148 mg, 0.388 mmol) to a mixture of tertiary butyl formate (70 mg, 0.194 mmol), N,N-diisopropylethylamine (68 μL, 0.388 mmol) and DMF (5 mL) , and stirred for 6 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and then with saturated brine. After the organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. Trifluoroacetic acid (2 mL) was added to a mixture of the obtained crude product and dichloromethane (4 mL), followed by stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, added with saturated aqueous sodium bicarbonate, and extracted with dichloromethane. The obtained organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. A mixture of ethyl acetate and n-heptane was added to the residue, and the precipitate was collected by filtration to obtain the title compound (90.5 mg). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 1.52-1.66 (2H, m), 1.72-1.90 (4H, m), 1.93-2.09 (2H, m), 2.65 (2H, t, J = 5.0 Hz), 2.98 (2H, t, J = 5.5 Hz), 3.78 (2H, s), 4.74-4.87 (1H, m), 7.23-7.36 (3H, m), 7.36-7.44 (3H , m), 7.82-7.90 (1H, m), 8.39 (1H, s), 8.58 (1H, s), 10.94 (1H, s).

[Example 10] N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)acetyl)-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3 ,4-tetrahydropyrimidine-5-formamide [Chem. 45]

4-(2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-di Oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl )-2-oxoethyl)piperidine-1-carboxylic acid tert-butyl ester (52.9 mg, 0.07 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), stirred at room temperature 1.5 hours. The reaction solution was concentrated under reduced pressure. A 35-37% aqueous formaldehyde solution (0.037 mL) and sodium triacetyloxyborohydride (21.2 mg, 0.10 mmol) were added to a solution of the residue and THF (2 mL), and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (14.7 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.26-1.40 (2H, m), 1.49 (6H, d, J = 6.7 Hz), 1.77 (2H, t, J = 14.7 Hz), 1.81-1.90 (1H, m), 1.91-2.00 (2H, m), 2.25 (3H, d, J = 6.1 Hz), 2.35 (2H, dd, J = 12.8, 6.7 Hz), 2.82 (2H, t, J = 11.6 Hz), 2.89 (1H, t, J = 5.8 Hz), 2.94 (1H, t, J = 5.8 Hz), 3.79 (1H, t, J = 5.8 Hz), 3.94 (1H, t, J = 6.1 Hz), 4.64 (1H, s), 4.80 (1H, s), 4.89-5.03 (1H, m), 7.08-7.18 (1H, m), 7.21-7.30 (5H, m), 7.84 (1H, dd , J = 12.2, 2.4 Hz), 8.53 (1H, d, J = 8.0 Hz), 8.67 (1H, s), 10.91 (1H, s). ESI-MS (m/z): 674.55 [M+H] ⁺ .

[Production Example 10-1] 4-(2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1, 2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-oxo Ethyl) piperidine-1-carboxylic acid tertiary butyl ester [Chem. 46]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (50 mg, 0.094 mmol ), 2-(1-((tertiary butoxy)carbonyl)piperidin-4-yl)acetic acid (29.6 mg, 0.122 mmol), N,N-diisopropylethylamine (0.032 mL, 0.187 mmol ), HATU (53.4 mg, 0.14 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (52.9 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.08-1.22 (2H, m), 1.44 (9H, s), 1.48 (6H, d, J = 6.7 Hz), 1.74 (2H, t , J = 14.4 Hz), 1.98-2.11 (1H, m), 2.30-2.39 (2H, m), 2.66-2.77 (2H, m), 2.91 (1H, t, J = 5.8 Hz), 2.93-2.98 ( 1H, m), 3.79 (1H, t, J = 5.8 Hz), 3.94 (1H, t, J = 5.8 Hz), 3.97-4.20 (2H, m), 4.64 (1H, s), 4.80 (1H, s ), 4.90-5.05 (1H, m), 7.13 (1H, t, J = 8.6 Hz), 7.21-7.31 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.53 (1H, d, J = 8.0 Hz), 8.66 (1H, s), 10.91 (1H, s).

[Example 11] N-(4-((7-(2-(tetrahydroacri-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2 ,3,4-tetrahydropyrimidine-5-formamide [Chem. 47]

To 2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxyl) described in Production Example 11-1 at 0°C -1,2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)acetic acid tris Trifluoroacetic acid (2 mL) was added to a solution of butyl ester (55.6 mg, 0.086 mmol) in dichloromethane (3 mL), and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain a residue (60 mg). Part of the residue (25 mg), tetrahydroacridine (4.27 μL, 0.063 mmol), N,N-diisopropylethylamine (0.022 mL, 0.127 mmol), HATU (24.1 mg, 0.063 mmol) in DMF (2 mL) solution was stirred overnight at room temperature. Water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (20.5 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 7.3 Hz), 2.29 (2H, quin, J = 7.6 Hz), 2.88-2.96 (4H, m), 3.25 (2H, s), 3.74 (2H, s), 4.02-4.09 (2H, m), 4.24 (2H, t, J = 7.6 Hz), 4.90-5.00 (1H, m), 7.10-7.17 (1H, m), 7.22-7.29 (5H, m), 7.82 (1H, dd, J = 12.2, 2.5 Hz), 8.47 (1H, s), 8.66 (1H, s), 10.88 (1H, s). ESI-MS (m/z): 632.49 [M+H] ⁺ .

[Production Example 11-1] 2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3 ,4-tetrahydropyrimidin-5-formamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)acetic acid tertiary butyl ester [Chem. 48 ]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (100 mg, 0.187 mmol ), tertiary butyl bromoacetate (0.032 mL, 0.215 mmol) in DMF (3 mL) was stirred overnight at room temperature. Water and a saturated aqueous sodium bicarbonate solution were added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (55.6 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.43-1.52 (15H, m), 2.89-3.04 (4H, m), 3.38 (2H, s), 3.84 (2H, s), 4.90 -5.01 (1H, m), 7.13 (1H, t, J = 8.6 Hz), 7.22-7.30 (5H, m), 7.82 (1H, dd, J = 11.9, 2.1 Hz), 8.47 (1H, s), 8.67 (1H, s), 10.88 (1H, brs).

[Example 12] N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl) ethyl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide [Chem. 49]

4-(2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy- 1,2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethyl) To a solution of tert-butyl piperidine-1-carboxylate (948 mg, 1.27 mmol) in dichloromethane (9 mL) was added trifluoroacetic acid (3 mL). Thereafter, it was stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. To a THF (20 mL) solution of the residue were added 35-37% aqueous formaldehyde (0.938 mL) and sodium triacetyloxyborohydride (404 mg, 1.91 mmol), and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (353 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.28-1.38 (3H, m), 1.48 (6H, d, J = 7.3 Hz), 1.52-1.58 (2H, m), 1.66-1.71 (2H, m), 1.90 (2H, t, J = 10.7 Hz), 2.25 (3H, s), 2.56-2.62 (2H, m), 2.77-2.86 (4H, m), 2.88-2.94 (2H, m ), 3.64 (2H, s), 4.92-5.00 (1H, m), 7.12 (1H, t, J = 8.6 Hz), 7.17-7.29 (5H, m), 7.82 (1H, dd, J = 11.6, 2.5 Hz), 8.47 (1H, s), 8.66 (1H, s), 10.88 (1H, s). ESI-MS (m/z): 660.45 [M+H] ⁺ .

[Production Example 12-1] 4-(2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1, 2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethyl)piperidine -1-Tertiary butyl carboxylate [Chemical 50]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (700 mg, 1.31 mmol ), tertiary butyl 4-(2-oxoethyl)piperidine-1-carboxylate (400 mg, 1.76 mmol), sodium triacetyloxyborohydride (555 mg, 2.62 mmol) in THF (20 mL ) solution was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (948 mg). ESI-MS (m/z): 746.52 [M+H] ⁺ .

[Example 13] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-((1-methylpiperidin-4-yl)methyl) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-formamide [Chem. 51]

4-((4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1, 2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl)piperidine - Trifluoroacetic acid (8 mL) was added to a mixture of tertiary-butyl 1-carboxylate (1.19 g, 1.64 mmol) and dichloromethane (25 mL), and stirred at room temperature for 15 minutes. Toluene (25 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Toluene (25 mL) was added to the obtained residue, and the solvent was distilled off under reduced pressure. To a mixture of the obtained residue and THF (25 mL), 35-37% formaldehyde aqueous solution (0.452 mL) and sodium triacetyloxyborohydride (1.04 g, 4.91 mmol) were sequentially added, and stirred at room temperature for 28 minutes . Add 35-37% formaldehyde aqueous solution (0.770 mL) to the reaction solution, and stir at room temperature for 25 minutes. Sodium triacetyloxyborohydride (0.340 g, 1.60 mmol) was added to the reaction liquid, followed by stirring at room temperature for 25 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography to obtain the title compound (870 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.47 (2H, d, J = 4.3 Hz), 0.74 (2H, d, J = 8.0 Hz), 1.16-1.44 (3H, m), 1.52-2.09 (5H, m), 2.28 (3H, s), 2.42 (2H, d, J = 7.3 Hz), 2.78 (2H, d, J = 5.5 Hz), 2.87 (4H, d, J = 6.1 Hz ), 3.61 (2H, s), 3.81 (2H, d, J = 7.3 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.26 (4H, brs), 7.71 (2H, d, J = 9.2 Hz ), 8.49 (1H, s), 8.73 (1H, s), 10.81 (1H, s). ESI-MS (m/z): 640.53 [M+H] ⁺ .

[Production Example 13-1] 4-((4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2, 3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl)piperidine-1 - Tertiary butyl formate [Chem. 52]

1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-N-(4-((5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (972 mg, 1.84 mmol ) and THF (30 mL) were ultrasonically pulverized, and tertiary butyl 4-formylpiperidine-1-carboxylate (784 mg, 3.68 mmol) and sodium triacetyloxyborohydride (1.17 g, 5.52 mmol), stirred at room temperature for 25 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-0:1) to obtain the title compound (1.19 g). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.40-0.54 (2H, m), 0.69-0.79 (2H, m), 1.04-1.22 (2H, m), 1.23-1.37 (1H, m), 1.46 (9H, s), 1.73-1.83 (3H, m), 2.42 (2H, d, J = 6.7 Hz), 2.60-2.76 (2H, m), 2.76-2.82 (2H, m), 2.82 -2.92 (2H, m), 3.62 (2H, s), 3.81 (2H, d, J = 7.3 Hz), 3.93-4.40 (2H, m), 7.05-7.15 (2H, m), 7.20-7.32 (4H , m), 7.66-7.76 (2H, m), 8.49 (1H, s), 8.73 (1H, s), 10.81 (1H, s). ESI-MS (m/z): 726.67 [M+H] ⁺ .

[Example 14] 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d] Pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-formamide [53]

1-(cyclopropylmethyl)-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 5-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (10 mg, 0.018 mmol) in THF (2 mL) and acetic acid (0.1 mL) solution, add 35-37% formaldehyde aqueous solution (14.9 mg) and sodium triacetyloxyborohydride (5.82 mg, 0.027 mmol), at room temperature Stirring was continued for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (9 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.43-0.50 (2H, m), 0.68-0.78 (2H, m), 1.23-1.35 (1H, m), 2.50 (3H, s) , 2.74-2.81 (2H, m), 2.90-2.96 (2H, m), 3.61 (2H, s), 3.81 (2H, d, J = 7.3 Hz), 7.08-7.19 (1H, m), 7.20-7.29 (5H, m), 7.77-7.89 (1H, m), 8.47 (1H, s), 8.71 (1H, s), 10.87 (1H, s). ESI-MS (m/z): 561.36 [M+H] ⁺ .

[Example 15] 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide [Chem. 54]

To 4-((4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxygen) described in Production Example 15-1 at room temperature Base-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (20 mg, 0.027 mmol) in dichloromethane (2 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. THF (2 mL), 35-37% aqueous formaldehyde (21.8 mg), and sodium triacetyloxyborohydride (11.4 mg, 0.054 mmol) were added to the residue, followed by stirring at room temperature for 1 hour and 5 minutes. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (12 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.41-0.51 (2H, m), 0.68-0.79 (2H, m), 1.20-1.35 (4H, m), 1.74-1.83 (2H, m), 1.87-1.99 (2H, m), 2.27 (3H, s), 2.38-2.45 (2H, m), 2.73-2.81 (2H, m), 2.83-2.94 (4H, m), 3.61 (2H, s), 3.77-3.84 (2H, m), 7.08-7.18 (1H, m), 7.18-7.33 (5H, m), 7.79-7.86 (1H, m), 8.46 (1H, s), 8.71 (1H, s), 10.87 (1H, s). ESI-MS (m/z): 658.58 [M+H] ⁺ .

[Production Example 15-1] 4-((4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl) tertiary butyl piperidine-1-carboxylate [Chem. 55]

1-(cyclopropylmethyl)-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 5-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.027 mmol) in THF (2 mL) and acetic acid (0.1 mL) were added tertiary butyl 4-formylpiperidine-1-carboxylate (7.61 mg, 0.036 mmol) and triacetyloxyhydroboration Sodium (8.73 mg, 0.041 mmol), stirred at room temperature for 21 hours and 20 minutes. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (20 mg). ESI-MS (m/z): 744.58 [M+H] ⁺ .

[Example 16] N-(4-((7-(2-(tetrahydroacri-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy -1,2,3,4-tetrahydropyrimidine-5-formamide [Chem. 56]

To 2-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-diendoxyl) described in Production Example 16-1 at room temperature -1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl acetate (11 mg, 0.017 mmol) in dichloromethane (2 mL), and stirred at room temperature for 6 hours and 50 minutes. The reaction mixture was concentrated under reduced pressure. DMF (2 mL), N,N-diisopropylethylamine (0.029 mL, 0.166 mmol), tetrahydroacridine (1.90 mg, 0.033 mmol), HATU (8.23 mg, 0.022 mmol) were added to the residue, Stir at room temperature for 15 hours and 15 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (6 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.42-0.49 (2H, m), 0.69-0.77 (2H, m), 1.23-1.33 (1H, m), 2.23-2.35 (2H, m), 2.86-2.98 (4H, m), 3.25 (2H, s), 3.75 (2H, s), 3.81 (2H, d, J = 7.3 Hz), 4.04-4.11 (2H, m), 4.21-4.30 (2H, m), 7.08-7.16 (1H, m), 7.23-7.26 (5H, m), 7.78-7.88 (1H, m), 8.47 (1H, s), 8.71 (1H, s), 10.87 (1H , s). ESI-MS (m/z): 644.34 [M+H] ⁺ .

[Production Example 16-1] 2-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3 ,4-tetrahydropyrimidin-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)acetic acid tertiary butyl Ester [Chem. 57]

1-(cyclopropylmethyl)-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 5-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.027 mmol) in DMF (2 mL) was added tert-butyl bromoacetate (6.96 mg, 0.036 mmol), and stirred at room temperature for 47 hours and 45 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (11 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.42-0.50 (2H, m), 0.69-0.78 (2H, m), 1.18-1.33 (1H, m), 1.49 (9H, s) , 2.90-3.03 (4H, m), 3.38 (2H, s), 3.78-3.89 (4H, m), 7.09-7.18 (1H, m), 7.18-7.35 (5H, m), 7.76-7.87 (1H, m), 8.47 (1H, s), 8.71 (1H, s), 10.87 (1H, brs). ESI-MS (m/z): 661.51 [M+H] ⁺ .

[Example 17] N-(4-((7-(1-ethyltetrahydroazil-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine- 4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydro Pyrimidine-5-formamide [Chemical 58]

N-(4-((7-(tetrahydroazil-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine- 4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro Add acetaldehyde (155 mg, 3.00 mmol) and sodium triacetyloxyborohydride (793 mg, 3.74 mmol) to a mixture of pyrimidine-5-carboxamide (883 mg, 1.50 mmol) and THF (50 mL), Stir for 1 hour and 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1:1 to 3:7) to obtain a crude product. A mixture of ethyl acetate and n-heptane was added to the obtained crude product, and the precipitate was collected by filtration to obtain the title compound (538 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.98 (3H, t, J = 7.3 Hz), 1.48 (6H, d, J = 6.7 Hz), 2.50 (2H, q, J = 7.3 Hz), 2.67 (2H, t, J = 5.0 Hz), 2.86-2.93 (4H, m), 3.17-3.24 (1H, m), 3.52 (2H, s), 3.62 (2H, t, J = 5.0 Hz ), 4.90-5.00 (1H, m), 7.11 (1H, t, J = 5.0 Hz), 7.22-7.26 (5H, m), 7.79-7.85 (1H, m), 8.47 (1H, s), 8.66 ( 1H, s), 10.89 (1H, s).

[Production Example 17-1] N-(4-((7-(tetrahydroazan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- Base) oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-Formamide [Chemical 59]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (428 mg, 0.80 mmol ) and dichloromethane (30 mL) was added tertiary-butyl 3-oxotetrahydroazia-1-carboxylate (274 mg, 1.60 mmol), and stirred for 1 hour. Sodium triacetyloxyborohydride (509 mg, 2.40 mmol) was added to the reaction mixture, followed by stirring at room temperature for 15 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1) to obtain a crude product. Trifluoroacetic acid (5 mL) was added to a mixture of the obtained crude product and dichloromethane (20 mL), followed by stirring for 6 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, and saturated aqueous sodium bicarbonate was added. The reaction mixture was extracted with dichloromethane and concentrated under reduced pressure. A mixture of ethyl acetate and n-heptane was added to the obtained crude product, and the precipitate was collected by filtration to obtain the title compound (422 mg). ESI-MS (m/z): 590.45 [M+H] ⁺ .

[Example 18] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methyltetrahydroazin-3-yl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydro Pyrimidine-5-formamide [Chemical 60]

3-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-diendoxy-1,2) described in Production Example 18-1 ,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)tetrahydroazepine-1 - Add trifluoroacetic acid (1.5 mL) to a solution of tert-butyl formate (15 mg, 0.022 mmol) in dichloromethane (4.5 mL), and stir at room temperature for 1 hour. Toluene was added to the reaction solution for dilution, followed by concentration under reduced pressure. THF (3 mL), 35-37% aqueous formaldehyde solution (0.017 mL), and sodium triacetyloxyborohydride (6.97 mg, 0.033 mmol) were added to the residue, followed by stirring at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (3.54 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.42-0.48 (2H, m), 0.69-0.76 (2H, m), 1.23-1.32 (1H, m), 2.37 (3H, s) , 2.66 (2H, t, J = 6.1 Hz), 2.88 (2H, t, J = 5.8 Hz), 2.92-2.98 (2H, m), 3.13-3.21 (1H, m), 3.50 (2H, s), 3.60-3.65 (2H, m), 3.80 (2H, d, J = 7.3 Hz), 7.08 (2H, d, J = 9.2 Hz), 7.20-7.31 (4H, m), 7.70 (2H, d, J = 9.2 Hz), 8.48 (1H, s), 8.71 (1H, s), 10.80 (1H, s). ESI-MS (m/z): 598.40 [M+H] ⁺ .

[Production Example 18-1] 3-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3 ,4-tetrahydropyrimidin-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)tetrahydroazia-1-carboxylic acid Tertiary butyl ester [Chemical 61]

1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-N-(4-((5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.26 g, 2.38 mmol ), tert-butyl 3-oxotetrahydroazia-1-carboxylate (612 mg, 3.58 mmol) in dichloromethane (20 mL) was stirred at room temperature for 2 hours. Thereafter, sodium triacetyloxyborohydride (758 mg, 3.58 mmol) was added, and the reaction solution was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1~1:1~1:2) to obtain the title compound quantitatively. ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.42-0.48 (2H, m), 0.69-0.76 (2H, m), 1.24-1.32 (1H, m), 1.43 (9H, s) , 2.72 (2H, brs), 2.90 (2H, t, J = 5.8 Hz), 3.30-3.38 (1H, m), 3.56 (2H, s), 3.80 (2H, d, J = 7.3 Hz), 3.90 ( 2H, dd, J = 8.9, 5.2 Hz), 4.03 (2H, dd, J = 8.6, 7.3 Hz), 7.09 (2H, d, J = 9.2 Hz), 7.22-7.29 (4H, m), 7.70 (2H , d, J = 9.2 Hz), 8.49 (1H, s), 8.72 (1H, s), 10.80 (1H, s). ESI-MS (m/z): 684.60 [M+H] ⁺ .

[Example 19] 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-(1-methyltetrahydroazin-3-yl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- Formamide [Chemical 62]

3-(4-(4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4) described in Production Example 19-3 -tetrahydropyrimidin-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)tetrahydroacridine-1-carboxylic acid tertiary To a solution of butyl ester (1.64 g, 2.44 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (4.5 mL). Thereafter, it was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added, extracted with dichloromethane, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. THF (20 mL) was added to the residue, followed by 35-37% formaldehyde aqueous solution (0.571 mL) and sodium triacetyloxyborohydride (776 mg, 3.66 mmol), and stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 ~ 1: 5 ~ 0: 1 ~ methanol: ethyl acetate = 1: 10) Purification gave the title compound (831 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.7 Hz), 2.37 (3H, s), 2.66 (2H, t, J = 5.8 Hz), 2.88 ( 2H, t, J = 5.8 Hz), 2.96 (2H, t, J = 7.0 Hz), 3.12-3.22 (1H, m), 3.50 (2H, s), 3.60-3.67 (2H, m), 4.95 (1H , sep, J = 6.7 Hz), 7.04-7.12 (2H, m), 7.21-7.29 (4H, m), 7.65-7.72 (2H, m), 8.48 (1H, s), 8.67 (1H, s), 10.81 (1H, s). ESI-MS (m/z): 586.49 [M+H] ⁺ .

[Production Example 19-1] 4-(4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine- 5-formamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 63]

4-(4-aminophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-formic acid tertiary butyl ester (3 g, 8.76 mmol), 3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5 described in WO 2013074633 A1 -Formic acid (2.94 g, 10.1 mmol), N,N-diisopropylethylamine (2.24 mL, 13.1 mmol), HATU (4.00 g, 10.5 mmol) in DMF (50 mL) was stirred at 70°C for 40 minute. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=10:1～3:1～1:1) to obtain the title compound (5.3 g) . ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.46-1.51 (15H, m), 2.81-2.91 (2H, m), 3.74 (2H, t, J = 5.5 Hz), 4.60 (2H , s), 4.89-5.01 (1H, m), 7.07-7.12 (2H, m), 7.22-7.27 (4H, m), 7.71 (2H, d, J = 8.6 Hz), 8.52 (1H, s), 8.67 (1H, s), 10.82 (1H, s).

[Production Example 19-2] 3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-N-(4-((5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 64]

4-(4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydro as described in Production Example 19-1 Dichloropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate tertiary butyl ester (5.3 g, 8.60 mmol) To the solution in methane (15 mL) was added trifluoroacetic acid (9 mL). Thereafter, it was stirred at room temperature for 1.5 hours. Toluene (15 mL) was added to the reaction mixture, and concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (4.4 g). ESI-MS (m/z): 517.47 [M+H] ⁺ .

[Production Example 19-3] 3-(4-(4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetra Hydropyrimidin-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)tetrahydroazia-1-carboxylic acid tertiary butyl ester [chem 65]

3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-N-(4-((5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1.3 g, 2.52 mmol), 3- A solution of tert-butyl-oxytetrahydroacridine-1-carboxylate (646 mg, 3.78 mmol) in dichloromethane (15 mL) was stirred at room temperature for 1 hour. Thereafter, sodium triacetyloxyborohydride (800 mg, 3.78 mmol) was added, and the reaction solution was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=5:1～1:1～1:2) to obtain the title compound (1.64 g) . ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.40-1.44 (9H, m), 1.47-1.52 (6H, m), 2.64-2.78 (2H, m), 2.86-2.94 (2H, m), 3.28-3.39 (1H, m), 3.56 (2H, s), 3.90 (2H, dd, J = 8.8, 5.4 Hz), 4.03 (2H, dd, J = 8.8, 7.3 Hz), 4.89-5.00 (1H, m), 7.09 (2H, d, J = 8.8 Hz), 7.18-7.26 (4H, m), 7.70 (2H, d, J = 8.8 Hz), 8.49 (1H, s), 8.67 (1H, s), 10.82 (1H, s). ESI-MS (m/z): 672.55 [M+H] ⁺ .

[Example 20] 1-(cyclopropylmethyl)-N-(2-fluoro-4-((7-(1-methyltetrahydroazin-3-yl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1, 2,3,4-tetrahydropyrimidine-5-carboxamide [Chem. 66]

3-(4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-diendoxyl) described in Production Example 20-5 -1,2,3,4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- Add trifluoroacetic acid (800 μL) to a mixture of tertiary-butyl tetrahydroacridine-1-carboxylate (13.1 mg, 0.019 mmol) and dichloromethane (2.5 mL), and stir at room temperature for 3 hours and 45 minutes . Toluene (2 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. To a mixture of the obtained residue and THF (2 mL), 35-37% formaldehyde aqueous solution (5.16 μL) and sodium triacetyloxyborohydride (5.96 mg, 0.028 mmol) were sequentially added, and stirred at room temperature for 2 hours 40 minutes. Saturated aqueous sodium bicarbonate solution and water were added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 ~ 0: 1 ~ methanol: ethyl acetate = 1: 9), diethyl ether was added to the obtained residue, Sonication was performed, and the solid was collected by filtration to obtain the title compound (5.01 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.42-0.54 (2H, m), 0.68-0.80 (2H, m), 1.21-1.37 (1H, m), 2.43 (6H, d, J = 9.8 Hz), 2.67 (2H, t, J = 5.8 Hz), 2.88 (2H, t, J = 5.8 Hz), 3.03 (2H, t, J = 7.0 Hz), 3.23 (1H, quin, J = 6.4 Hz), 3.47-3.59 (2H, m), 3.71 (2H, t, J = 6.7 Hz), 3.75-3.88 (2H, m), 6.87-7.02 (2H, m), 7.21-7.32 (1H, m ), 7.75 (1H, dd, J = 8.0, 2.5 Hz), 8.44-8.61 (3H, m), 8.71 (1H, s), 10.96 (1H, d, J = 2.5 Hz). ESI-MS (m/z): 613.49 [M+H] ⁺ .

[Production Example 20-1] 1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydro Ethyl pyrimidine-5-carboxylate [Chem. 67]

3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester described in Production Example 1-6 ( Bromomethylcyclopropane (1.4 mL, 14.4 mmol) was added to a mixture of 1.5 g, 5.45 mmol), potassium carbonate (1.88 g, 13.6 mmol) and DMF (15 mL), and stirred at 70°C for 24 hours. After cooling the reaction liquid to room temperature, it was filtered, the solid was washed with ethyl acetate, and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:1-1:1) to obtain the title compound (1.15 g). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.42 (2H, d, J = 4.9 Hz), 0.65-0.78 (2H, m), 1.13-1.30 (1H, m), 1.35 (3H , t, J = 7.0 Hz), 2.40 (3H, s), 3.63-3.83 (2H, m), 4.34 (2H, q, J = 6.7 Hz), 7.19 (1H, d, J = 8.0 Hz), 7.62 -7.74 (1H, m), 8.42 (1H, s), 8.47 (1H, s).

[Production Example 20-2] 1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4-tetrahydro Pyrimidine-5-carboxylic acid [Chemical 68]

The 1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4- A mixture of ethyl tetrahydropyrimidine-5-carboxylate (1.15 g, 3.49 mmol), 4 M hydrogen chloride-1,4-dioxane solution (5 mL) and water (1 mL) was stirred at 70°C for 14 hours and 50 minutes . Add 4 M hydrogen chloride-1,4-dioxane solution (1 mL) to the reaction solution, and stir at 70°C for 30 minutes. After air-cooling the reaction liquid, the solvent was distilled off under reduced pressure. Water was added to the residue, and extracted 4 times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain the title compound (1.33 g). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 0.35-0.44 (2H, m), 0.47-0.63 (2H, m), 1.13-1.33 (1H, m), 2.37 (3H, s), 3.79 (2H, d, J = 7.3 Hz), 7.33-7.40 (1H, m), 7.74-7.87 (1H, m), 8.34-8.48 (1H, m), 8.82 (1H, s). ESI-MS (m/z): 302.20 [M+H] ⁺ .

[Production Example 20-3] tertiary butyl 4-(4-amino-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate [chem 69]

Potassium tertiary butoxide (7 g, 62.4 mmol) was added to a mixture of 4-amino-3-fluorophenol (4.5 g, 35.4 mmol) and DMF (150 mL), and cooled to 0°C. To this mixture was added tertiary butyl 4-chloro-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (8 g, 29.7 mmol ), and stirred at room temperature for 1 hour. Water was added to the reaction liquid, and extracted three times with ethyl acetate. The combined organic layers were washed with 5% brine, dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:1) to obtain the title compound (4.26 g). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.50 (9H, s), 2.79-2.91 (2H, m), 3.68-3.78 (4H, m), 4.61 (2H, s), 6.73 -6.88 (3H, m), 8.54 (1H, s). ESI-MS (m/z): 361.24 [M+H] ⁺ .

[Production Example 20-4] 4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [chem 70]

The third grade of 4-(4-amino-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid described in Production Example 20-3 Butyl ester (50 mg, 0.139 mmol), 1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy as described in Production Example 20-2 -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (62.7 mg, 0.166 mmol), HATU (68.6 mg, 0.18 mmol) and DMF (1 mL) in the Ethylamine (0.073 mL, 0.416 mmol), stirred at room temperature for 51 hours and 10 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7:3 to 1:4) to obtain the title compound (89.4 mg). ESI-MS (m/z): 644.46 [M+H] ⁺ .

[Production Example 20-5] 3-(4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1 ,2,3,4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl) Tertiary butyl tetrahydroacridine-1-carboxylate [Chem. 71]

4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1, as described in Production Example 20-4, 2,3,4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary Trifluoroacetic acid (0.660 mL) was added to a mixture of butyl ester (89.4 mg, 0.139 mmol) and dichloromethane (2 mL), and stirred at room temperature for 30 minutes. Toluene (2 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the obtained residue, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product (80 mg). To a mixture of a portion of the obtained crude product (10 mg) and dichloromethane (2 mL) was added successively tertiary butyl 3-oxotetrahydroazine-1-carboxylate (15.8 mg, 0.092 mmol) and Acetic acid (5 μL), stirred at room temperature for 14 hours. Sodium triacetyloxyborohydride (5.85 mg, 0.028 mmol) was added to the mixture, followed by stirring at room temperature for 1 hour and 15 minutes. To this mixture was added tertiary-butyl 3-oxotetrahydroazepine-1-carboxylate (15.8 mg, 0.092 mmol), followed by stirring at room temperature for 1 hour and 15 minutes. Sodium triacetyloxyborohydride (5.85 mg, 0.028 mmol) was added to the mixture, followed by stirring at room temperature for 3 hours and 45 minutes. Sodium triacetoxyborohydride was continuously added to the mixture at room temperature over 15 minutes until disappearance of starting material was confirmed by TLC. Saturated aqueous sodium bicarbonate solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (13.1 mg). ESI-MS (m/z): 699.71 [M+H] ⁺ .

[Example 21] 1-cyclopentyl-3-(4-fluorophenyl)-N-(4-((7-(1-methyltetrahydroazin-3-yl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- Formamide [Chem. 72]

1-cyclopentyl-3-(4-fluorophenyl)-2,4-dipentoxy-N-(4-((5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.074 mmol), 3- Sodium triacetyloxyborohydride (31.3 mg, 0.147 mmol) was added to a mixture of tertiary butyl tetrahydroazine-1-carboxylate (25.2 mg, 0.147 mmol) and dichloromethane (4 mL), and stirred for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. Trifluoroacetic acid (1 mL) was added to a mixture of the obtained crude product and dichloromethane (5 mL), followed by stirring for 30 minutes. The reaction mixture was concentrated under reduced pressure, and toluene was added to the residue to carry out azeotropy. A 35-37% aqueous formaldehyde solution (12.0 mg) and sodium triacetyloxyborohydride (31.3 mg, 0.147 mmol) were added to a mixture of the obtained residue and THF (5 mL), and stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1:1 to 0:1) to obtain the title compound (12.6 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.71-1.86 (4H, m), 1.89-1.98 (2H, m), 2.17-2.30 (2H, m), 2.37 (3H, s) , 2.66 (2H, t, J = 6.1 Hz), 2.88 (2H, t, J = 5.8 Hz), 2.96 (2H, t, J = 7.0 Hz), 3.17 (1H, quin, J = 5.0 Hz), 3.50 (2H, s), 3.63 (2H, t, J = 7.0 Hz), 4.93-5.04 (1H, m), 7.07 (2H, d, J = 8.0 Hz), 7.22-7.26 (4H, m), 7.69 ( 2H, d, J = 8.0 Hz), 8.48 (1H, s), 8.66 (1H, s), 10.81 (1H, s). ESI-MS (m/z): 612.44 [M+H] ⁺ .

[Production Example 21-1] 1-cyclopentyl-3-(4-fluorophenyl)-2,4-dioxo-N-(4-((5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 73]

1-cyclopentyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (223 mg , 0.701 mmol), 4-(4-aminophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary Add HATU (444 mg, 1.17 mmol) to a mixture of butyl ester (200 mg, 0.584 mmol), N,N-diisopropylethylamine (204 μL, 1.17 mmol) and DMF (10 mL), and stir for 2 hour and 30 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with water and then with saturated brine. After the organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. Trifluoroacetic acid (3 mL) was added to a mixture of the obtained crude product and dichloromethane (10 mL), followed by stirring for 2 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, and saturated aqueous sodium bicarbonate was added. The reaction mixture was extracted with dichloromethane, the organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Tertiary butyl methyl ether was added to the residue, and the precipitate was collected by filtration to obtain the title compound (304 mg). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 1.57-1.66 (2H, m), 1.72-1.88 (4H, m), 1.99-2.09 (2H, m), 2.63 (2H, t, J = 5.0 Hz), 2.96 (2H, t, J = 5.8 Hz), 3.76 (2H, s), 4.77-4.86 (1H, m), 7.12 (2H, d, J = 8.2 Hz), 7.31 ( 2H, t, J = 5.0 Hz), 7.36-7.42 (2H, m), 7.67 (2H, d, J = 8.1 Hz), 8.37 (1H, s), 8.57 (1H, s), 10.83 (1H, s ).

[Example 22] N-(3-fluoro-4-((7-(3-(pyrrolidin-1-yl)propionyl)-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetra Hydropyrimidine-5-formamide [Chem. 74]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (30 mg, 0.056 mmol ), 3-pyrrolidin-1-yl-propionic acid (12.1 mg, 0.084 mmol), N,N-diisopropylethylamine (0.019 mL, 0.112 mmol), HATU (32.0 mg, 0.084 mmol) in DMF (2 mL) and the solution was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (25.8 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.7 Hz), 1.70-1.83 (4H, m), 2.48-2.61 (4H, m), 2.63-2.74 (2H, m), 2.78-2.91 (3H, m), 2.95 (1H, t, J = 5.2 Hz), 3.80 (1H, t, J = 5.8 Hz), 3.93 (1H, t, J = 5.8 Hz) , 4.66 (1H, s), 4.79 (1H, s), 4.90-5.00 (1H, m), 7.09-7.16 (1H, m), 7.22-7.30 (5H, m), 7.83 (1H, dd, J = 11.6, 2.5 Hz), 8.52 (1H, d, J = 4.3 Hz), 8.66 (1H, s), 10.90 (1H, s). ESI-MS (m/z): 660.53 [M+H] ⁺ .

[Example 23] (S)-N-(3-fluoro-4-((7-(2-(1-methylpyrrolidin-2-yl)acetyl)-5,6,7,8- Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidine-5-formamide [Chem. 75]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20 mg, 0.037 mmol ), 2-((2S)-1-methylpyrrolidin-2-yl)acetic acid (6.96 mg, 0.049 mmol), N,N-diisopropylethylamine (0.013 mL, 0.075 mmol), HATU ( 21.3 mg, 0.056 mmol) in DMF (2 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (4.41 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.41-1.56 (8H, m), 2.12-2.31 (2H, m), 2.32-2.48 (5H, m), 2.66-2.86 (2H, m), 2.87-2.98 (2H, m), 3.00-3.13 (1H, m), 3.74-4.03 (2H, m), 4.63-4.87 (2H, m), 4.89-5.02 (1H, m), 7.13 ( 1H, t, J = 8.6 Hz), 7.21-7.27 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.53 (1H, d, J = 4.3 Hz), 8.67 (1H, s ), 10.90 (1H, s).

[Example 24] N-(3-fluoro-4-((7-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2, 3,4-tetrahydropyrimidine-5-carboxamide [Chem. 76]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20 mg, 0.037 mmol ), tetrahydropyranyl-4-acetic acid (7.01 mg, 0.049 mmol), N,N-diisopropylethylamine (0.013 mL, 0.075 mmol), HATU (21.3 mg, 0.056 mmol) in DMF (2 mL) solution was stirred at room temperature for 3 days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (20.0 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.28-1.41 (2H, m), 1.48 (6H, d, J = 6.7 Hz), 1.61-1.77 (2H, m), 2.06-2.21 (1H, m), 2.30-2.40 (2H, m), 2.85-2.97 (2H, m), 3.35-3.48 (2H, m), 3.75-3.83 (1H, m), 3.88-3.98 (3H, m) , 4.65 (1H, s), 4.79 (1H, s), 4.90-5.00 (1H, m), 7.13 (1H, t, J = 8.6 Hz), 7.20-7.29 (5H, m), 7.83 (1H, dd , J = 12.2, 2.5 Hz), 8.52 (1H, d, J = 6.1 Hz), 8.66 (1H, s), 10.91 (1H, s).

[Example 25] N-(3-fluoro-4-((7-(2-(4-methylpiperone-1-yl)-2-oxoethyl)-5,6,7,8- Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidine-5-formamide [Chem. 77]

To 2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxyl) described in Production Example 11-1 at 0°C -1,2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)acetic acid tris Trifluoroacetic acid (1 mL) was added to a solution of butyl ester (19.6 mg, 0.03 mmol) in dichloromethane (2 mL), and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL), and 1-methylpiperone (0.018 mL, 0.151 mmol), N,N-diisopropylethylamine (0.051 mL, 0.302 mmol), HATU (57.4 mg, 0.151 mmol). The reaction solution was stirred overnight at room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (6.68 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 7.3 Hz), 2.29 (3H, s), 2.38 (4H, t, J = 4.9 Hz), 2.91 ( 4H, s), 3.43 (2H, s), 3.59-3.68 (4H, m), 3.74 (2H, s), 4.87-5.03 (1H, m), 7.08-7.17 (1H, m), 7.23-7.31 ( 5H, m), 7.83 (1H, dd, J = 12.2, 2.5 Hz), 8.48 (1H, s), 8.66 (1H, s), 10.89 (1H, s).

[Example 26] N-(4-((7-(cyclopentylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)- 3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide[ Chemical 78]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20 mg, 0.037 mmol ), N,N-diisopropylethylamine (9.54 μL, 0.056 mmol), cyclopentylformyl chloride (5.86 μL, 0.049 mmol) in dichloromethane (2 mL) at room temperature overnight Stir. The reaction solution was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (20.0 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (6H, d, J = 6.7 Hz), 1.53-1.65 (2H, m), 1.68-1.80 (2H, m), 1.81-1.95 (4H, m), 2.85-3.05 (3H, m), 3.80-3.89 (1H, m), 3.91-3.99 (1H, m), 4.70 (1H, s), 4.81 (1H, s), 4.89-5.01 (1H, m), 7.10-7.17 (1H, m), 7.21-7.28 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.53 (1H, d, J = 6.1 Hz), 8.67 (1H, s), 10.90 (1H, s).

[Example 27] N-(4-((7-(2-cyclopropylacetyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Formamide [Chem. 79]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.028 mmol ), cyclopropylacetic acid (3.13 μL, 0.034 mmol), N,N-diisopropylethylamine (9.54 μL, 0.056 mmol), HATU (16.0 mg, 0.042 mmol) in DMF (1 mL) in a chamber Stirring was carried out at room temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (12.0 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.13-0.25 (2H, m), 0.50-0.67 (2H, m), 1.01-1.15 (1H, m), 1.48 (6H, d, J = 6.7 Hz), 2.39 (2H, dd, J = 14.1, 6.7 Hz), 2.87-2.98 (2H, m), 3.72-3.83 (1H, m), 3.87-4.01 (1H, m), 4.63 (1H , s), 4.82 (1H, s), 4.89-5.02 (1H, m), 7.13 (1H, t, J = 8.6 Hz), 7.20-7.30 (5H, m), 7.84 (1H, dd, J = 12.2 , 2.5 Hz), 8.52 (1H, d, J = 9.8 Hz), 8.66 (1H, s), 10.90 (1H, s). ESI-MS (m/z): 617.41 [M+H] ⁺ .

[Example 28] N-(4-((7-(3,3-difluorocyclobutylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- Base) oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-Formamide [Chem. 80]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.028 mmol ), 3,3-difluorocyclobutanecarboxylic acid (4.58 mg, 0.034 mmol), N,N-diisopropylethylamine (9.54 μL, 0.056 mmol), HATU (16.0 mg, 0.042 mmol) in DMF ( 1 mL) solution was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (13.9 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (6H, d, J = 6.7Hz), 2.72-2.85 (2H, m), 2.87-3.06 (4H, m), 3.09-3.24 (1H, m), 3.73 (1H, t, J = 5.8 Hz), 3.96 (1H, t, J = 6.1 Hz), 4.56 (1H, s), 4.81 (1H, s), 4.95 (1H, sep, J = 6.8 Hz), 7.13 (1H, t, J = 8.6 Hz), 7.23-7.30 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.53 (1H, d, J = 11.6 Hz), 8.67 (1H, s), 10.91 (1H, s). ESI-MS (m/z): 653.40 [M+H] ⁺ .

[Example 29] N-(4-((7-(2,2-difluorocyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- Base) oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-Formamide [Chem. 81]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.028 mmol ), 2,2-difluorocyclopropanecarboxylic acid (4.11 mg, 0.034 mmol), N,N-diisopropylethylamine (9.54 μL, 0.056 mmol), HATU (16.0 mg, 0.042 mmol) in DMF (1 mL) solution was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (12.2 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (6H, d, J = 6.7 Hz), 1.66-1.81 (1H, m), 2.14-2.27 (1H, m), 2.55-69 (1H, m), 2.88-2.96 (1H, m), 2.99-3.05 (1H, m), 3.83-4.17 (2H, m), 4.75-5.01 (3H, m), 7.14 (1H, t, J = 8.6 Hz), 7.21-7.29 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.55 (1H, s), 8.67 (1H, s), 10.91 (1H, s). ESI-MS (m/z): 639.40 [M+H] ⁺ .

[Example 30] N-(3-fluoro-4-((7-(1-methylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d] Pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-Formamide [Chem. 82]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.028 mmol ), 1-methyl-piperidine-4-carboxylate hydrochloride (6.05 mg, 0.034 mmol), N,N-diisopropylethylamine (0.014 mL, 0.084 mmol), HATU (16.0 mg, 0.042 mmol) in DMF (1 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (10.8 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.7Hz), 1.69-1.80 (2H, m), 1.83-2.05 (4H, m), 2.22-2.32 (3H, m), 2.45-2.60 (1H, m), 2.84-3.01 (4H, m), 3.78-3.86 (1H, m), 3.88-3.98 (1H, m), 4.68 (1H, brs), 4.79 (1H, brs), 4.95 (1H, sep, J = 6.8 Hz), 7.13 (1H, t, J = 8.6 Hz), 7.21-7.28 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.52 (1H, s), 8.66 (1H, s), 10.91 (1H, s). ESI-MS (m/z): 660.45 [M+H] ⁺ .

[Example 31] N-(4-((7-(cyclobutylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)- 3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide[ [83]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.028 mmol ), cyclobutanecarboxylic acid (3.18 μL, 0.034 mmol), N,N-diisopropylethylamine (0.014 mL, 0.084 mmol), HATU (16.0 mg, 0.042 mmol) in DMF (2 mL) in room Stirring was carried out at room temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (9.76 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.7 Hz), 1.83-1.93 (1H, m), 1.94-2.05 (1H, m), 2.14-2.26 (2H, m), 2.28-2.47 (2H, m), 2.84-2.96 (2H, m), 3.26-3.43 (1H, m), 3.67 (1H, t, J = 5.8 Hz), 3.92 (1H, t , J = 5.8 Hz), 4.52 (1H, s), 4.78 (1H, s), 4.95 (1H, sep, J = 6.7 Hz), 7.13 (1H, t, J = 8.6 Hz), 7.21-7.29 (5H , m), 7.83 (1H, dd, J = 12.2, 2.5 Hz), 8.52 (1H, d, J = 10.4 Hz), 8.66 (1H, s), 10.90 (1H, s). ESI-MS (m/z): 617.41 [M+H] ⁺ .

[Example 32] N-(3-fluoro-4-((7-(2-(4-methylpiperone-1-yl)acetyl)-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3 ,4-tetrahydropyrimidine-5-formamide [Chem. 84]

4-(2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy- 1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2- Trifluoroacetic acid (4 mL) was added to a solution of tert-butylpiperone-1-carboxylate (1.38 g, 1.81 mmol) in dichloromethane (15 mL), and stirred at room temperature for 1.5 hours. Toluene was added to the reaction mixture, and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution and water were added to the residue, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. THF (30 mL), 35-37% aqueous formaldehyde solution (1.34 mL), and sodium triacetyloxyborohydride (1.15 g, 5.44 mmol) were added to the residue, followed by stirring at room temperature for 2.5 hours. Saturated aqueous sodium bicarbonate solution and water were added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (610 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (6H, d, J = 7.3 Hz), 2.22-2.32 (3H, m), 2.34-2.68 (8H, m), 2.84-3.03 (2H, m), 3.22-3.33 (2H, m), 3.86-3.97 (2H, m), 4.76 (1H, s), 4.85 (1H, s), 4.91-5.02 (1H, m), 7.12-7.17 (1H, m), 7.22-7.29 (5H, m), 7.80-7.88 (1H, m), 8.54 (1H, s), 8.67 (1H, s), 10.91 (1H, s). ESI-MS (m/z): 675.45 [M+H] ⁺ .

[Production Example 32-1] 4-(2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1, 2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-2-oxo Ethyl)piperone-1-carboxylic acid tertiary butyl ester[Chemical 85]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (1 g, 1.87 mmol ), 2-(4-((tertiary butoxy)carbonyl)piperone-1-yl)acetic acid dihydrate (604 mg, 2.16 mmol), N,N-diisopropylethylamine (0.636 mL , 3.74 mmol), HATU (925 mg, 2.43 mmol) in DMF (20 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (1.39 g). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.41-1.46 (9H, m), 1.48 (6H, d, J = 6.8 Hz), 2.38-2.54 (4H, m), 2.84-3.01 (2H, m), 3.24-3.32 (2H, m), 3.34-3.50 (4H, m), 3.84-3.98 (2H, m), 4.72-4.84 (2H, m), 4.87-5.04 (1H, m) , 7.09-7.19 (1H, m), 7.09-7.19 (5H, m), 7.84 (1H, dd, J = 12.2, 2.4 Hz), 8.53 (1H, d, J = 3.9 Hz), 8.66 (1H, s ), 10.91 (1H, s).

[Example 33] N-(3-fluoro-4-((7-((1-methylpiperidin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-formamide [Chem. 86]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (30 mg, 0.056 mmol ), tertiary-butyl 3-formylpiperidine-1-carboxylate (23.9 mg, 0.112 mmol), sodium triacetyloxyborohydride (35.7 mg, 0.168 mmol) in THF (2 mL) at room temperature Stirring was continued for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude product (50 mg). The crude product was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. Thereafter, it was stirred at room temperature for 1.5 hours. A saturated aqueous sodium bicarbonate solution and water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed twice with water, and then washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (2 mL), 35-37% aqueous formaldehyde (0.015 mL) and sodium triacetyloxyborohydride (35.6 mg, 0.168 mmol) were added, and stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (8.97 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 7.3 Hz), 1.55-1.72 (4H, m), 1.73-1.79 (1H, m), 1.84-1.92 (1H, m), 1.93-2.02 (1H, m), 2.25 (3H, s), 2.39 (2H, d, J = 7.3 Hz), 2.63-2.71 (1H, m), 2.77 (1H, d, J = 11.0 Hz), 2.83-2.92 (3H, m), 2.93-2.99 (1H, m), 3.62 (2H, s), 4.90-5.01 (1H, m), 7.12 (1H, t, J = 8.6 Hz) , 7.18-7.27 (5H, m), 7.82 (1H, dd, J = 12.2, 2.5 Hz), 8.47 (1H, s), 8.66 (1H, s), 10.88 (1H, s). ESI-MS (m/z): 646.45 [M+H] ⁺ .

[Example 34] N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)- 3-fluorophenyl)-1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Formamide [Chemical 87]

4-(2-fluoro-4-(1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-dioxo-1, as described in Production Example 34-3, 2,3,4-tetrahydropyrimidine-5-formamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (33.9 mg, 0.053 mmol) and dichloromethane (1.5 mL) was added trifluoroacetic acid (0.500 mL), and stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. To a mixture of the obtained residue and dichloromethane (2 mL), N,N-diisopropylethylamine (13.9 μL, 0.08 mmol) and cyclopropylformyl chloride (6.27 μL, 0.069 mmol) were sequentially added , stirred at room temperature for 40 minutes. The solvent of the reaction solution was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography. Diethyl ether was added to the obtained residue, followed by ultrasonic pulverization, and the solid was collected by filtration to obtain the title compound (27.4 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.78-0.94 (2H, m), 1.06 (2H, brs), 1.76-1.97 (1H, m), 2.82-3.15 (2H, m) , 3.89-4.08 (2H, m), 4.21-4.36 (2H, m), 4.64-4.96 (4H, m), 7.10-7.20 (1H, m), 7.22-7.32 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.54 (1H, s), 8.64 (1H, s), 10.82 (1H, s). ESI-MS (m/z): 607.38 [M+H] ⁺ .

[Production Example 34-1] 1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5- Ethyl formate [Chem. 88]

3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester described in WO 2013074633 A1 (100 mg, 0.359 mmol) 1-Fluoro-2-iodoethane (188 mg, 1.08 mmol) and potassium carbonate (149 mg, 1.08 mmol) were sequentially added to a mixture with DMF (2 mL), and stirred at 60°C for 21 hours. After air-cooling the reaction liquid, water was added, and it extracted 4 times with ethyl acetate. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=4:1-1:4) to obtain the title compound (105 mg). ESI-MS (m/z): 325.18 [M+H] ⁺ .

[Production Example 34-2] 1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5- Formic acid[Chem. 89]

1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine- A mixture of ethyl 5-carboxylate (105 mg, 0.322 mmol), 4 M hydrogen chloride-1,4-dioxane solution (2 mL) and water (0.4 mL) was stirred at 70°C for 3 hours and 10 minutes. After air-cooling the reaction solution, cooling water in an ice bath was added, and ultrasonic pulverization was performed. The precipitate was collected by filtration, washed with ice-cooled water, and dried to obtain the title compound (80.1 mg). ESI-MS (m/z): 297.15 [M+H] ⁺ .

[Production Example 34-3] 4-(2-fluoro-4-(1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem.90]

The third grade of 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid described in Production Example 1-4 Butyl ester (20 mg, 0.055 mmol), 1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2 as described in Production Example 34-2 , 3,4-tetrahydropyrimidine-5-carboxylic acid (19.7 mg, 0.067 mmol), HATU (27.4 mg, 0.072 mmol) and DMF (2 mL) were added with N,N-diisopropylethylamine ( 0.019 mL, 0.111 mmol), stirred at room temperature for 14 hours and 30 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water, filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7:3 to 1:9) to obtain the title compound (33.9 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.50 (9H, s), 2.80-2.91 (2H, m), 3.76 (2H, t, J = 5.5 Hz), 4.21-4.33 (2H , m), 4.57-4.83 (4H, m), 7.09-7.17 (1H, m), 7.23-7.32 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.52 (1H, s ), 8.64 (1H, s), 10.81 (1H, s). ESI-MS (m/z): 639.36 [M+H] ⁺ .

[Example 35] N-(3-fluoro-4-((7-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)-5,6, 7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two sides Oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 91]

2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2) described in Production Example 11-1 ,3,4-tetrahydropyrimidin-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)acetic acid tertiary butyl ester ( 65 mg, 0.10 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL), and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain crude product. To a part (13 mg) of the obtained crude product in DMF (1 mL) was added 4-amino-1-methyl-piperidine (2.21 μL, 0.018 mmol), N,N-diisopropylethyl Amylamine (5.96 μL, 0.035 mmol), HATU (7.99 mg, 0.021 mmol), and stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (5.70 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.41-1.56 (8H, m), 1.88-1.96 (2H, m), 2.05-2.16 (2H, m), 2.25 (3H, s) , 2.68-2.79 (2H, m), 2.85-2.96 (4H, m), 3.22 (2H, s), 3.75 (2H, s), 3.76-3.88 (1H, m), 4.92-5.00 (1H, m) , 6.95 (1H, d, J = 8.6 Hz), 7.15 (1H, t, J = 8.6 Hz), 7.21-7.28 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.50 ( 1H, s), 8.67 (1H, s), 10.90 (1H, s). ESI-MS (m/z): 689.42 [M+H] ⁺ .

[Example 36] N-(3-fluoro-4-((7-(3-(1-methylpiperidin-4-yl)propionyl)-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3 ,4-tetrahydropyrimidine-5-formamide[Chemical 92]

4-(3-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy- 1,2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-3- Dissolve tert-butyl piperidine-1-carboxylate (44 mg, 0.057 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and stir at room temperature for 1.5 hours . The reaction solution was concentrated under reduced pressure. The residue was dissolved in THF (2 mL), 35 to 37% aqueous formaldehyde (0.042 mL) and sodium triacetyloxyborohydride (36.2 mg, 0.171 mmol) were added, and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (28.3 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.23-1.37 (2H, m), 1.48 (6H, d, J = 7.3 Hz), 1.58-1.76 (4H, m), 1.80-1.94 (3H, m), 2.23 (3H, d, J = 4.3 Hz), 2.39-2.49 (2H, m), 2.78-2.85 (2H, m), 2.88 (1H, t, J = 5.8 Hz), 2.94 ( 1H, t, J = 5.2 Hz), 3.74-3.82 (1H, m), 3.93 (1H, t, J = 5.8 Hz), 4.63 (1H, s), 4.78 (1H, s), 4.90-5.00 (1H , m), 7.05-7.17 (1H, m), 7.21-7.31 (5H, m), 7.83 (1H, dd, J = 12.2, 2.5 Hz), 8.52 (1H, d, J = 5.5 Hz), 8.66 ( 1H, s), 10.90 (1H, s). ESI-MS (m/z): 688.45 [M+H] ⁺ .

[Production Example 36-1] 4-(3-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1, 2,3,4-tetrahydropyrimidin-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-3-oxo Propyl)piperidine-1-carboxylic acid tertiary butyl ester [Chemical 93]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.06 mmol ), 3-(1-((tertiary butoxy)carbonyl)piperidin-4-yl)propionic acid (18.5 mg, 0.072 mmol), N,N-diisopropylethylamine (0.020 mL, 0.12 mmol), HATU (29.6 mg, 0.078 mmol) in DMF (2 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (44 mg). ESI-MS (m/z): 774.49 [M+H] ⁺ .

[Example 37] N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)- 3-fluorophenyl)-1-cyclopropyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide[ [94]

4-(4-(1-cyclopropyl-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydro as described in Production Example 37-3 Pyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (88 mg, 0.139 mmol ) and dichloromethane (3.00 mL) was added trifluoroacetic acid (1.00 mL), and stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product (84.4 mg). To a mixture of a portion (15 mg) of the obtained crude product and dichloromethane (1.00 mL) were added successively N,N-diisopropylethylamine (7.38 μL, 0.042 mmol) and cyclopropylformyl chloride (3.33 μL, 0.037 mmol), stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=7:3～3:7). Diethyl ether was added to the obtained residue, followed by ultrasonic pulverization, and the solid was collected by filtration to obtain the title compound (6.53 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.81-0.90 (2H, m), 1.00-1.11 (4H, m), 1.14-1.25 (2H, m), 1.78-1.97 (1H, m), 2.85-3.11 (2H, m), 3.33 (1H, tt, J = 7.3, 3.7 Hz), 3.86-4.11 (2H, m), 4.74-4.95 (2H, m), 7.14 (1H, t, J = 8.6 Hz), 7.22-7.33 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.54 (1H, s), 8.66 (1H, s), 10.87 (1H, s). ESI-MS (m/z): 601.48 [M+H] ⁺ .

[Production Example 37-1] Ethyl 1-cyclopropyl-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylate[ [95]

To a mixture of cyclopropylamine (6.09 mL, 88.0 mmol) and THF (200 mL) was added 1-fluoro-4-isocyanatobenzene (10 mL, 88.0 mmol) dropwise over 8 minutes at 0°C. The ice bath was removed and stirred for 30 minutes. The solvent of the reaction solution was distilled off under reduced pressure. Add ethanol (300 mL), 1,3-diethyl 2-(ethoxymethylene)malonate (18.0 mL, 89.1 mmol) and about 20% sodium ethoxide-ethanol solution in sequence to the obtained residue (50.0 mL), stirred at 50°C for 2 hours and 5 minutes. The reaction solution was cooled using an ice bath, and a 4 M hydrogen chloride-ethyl acetate solution (35 mL) was added. Water and 2N hydrochloric acid were added to the mixed liquid to adjust the pH to 6, and extracted four times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 2:1 to 1:1) to obtain the title compound (10.5 g). ESI-MS (m/z): 319.29 [M+H] ⁺ .

[Production Example 37-2] 1-cyclopropyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [Chem. 96 ]

1-Cyclopropyl-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl A mixture of ester (10.5 g, 33.0 mmol), 4 M hydrogen chloride-1,4-dioxane solution (50 mL) and water (10 mL) was stirred at 70°C for 2 hours and 20 minutes. After air-cooling the reaction solution, water (50 mL) was added, and stirred at 0°C for 1 hour. The precipitate was collected by filtration, washed with ice-cooled water, and dried to obtain the title compound (7.28 g). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 0.91-1.07 (4H, m), 3.18-3.27 (1H, m), 7.33 (4H, d, J = 6.7 Hz), 8.40 (1H, s), 12.63 (1H, brs). ESI-MS (m/z): 291.21 [M+H] ⁺ .

[Production Example 37-3] 4-(4-(1-cyclopropyl-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine- 5-Formamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chemical 97]

The third grade of 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid described in Production Example 1-4 Butyl ester (50 mg, 0.139 mmol), 1-cyclopropyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4 as described in Production Example 37-2 - Add N,N-diisopropylethylamine (0.050 mL, 0.286 mmol), stirred at room temperature for 17 hours and 30 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with water, filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7:3 to 1:9) to obtain the title compound (88.2 mg). ESI-MS (m/z): 633.35 [M+H] ⁺ .

[Example 38] N-(3-fluoro-4-((7-(oxetane-3-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5 -Formamide [Chemical 98]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 0.036 mmol , 78% purity), oxetane-3-carboxylic acid (4.84 mg, 0.047 mmol), N,N-diisopropylethylamine (0.019 mL, 0.109 mmol), HATU (20.8 mg, 0.055 mmol) A solution in DMF (1 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (6.31 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (6H, d, J = 6.7 Hz), 2.88-2.94 (2H, m), 3.51 (1H, t, J = 5.8 Hz), 3.91-4.01 (1H, m), 4.04-4.16 (1H, m), 4.34 (1H, s), 4.81-4.87 (3H, m), 4.90-5.04 (3H, m), 7.13 (1H, t, J = 8.6 Hz), 7.21-7.31 (5H, m), 7.84 (1H, dd, J = 12.2, 2.5 Hz), 8.53 (1H, d, J = 18.3 Hz), 8.67 (1H, s), 10.91 (1H , brs).

[Example 39] N-cyclopropyl-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide [Chemical 99]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 0.047 mmol ), isocyanatocyclopropane (4.89 μL, 0.07 mmol) in dichloromethane (2 mL) and stirred at room temperature for 10 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (23.2 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.47-0.52 (2H, m), 0.74 (2H, dd, J = 6.7, 1.8 Hz), 1.48 (6H, d, J = 6.7 Hz ), 2.66-2.73 (1H, m), 2.90 (2H, t, J = 5.8 Hz), 3.74 (2H, t, J = 5.8 Hz), 4.48 (2H, s), 4.86 (1H, s), 4.90 -5.03 (1H, m), 7.12 (1H, t, J = 8.6 Hz), 7.21-7.27 (5H, m), 7.83 (1H, dd, J = 12.2, 2.5 Hz), 8.50 (1H, s), 8.66 (1H, s), 10.90 (1H, s). ESI-MS (m/z): 618.34[M+H] ⁺ .

[Example 40] N-(4-((7-cyclobutyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluoro Phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 100]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20 mg, 0.037 mmol ), cyclobutanone (0.014 mL, 0.187 mmol), and sodium triacetyloxyborohydride (23.8 mg, 0.112 mmol) in THF (2 mL) were stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (13.4 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.7 Hz), 1.69-1.83 (2H, m), 1.91-2.01 (2H, m), 2.10-2.21 (2H, m), 2.68 (2H, t, J = 6.1 Hz), 2.90 (2H, t, J = 5.8 Hz), 2.93-3.00 (1H, m), 3.54 (2H, s), 4.95 (1H, sep, J = 6.7 Hz), 7.11 (1H, t, J = 8.6 Hz), 7.20-7.29 (5H, m), 7.82 (1H, dd, J = 11.6, 2.5 Hz), 8.47 (1H, s), 8.66 (1H, s), 10.88 (1H, s). ESI-MS (m/z): 589.38 [M+H] ⁺ .

[Example 41] N-(3-fluoro-4-((7-(4-(4-methylpiperone-1-yl)piperidine-1-carbonyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-formamide [Chem. 101]

4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3, 4-tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4-nitrophenyl ester (20 mg, 0.029 mmol), N,N-diisopropylethylamine (9.72 μL, 0.057 mmol), 1-methyl-4-(piperidin-4-yl)-piperone (6.29 mg, 0.034 mmol) in DMF (2 mL) solution was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (10.5 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.43-1.57 (8H, m), 1.86 (2H, d, J = 11.0 Hz), 2.27 (3H, s), 2.35-2.69 (9H , m), 2.82 (2H, t, J = 11.6 Hz), 2.95 (2H, t, J = 5.8 Hz), 3.57 (2H, t, J = 5.8 Hz), 3.80 (2H, d, J = 12.8 Hz ), 4.44 (2H, s), 4.95 (1H, sep, J = 6.9 Hz), 7.11 (1H, t, J = 8.6 Hz), 7.21-7.30 (5H, m), 7.83 (1H, dd, J = 12.2, 2.5 Hz), 8.50 (1H, s), 8.66 (1H, s), 10.89 (1H, s). ESI-MS (m/z): 744.45 [M+H] ⁺ .

[Production Example 41-1] 4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4-nitrophenyl ester [Chem. 102]

N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 2-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (200 mg, 0.292 mmol , 78% purity), pyridine (0.071 mL, 0.876 mmol), and 4-nitrophenyl chloroformate (76 mg, 0.379 mmol) in dichloromethane (5 mL) were stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (152 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (6H, d, J = 7.3 Hz), 3.00-3.09 (2H, m), 3.88-4.06 (2H, m), 4.77 (1H , s), 4.87 (1H, s), 4.96 (1H, sep, J = 6.7 Hz), 7.10-7.18 (1H, m), 7.22-7.30 (5H, m), 7.34 (2H, d, J = 9.2 Hz), 7.86 (1H, dd, J = 11.6, 2.5 Hz), 8.24-8.33 (2H, m), 8.56 (1H, s), 8.67 (1H, s), 10.92 (1H, brs).

[Example 42] N-(2,5-difluoro-4-((7-(2-(1-methylpiperidin-4-yl)acetyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-formamide [Chem. 103]

N-(2,5-difluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy) as described in Production Example 42-2 )phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg , 0.027 mmol), 1-methyl-4-piperidineacetic acid (5.12 mg, 0.033 mmol), N,N-diisopropylethylamine (9.23 μL, 0.054 mmol), HATU (13.4 mg, 0.035 mmol) A solution in DMF (1.5 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with water. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (5.12 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.28-1.39 (2H, m), 1.49 (6H, d, J = 6.7 Hz), 1.73-2.02 (5H, m), 2.25 (3H , d, J = 6.1 Hz), 2.30-2.39 (2H, m), 2.77-2.97 (4H, m), 3.79 (1H, t, J = 5.8 Hz), 3.93 (1H, t, J = 5.8 Hz) , 4.65 (1H, s), 4.80 (1H, s), 4.95 (1H, sep, J = 6.9 Hz), 7.02 (1H, dd, J = 9.8, 6.7 Hz), 7.19-7.28 (4H, m), 8.47 (1H, dd, J = 11.9, 7.0 Hz), 8.54 (1H, d, J = 7.3 Hz), 8.65 (1H, s), 11.12 (1H, brs). ESI-MS (m/z): 692.42 [M+H] ⁺ .

[Production Example 42-1] 4-(2,5-Difluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidine-5-formamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 104]

4-(4-Amino-2,5-difluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- Tertiary butyl formate (48 mg, 0.127 mmol), 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3, as described in WO 2013074633 A1 4-Ectrahydropyrimidine-5-carboxylic acid (44.5 mg, 0.152 mmol), N,N-diisopropylethylamine (86 μL, 0.507 mmol), HATU (96 mg, 0.254 mmol) in DMF (2 mL) The solution was stirred at 70°C for 6 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, and then washed with saturated brine. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (65.7 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.45-1.52 (15H, m), 2.80-2.95 (2H, m), 3.70-3.81 (2H, m), 4.62 (2H, brs) , 4.92-5.02 (1H, m), 7.01 (1H, dd, J = 10.0, 6.6 Hz), 7.18-7.27 (4H, m), 8.46 (1H, dd, J = 11.7, 7.2 Hz), 8.52 (1H , s), 8.65 (1H, s), 11.11 (1H, brs).

[Production Example 42-2] N-(2,5-difluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)benzene Base)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 105]

4-(2,5-difluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2) described in Production Example 42-1 ,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (100 mg , 0.153 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (57.8 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.49 (6H, d, J = 6.7 Hz), 2.82 (2H, t, J = 5.8 Hz), 3.18-3.24 (2H, m), 4.00-4.06 (2H, m), 4.89-5.01 (1H, m), 7.02 (1H, dd, J = 10.4, 7.3 Hz), 7.19-7.29 (4H, m), 8.42-8.54 (2H, m), 8.66 (1H, s), 11.10 (1H, brs).

[Example 43] N-(2-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-formamide [Chem. 106]

4-((4-(3-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1, 2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl)piperidine - A solution of tertiary-butyl-1-carboxylate (35.8 mg, 0.049 mmol) in 4 M hydrogen chloride-1,4-dioxane (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. THF (5 mL) was added to the residue, 35-37% formaldehyde aqueous solution (0.013 mL) and sodium triacetyloxyborohydride (31.1 mg, 0.147 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (14.0 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.22-1.34 (2H, m), 1.48 (6H, d, J = 6.7 Hz), 1.53-1.64 (1H, m), 1.77 (2H , d, J = 11.0 Hz), 1.90 (2H, td, J = 11.6, 1.8 Hz), 2.26 (3H, s), 2.40 (2H, d, J = 7.3 Hz), 2.70-2.79 (2H, m) , 2.81-2.90 (4H, m), 3.60 (2H, s), 4.95 (1H, sep, J = 6.7 Hz), 6.88-7.00 (2H, m), 7.18-7.29 (4H, m), 8.42-8.52 (2H, m), 8.66 (1H, s), 10.99 (1H, d, J = 2.5 Hz). ESI-MS (m/z): 646.41 [M+H] ⁺ .

[Production Example 43-1] 4-(3-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 107]

4-(4-Amino-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-formic acid as described in Production Example 20-3 Butyl ester (66 mg, 0.183 mmol), 3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetra Hydropyrimidine-5-carboxylic acid (58.9 mg, 0.201 mmol), N,N-diisopropylethylamine (0.062 mL, 0.366 mmol), HATU (84 mg, 0.22 mmol) in DMF (3 mL) in room Stirring was carried out at room temperature overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, and then washed with saturated brine. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (106 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.47-1.51 (15H, m), 2.86 (2H, d, J = 6.7 Hz), 3.74 (2H, t, J = 5.8 Hz), 4.61 (2H, brs), 4.89-5.04 (1H, m), 6.92-6.99 (2H, m), 7.18-7.27 (4H, m), 8.44-8.55 (2H, m), 8.66 (1H, s), 11.00 (1H, d, J = 2.5 Hz).

[Production Example 43-2] N-(2-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)- 3-(4-Fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chem. 108]

4-(3-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3, 4-tetrahydropyrimidine-5-formamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (106 mg, 0.167 mmol ) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), and stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water and then with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound quantitatively. ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.7 Hz), 3.09 (2H, brs), 3.47 (2H, brs), 4.26 (2H, brs), 4.91-5.00 (1H, m), 6.93-7.04 (2H, m), 7.20-7.29 (4H, m), 8.45-8.55 (1H, m), 8.57 (1H, s), 8.66 (1H, s), 11.02 (1H, brs).

[Production Example 43-3] 4-((4-(3-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2, 3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl)piperidine-1 - Tertiary butyl formate [Chem. 109]

N-(2-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl as described in Production Example 43-2 )-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (27 mg, 0.051 mmol ), tert-butyl 4-formylpiperidine-1-carboxylate (21.6 mg, 0.101 mmol), sodium triacetyloxyborohydride (32.1 mg, 0.152 mmol) in THF (4 mL), dichloromethane (1 mL) solution was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (35.8 mg). ESI-MS (m/z): 732.45 [M+H] ⁺ .

[Example 44] N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)benzene Base)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 110]

3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-N-(4-((5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.029 mmol), N, A solution of N-diisopropylethylamine (0.025 mL, 0.145 mmol), cyclopropylformyl chloride (7.92 μL, 0.087 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (14.9 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.80-0.87 (2H, m), 1.04 (2H, brs), 1.48 (6H, d, J = 8.6 Hz), 1.76-1.90 (1H , m), 2.81-3.02 (2H, m), 3.88-4.05 (2H, m), 4.75-4.91 (2H, m), 4.92-5.02 (1H, m), 7.10 (2H, d, J = 8.6 Hz ), 7.21-7.28 (4H, m), 7.71 (2H, d, J = 8.6 Hz), 8.54 (1H, s), 8.68 (1H, s), 10.83 (1H, brs). ESI-MS (m/z): 585.37 [M+H] ⁺ .

[Example 45] N-(2,5-difluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3 ,4-tetrahydropyrimidine-5-formamide[Chem. 111]

N-(2,5-difluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy) as described in Production Example 42-2 )phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (29 mg , 0.052 mmol), tertiary butyl 4-formylpiperidine-1-carboxylate (22.4 mg, 0.105 mmol), sodium triacetyloxyborohydride (33.4 mg, 0.157 mmol) in THF (3 mL) Stirring was carried out overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 mL), 4 M hydrogen chloride-1,4-dioxane solution (0.013 mL, 0.052 mmol) was added, stirred at room temperature for 2 hours, and concentrated under reduced pressure. THF (3 mL) was added to the residue, 35-37% formaldehyde aqueous solution (0.014 mL) and sodium triacetyloxyborohydride (22.1 mg, 0.104 mmol) were added, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (1.84 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.23-1.34 (2H, m), 1.49 (6H, d, J = 6.7 Hz), 1.53-1.65 (1H, m), 1.78 (2H , d, J = 12.2 Hz), 1.87-1.95 (2H, m), 2.26 (3H, s), 2.41 (2H, d, J = 7.3 Hz), 2.75-2.81 (2H, m), 2.82-2.92 ( 4H, m), 3.62 (2H, s), 4.85-5.02 (1H, m), 7.01 (1H, dd, J = 10.1, 7.0 Hz), 7.17-7.33 (4H, m), 8.40-8.51 (2H, m), 8.65 (1H, s), 11.09 (1H, brs). ESI-MS (m/z): 664.42[M+H] ⁺ .

[Example 46] 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-formamide [Chem. 112]

1-cyclopentyl-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) as described in Production Example 9-1 )oxy)phenyl)-3-(4-fluorophenyl)-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (90.5 mg, 0.161 mmol ), tert-butyl 4-formylpiperidine-1-carboxylate (68.9 mg, 0.323 mmol) and THF (15 mL) were added sodium triacetyloxyborohydride (68.4 mg, 0.323 mmol), and stirred for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. After the mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. Trifluoroacetic acid (1 mL) was added to a mixture of the obtained crude product and dichloromethane (5 mL), followed by stirring for 1 hour. The reaction mixture was concentrated under reduced pressure, and toluene was added to the residue to carry out azeotropy. A 35-37% aqueous formaldehyde solution (35.9 mg) and sodium triacetyloxyborohydride (68.4 mg, 0.323 mmol) were added to a mixture of the obtained residue and THF (5 mL), followed by stirring for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. After the mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1 : 1 to 0 : 1). A mixture of ethyl acetate and n-heptane was added to the obtained solid, and the precipitate was collected by filtration to obtain the title compound (47.2 mg). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 1.04-1.15 (2H, m), 1.46-1.68 (5H, m), 1.73-1.88 (6H, m), 2.00-2.08 ( 2H, m), 2.09 (3H, s), 2.32 (2H, d, J = 7.3 Hz), 2.65-2.73 (4H, m), 2.73-2.80 (2H, m), 3.51 (2H, s), 4.77 -4.85 (1H, m), 7.25-7.34 (3H, m), 7.34-7.43 (3H, m), 7.83-7.90 (1H, m), 8.42 (1H, s), 8.58 (1H, s), 10.94 (1H, s).

[Example 47] 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-((1-methylpiperidin-4-yl)methyl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-Formamide [Chem. 113]

3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-N-(4-((5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 0.048 mmol), 4- Formylpiperidine-1-carboxylic acid tertiary butyl ester (20.7 mg, 0.097 mmol), sodium triacetyloxyborohydride (15.4 mg, 0.073 mmol) in THF (3 mL) was incubated at room temperature overnight Stir. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography. The crude product was dissolved in dichloromethane (3 mL), added trifluoroacetic acid (1 mL), and stirred at room temperature for 1 hour. The reaction mixture was diluted with toluene and concentrated under reduced pressure. THF (3 mL) was added to the residue, and 35 to 37% aqueous formaldehyde (0.036 mL) and sodium triacetyloxyborohydride (25.6 mg, 0.121 mmol) were added, followed by stirring at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (16.0 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.22-1.34 (2H, m), 1.47 (6H, d, J = 6.8 Hz), 1.53-1.66 (1H, m), 1.71-1.96 (4H, m), 2.26 (3H, s), 2.40 (2H, d, J = 7.3 Hz), 2.71-2.78 (2H, m), 2.81-2.90 (4H, m), 3.60 (2H, s), 4.86-5.02 (1H, m), 7.08 (2H, d, J = 8.8 Hz), 7.20-7.27 (4H, m), 7.69 (2H, d, J = 8.8 Hz), 8.47 (1H, s), 8.67 (1H, s), 10.81 (1H, brs). ESI-MS (m/z): 628.44[M+H] ⁺ .

[Example 48] 1-(cyclopropylmethyl)-N-(2-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-formamide [Chem. 114]

To 4-((4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxygen) described in Production Example 48-3 at room temperature Base-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) Add trifluoroacetic acid (2 mL) to a solution of tertiary-butyl piperidine-1-carboxylate (15 mg, 0.02 mmol) in dichloromethane (2 mL), and stir at room temperature for 1 hour 15 minute. The reaction mixture was concentrated under reduced pressure. THF (2 mL), 35-37% aqueous formaldehyde solution (16.4 mg), and sodium triacetyloxyborohydride (8.55 mg, 0.04 mmol) were added to the residue, followed by stirring at room temperature for 35 minutes. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (8 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.41-0.50 (2H, m), 0.68-0.79 (2H, m), 1.19-1.38 (3H, m), 1.51-1.79 (3H, m), 1.88-2.02 (2H, m), 2.28 (3H, s), 2.41 (2H, d, J = 7.3 Hz), 2,74-2.80 (2H, m), 2.83-2.93 (4H, m) , 3.58-3.67 (2H, m), 3.80 (2H, d, J = 7.3 Hz), 6.90-7.00 (2H, m), 7.19-7.33 (4H, m), 8.43-8.52 (2H, m), 8.71 (1H, s), 10.98 (1H, brs). ESI-MS (m/z): 658.58 [M+H] ⁺ .

[Production Example 48-1] 4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 115]

The third grade of 4-(4-amino-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid described in Production Example 20-3 Butyl ester (50 mg, 0.139 mmol) in DMF (3 mL) was added with 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side Oxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (46.4 mg, 0.153 mmol), N,N-diisopropylethylamine (48 μL, 0.277 mmol), HATU (68.6 mg, 0.18 mmol), stirred at room temperature for 2 hours. The reaction mixture was further stirred at 60° C. for 14 hours. After cooling to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1～ethyl acetate) to obtain the title compound (90 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.40-0.50 (2H, m), 0.68-0.77 (2H, m), 1.18-1.33 (1H, m), 1.49 (9H, s) , 2.83-2.90 (2H, m), 3.70-3.78 (2H, m), 3.80 (2H, d, J = 7.3 Hz), 4.58-4.65 (2H, m), 6.93-7.00 (2H, m), 7.15 -7.33 (4H, m), 8.45-8.52 (1H, m), 8.53 (1H, s), 8.71 (1H, s), 10.99 (1H, brs). ESI-MS (m/z): 647.53 [M+H] ⁺ .

[Production Example 48-2] 1-(cyclopropylmethyl)-N-(2-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-formamide [Chemical 116]

4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3, 4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (90 mg, 0.139 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with dichloromethane twice. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (75 mg). ESI-MS (m/z): 547.22 [M+H] ⁺ .

[Production Example 48-3] 4-((4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methyl) tertiary butyl piperidine-1-carboxylate[Chem. 117]

1-(cyclopropylmethyl)-N-(2-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 48-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20 mg, 0.037 mmol) in THF (2 mL) and acetic acid (0.1 mL) were added tertiary butyl 4-formylpiperidine-1-carboxylate (11.7 mg, 0.055 mmol) and triacetyloxyhydroboration Sodium (15.5 mg, 0.073 mmol), stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound quantitatively. ESI-MS (m/z): 744.50 [M+H] ⁺ .

[Example 49] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-methyl-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 118]

1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-N-(4-((5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (13 mg, 0.025 mmol ), 35-37% formaldehyde aqueous solution (0.018 mL), sodium triacetyloxyborohydride (15.6 mg, 0.074 mmol) in THF (3 mL) and stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (8.27 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.41-0.49 (2H, m), 0.66-0.79 (2H, m), 1.20-1.32 (1H, m), 2.50 (3H, s) , 2.73-2.81 (2H, m), 2.86-2.94 (2H, m), 3.60 (2H, s), 3.80 (2H, d, J = 7.3 Hz), 7.03-7.13 (2H, m), 7.21-7.30 (4H, m), 7.68-7.73 (2H, m), 8.48 (1H, s), 8.71 (1H, s), 10.79 (1H, s). ESI-MS (m/z): 543.33 [M+H] ⁺ .

[Example 50] 3-(4-Fluorophenyl)-1-isopropyl-N-(4-((7-((1-methyltetrahydroazan-3-yl)methyl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydro Pyrimidine-5-formamide [Chem. 119]

3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-N-(4-((5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (30 mg, 0.058 mmol), 3- A THF (3 mL) solution of tert-butyl formyltetrahydroazine-1-carboxylate (21.5 mg, 0.116 mmol) and sodium triacetyloxyborohydride (36.9 mg, 0.174 mmol) was stirred at room temperature 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography. The crude product was dissolved in dichloromethane (4.5 mL), added trifluoroacetic acid (1.5 mL), and stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. THF (3 mL) was added to the residue, 35-37% aqueous formaldehyde solution (0.039 mL) and sodium triacetyloxyborohydride (17.0 mg, 0.08 mmol) were added, followed by stirring at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (17.5 mg). ¹ H-NMR spectrum (396 MHz, CDCl ₃ ) δ (ppm): 1.47 (6H, d, J = 6.8 Hz), 1.86 (1H, brs), 2.29 (2H, s), 2.65-2.97 (9H, m ), 3.38-3.53 (2H, m), 3.58 (2H, s), 4.87-5.04 (1H, m), 7.07 (2H, d, J = 8.6 Hz), 7.17-7.29 (4H, m), 7.69 ( 2H, d, J = 9.1 Hz), 8.47 (1H, s), 8.67 (1H, s), 10.81 (1H, brs). ESI-MS (m/z): 600.41 [M+H] ⁺ .

[Example 51] 1-cyclopentyl-N-(2-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- Base) oxy) phenyl) -3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 120]

1-cyclopentyl-N-(2-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) as described in Production Example 51-1 )oxy)phenyl)-3-(4-fluorophenyl)-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.027 mmol ) and THF (2 mL) were added 35-37% formaldehyde aqueous solution (6.51 mg) and sodium triacetyloxyborohydride (11.3 mg, 0.054 mmol), and stirred for 2 hours and 40 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-1:4). A mixture of ethyl acetate and n-heptane was added to the crude product, and the precipitated solid was collected by filtration to obtain the title compound (6.9 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.72-1.85 (4H, m), 1.88-1.98 (2H, m), 2.15-2.29 (2H, m), 2.50 (3H, s) , 2.76 (2H, t, J = 5.8 Hz), 2.88 (2H, t, J = 5.8 Hz), 3.60 (2H, s), 4.93-5.02 (1H, m), 6.92-7.00 (2H, m), 7.20-7.28 (4H, m), 8.47 (1H, t, J = 10.0 Hz), 8.50 (1H, s), 8.65 (1H, s), 10.99 (1H, brs). ESI-MS (m/z): 575.31 [M+H] ⁺ .

[Production Example 51-1] 1-cyclopentyl-N-(2-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy Base) phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 121]

1-cyclopentyl-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (81 mg , 0.255 mmol), 4-(4-amino-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) described in Production Example 20-3 - Add HATU (169 mg, 0.444 mmol) and N,N-diisopropylethylamine (116 μL, 0.666 mmol) to a mixture of tertiary butyl formate (80 mg, 0.222 mmol) and DMF (2 mL) , stirred for 16 hours and 30 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine. After the organic layer was dried over sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. Trifluoroacetic acid (855 μL) was added to a mixture of the obtained crude product and dichloromethane (2 mL), followed by stirring for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane three times. The obtained organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. A mixture of ethyl acetate and n-heptane was added to the obtained residue, and the precipitate was collected by filtration to obtain the title compound (120 mg). ¹ H-NMR spectrum (500 MHz, DMSO-d ₆ ) δ (ppm): 1.56-1.67 (2H, m), 1.71-1.88 (4H, m), 1.99-2.09 (2H, m), 2.63 (2H, t, J = 5.0 Hz), 2.96 (2H, t, J = 5.0 Hz), 3.77 (2H, s), 4.77-4.87 (1H, m), 7.02-7.07 (1H, m), 7.25-7.35 (3H , m), 7.36-7.42 (2H, m), 8.35 (1H, t, J = 10.0 Hz), 8.41 (1H, s), 8.59 (1H, s), 11.08 (1H, s).

[Example 52] N-(4-((7-(2-(tetrahydroacri-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)-oxyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two side oxygen Base-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chem. 122]

To 2-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-diendoxyl) described in Production Example 52-1 at room temperature -1,2,3,4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl acetate (35 mg, 0.053 mmol) in dichloromethane (2 mL), and stirred at room temperature for 4 hours and 5 minutes. The reaction mixture was concentrated under reduced pressure. Add tetrahydroacridine (6.05 mg, 0.106 mmol) and HATU (26.2 mg , 0.069 mmol), stirred at room temperature for 23 hours and 45 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1～ethyl acetate) to obtain the title compound (27 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.40-0.49 (2H, m), 0.67-0.77 (2H, m), 1.20-1.33 (1H, m), 2.22-2.34 (2H, m), 2.85-2.96 (4H, m), 3.25 (2H, s), 3.75 (2H, s), 3.80 (2H, d, J = 7.3 Hz), 4.02-4.13 (2H, m), 4.19-4.29 (2H, m), 6.90-7.00 (2H, m), 7.16-7.31 (4H, m), 8.43-8.54 (2H, m), 8.71 (1H, s), 10.98 (1H, brs). ESI-MS (m/z): 644.41 [M+H] ⁺ .

[Production Example 52-1] 2-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3 ,4-tetrahydropyrimidin-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)acetic acid tertiary butyl Ester [Chem. 123]

1-(cyclopropylmethyl)-N-(2-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 48-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (45 mg, 0.082 mmol) in DMF (2 mL) was added tert-butyl bromoacetate (14 μL, 0.095 mmol), and stirred at room temperature for 114 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1～ethyl acetate) to obtain the title compound (35 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.40-0.48 (2H, m), 0.68-0.76 (2H, m), 1.18-1.34 (1H, m), 1.48 (9H, s) , 2.85-2.93 (2H, m), 2.94-3.03 (2H, m), 3.38 (2H, s), 3.77-3.88 (4H, m), 6.90-6.99 (2H, m), 7.15-7.33 (4H, m), 8.44-8.52 (2H, m), 8.71 (1H, s), 10.97 (1H, brs). ESI-MS (m/z): 661.39 [M+H] ⁺ .

[Example 53] 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-formamide [Chem. 124]

To 4-(2-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-di Oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7( 8H)-yl)ethyl)piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.026 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), stirred at room temperature for 30 minute. The reaction mixture was concentrated under reduced pressure. Add 35-37% aqueous formaldehyde (21.4 mg) and sodium triacetyloxyborohydride (11.2 mg, 0.053 mmol) to a solution of the residue in THF (2 mL) at room temperature, and stir at room temperature for 16 hours 5 minute. Sodium bicarbonate and water were added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (10 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.41-0.49 (2H, m), 0.68-0.78 (2H, m), 1.20-1.38 (4H, m), 1.47-1.77 (4H, m), 1.83-1.97 (2H, m), 2.24 (3H, s), 2.54-2.63 (2H, m), 2.73-2.96 (6H, m), 3.64 (2H, s), 3.81 (2H, d, J = 7.3 Hz), 7.07-7.16 (1H, m), 7.19-7.32 (5H, m), 7.78-7.87 (1H, m), 8.46 (1H, s), 8.71 (1H, s), 10.87 (1H , brs). ESI-MS (m/z): 672.52 [M+H] ⁺ .

[Production Example 53-1] 4-(2-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethyl Base) tertiary butyl piperidine-1-carboxylate [Chem. 125]

1-(cyclopropylmethyl)-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 5-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.027 mmol) in THF (2 mL) and acetic acid (0.1 mL) were added tertiary butyl 4-(2-oxoethyl)piperidine-1-carboxylate (8.11 mg, 0.036 mmol), triethyl Sodium acyloxyborohydride (8.73 mg, 0.041 mmol), stirred at room temperature for 45 hours and 30 minutes. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (20 mg). ESI-MS (m/z): 758.56 [M+H] ⁺ .

[Example 54] N-(4-((7-(tetrahydroazil-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)-3-fluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydro Pyrimidine-5-formamide [Chem. 126]

4-(2-fluoro-4-(1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1, as described in Production Example 54-1, 2,3,4-tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4-nitrophenyl ester (23.8 mg, 0.034 mmol), N,N-diisopropylethylamine (0.012 mL, 0.068 mmol), tetrahydroacridine (4.61 μL, 0.068 mmol) in DMF (3 mL) was stirred at room temperature 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (17.2 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.47 (6H, d, J = 6.4 Hz), 2.26 (2H, quin, J = 7.7 Hz), 2.43 (3H, s), 2.89 ( 2H, t, J = 5.5 Hz), 3.65 (2H, t, J = 5.7 Hz), 4.00-4.17 (4H, m), 4.48 (2H, s), 4.89-5.01 (1H, m), 7.07-7.15 (1H, m), 7.21-7.30 (2H, m), 7.72-7.77 (1H, m), 7.78-7.84 (1H, m), 8.48-8.54 (2H, m), 8.64 (1H, s), 10.85 (1H, brs). ESI-MS (m/z): 615.41 [M+H] ⁺ .

[Production Example 54-1] 4-(2-fluoro-4-(1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2, 3,4-tetrahydropyrimidine-5-formamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4-nitrophenyl ester[Chem 127]

The 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-formic acid tertiary Butyl ester (150 mg, 0.416 mmol), 1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2 as described in Production Example 8-4 , 3,4-tetrahydropyrimidine-5-carboxylic acid (353 mg, 0.916 mmol), N,N-diisopropylethylamine (0.218 mL, 1.25 mmol), HATU (396 mg, 1.04 mmol) in DMF ( 3 mL) solution was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a crude product (208 mg). The obtained crude product was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (157 mg). A part (25 mg) of the obtained crude product, pyridine (0.011 mL, 0.141 mmol), and 4-nitrophenyl chloroformate (14.2 mg, 0.071 mmol) in dichloromethane (3 mL) were dissolved at room temperature Stirring was carried out overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (23.8 mg). ESI-MS (m/z): 697.36 [M+H] ⁺ .

[Example 55] N-4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3 -Fluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-methyl Amide [Chem. 128]

The 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-formic acid tertiary Butyl ester (150 mg, 0.416 mmol), 1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2 as described in Production Example 8-4 ,3,4-tetrahydropyrimidinecarboxylic acid (353 mg, 0.916 mmol), N,N-diisopropylethylamine (0.218 mL, 1.25 mmol), HATU (396 mg, 1.04 mmol) in DMF (3 mL) The solution was stirred at room temperature for 1.5 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a crude product (208 mg). Trifluoroacetic acid (1 mL) was added to a solution of the obtained crude product (208 mg) in dichloromethane (4 mL), followed by stirring at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with dichloromethane. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure to obtain a crude product (157 mg). Part of the obtained crude product (15 mg), N,N-diisopropylethylamine (9.60 μL, 0.056 mmol), cyclopropylformyl chloride (3.85 μL, 0.042 mmol) in dichloromethane ( 2 mL) solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (10.6 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.80-0.87 (2H, m), 1.04 (2H, brs), 1.47 (6H, d, J = 6.7 Hz), 1.72-1.90 (1H , m), 2.44 (3H, s), 2.90 (1H, brs), 3.00 (1H, brs), 3.88-4.04 (2H, m), 4.81 (1H, brs), 4.87 (1H, brs), 4.90- 5.01 (1H, m), 7.09-7.16 (1H, m), 7.22-7.28 (2H, m), 7.72-7.78 (1H, m), 7.82 (1H, dd, J = 12.2, 2.5 Hz), 8.53 ( 2H, brs), 8.65 (1H, s), 10.87 (1H, s). ESI-MS (m/z): 600.37 [M+H] ⁺ .

[Example 56] N-4-((7-(2-(1-ethylpiperidin-4-yl)ethyl)-5,6,7,8-tetrahydropyrido[3,4-d ]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4 -tetrahydropyrimidine-5-formamide [Chem. 129]

4-(2-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy- 1,2,3,4-tetrahydropyrimidin-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)ethyl) Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (948 mg, 1.27 mmol) in dichloromethane (9 mL), and stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid at room temperature, followed by extraction with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. A portion (15 mg) of the obtained crude product, sodium triacetyloxyborohydride (9.85 mg, 0.046 mmol), acetaldehyde (0.013 mL, 0.232 mmol) in THF (3 mL) was stirred at room temperature 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (6.80 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.01-1.12 (3H, m), 1.27-1.40 (3H, m), 1.48 (6H, d, J = 6.9 Hz), 1.50-1.78 (4H, m), 1.81-1.91 (2H, m), 2.32-2.42 (2H, m), 2.59 (2H, dd, J = 8.5, 6.6 Hz), 2.75-2.84 (2H, m), 2.85-2.98 (4H, m), 3.64 (2H, s), 4.90-5.01 (1H, m), 7.06-7.17 (1H, m), 7.22-7.30 (5H, m), 7.78-7.92 (1H, m), 8.47 (1H, s), 8.66 (1H, s), 10.88 (1H, s). ESI-MS (m/z): 674.49 [M+H] ⁺ .

[Example 57] N-cyclopropyl-4-((6-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2 ,3,4-tetrahydropyrimidine-5-carboxamide)pyridin-3-yl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide [chemical 130]

1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-N-(5-((5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (12 mg , 0.023 mmol), isocyanatocyclopropane (2.37 μL, 0.034 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (9.96 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.43-0.54 (4H, m), 0.70-0.78 (4H, m), 1.25-1.33 (1H, m), 2.69 (1H, ddd, J = 5.2, 3.4, 1.8 Hz), 2.89 (2H, t, J = 5.5 Hz), 3.74 (2H, t, J = 5.8 Hz), 3.80 (2H, d, J = 7.3 Hz), 4.48 (2H, s), 4.83 (1H, s), 7.16-7.31 (4H, m), 7.53 (1H, dd, J = 9.2, 3.1 Hz), 8.15 (1H, d, J = 3.1 Hz), 8.34 (1H, d , J = 9.2 Hz), 8.50 (1H, s), 8.71 (1H, s), 11.28 (1H, s). ESI-MS (m/z): 613.37[M+H] ⁺ .

[Example 58] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(5-((7-((1-methylpiperidin-4-yl)methyl) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-2,4-two-side oxy-1,2,3 ,4-tetrahydropyrimidine-5-formamide[Chem. 131]

1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-N-(5-((5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg , 0.047 mmol), tertiary butyl 4-formylpiperidine-1-carboxylate (15.1 mg, 0.071 mmol), sodium triacetyloxyborohydride (20.0 mg, 0.094 mmol) in THF (3 mL) Stir at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain a crude product. The obtained crude product was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 hour. Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, 35-37% aqueous formaldehyde solution (0.033 mL) and sodium triacetyloxyborohydride (18.0 mg, 0.085 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (14.1 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.42-0.48 (2H, m), 0.68-0.76 (2H, m), 1.20-1.33 (2H, m), 1.53-1.64 (1H, m), 1.74-1.82 (3H, m), 1.87-1.94 (2H, m), 2.25 (3H, s), 2.40 (2H, d, J = 7.3 Hz), 2.73-2.80 (2H, m), 2.81 -2.91 (4H, m), 3.61 (2H, s), 3.79 (2H, d, J = 7.3 Hz), 7.18-7.30 (4H, m), 7.52 (1H, dd, J = 8.9, 2.8 Hz), 8.14 (1H, d, J = 2.5 Hz), 8.33 (1H, d, J = 9.2 Hz), 8.46 (1H, s), 8.70 (1H, s), 11.26 (1H, s). ESI-MS (m/z): 641.47 [M+H] ⁺ .

[Example 59] 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydro Pyrimidine-5-formamide [Chem. 132]

3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-N-(4-((5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 0.048 mmol), 4- (2-oxoethyl)piperidine-1-carboxylic acid tertiary butyl ester (16.5 mg, 0.073 mmol), triacetyloxysodium borohydride (20.5 mg, 0.097 mmol) in THF (3 mL) in room Stir at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain a crude product. The obtained crude product was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 hour. Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, 35-37% aqueous formaldehyde (0.025 mL) and sodium triacetyloxyborohydride (14.0 mg, 0.066 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (15.7 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.28-1.35 (3H, m), 1.47 (6H, d, J = 6.7 Hz), 1.50-1.59 (2H, m), 1.66-1.73 (1H, m), 1.78 (1H, brs), 1.85-1.94 (2H, m), 2.24 (3H, s), 2.54-2.62 (2H, m), 2.74-2.84 (4H, m), 2.85-2.90 (2H, m), 3.62 (2H, s), 4.90-4.99 (1H, m), 7.08 (2H, d, J = 9.2 Hz), 7.20-7.29 (4H, m), 7.69 (2H, d, J = 8.6 Hz), 8.47 (1H, s), 8.67 (1H, s), 10.81 (1H, s). ESI-MS (m/z): 642.44 [M+H] ⁺ .

[Example 60] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(2-(1-methylpiperidin-4-yl)ethyl Base)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-formamide [Chem. 133]

1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-N-(4-((5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (25 mg, 0.047 mmol ), tertiary-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (16.1 mg, 0.071 mmol), sodium triacetyloxyborohydride (20.1 mg, 0.095 mmol) in THF (3 mL ) solution was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain a crude product. The obtained crude product was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 hour. Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, 35-37% formaldehyde aqueous solution (0.024 mL) and sodium triacetyloxyborohydride (9.88 mg, 0.047 mmol) were added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography and NH silica gel thin layer chromatography to obtain the title compound (2.66 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.42-0.47 (2H, m), 0.64-0.77 (2H, m), 1.22-1.40 (3H, m), 1.52-1.79 (5H, m), 1.87-1.99 (2H, m), 2.27 (3H, s), 2.55-2.62 (2H, m), 2.76-2.92 (6H, m), 3.63 (2H, s), 3.80 (2H, d, J = 7.3 Hz), 7.08 (2H, d, J = 8.6 Hz), 7.22-7.30 (4H, m), 7.70 (2H, d, J = 9.2 Hz), 8.48 (1H, s), 8.72 (1H, s), 10.79 (1H, brs). ESI-MS (m/z): 654.44 [M+H] ⁺ .

[Example 61] 1-(Cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methyltetrahydroazin-3-yl)methyl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-formamide [Chem. 134]

1-(cyclopropylmethyl)-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 5-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (30 mg, 0.055 mmol), tertiary butyl 3-formyltetrahydroazine-1-carboxylate (20.3 mg, 0.11 mmol), sodium triacetyloxyborohydride (17.5 mg, 0.082 mmol) in THF (3 mL) solution was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain a crude product. The obtained crude product was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The reaction was stirred at room temperature for 1 hour. Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, 35-37% aqueous formaldehyde solution (0.042 mL) and sodium triacetyloxyborohydride (17.3 mg, 0.082 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (14.7 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.43-0.47 (2H, m), 0.70-0.75 (2H, m), 1.20-1.32 (1H, m), 2.29 (3H, s) , 2.68-2.82 (5H, m), 2.84-2.93 (4H, m), 3.46 (2H, t, J = 7.3 Hz), 3.60 (2H, s), 3.80 (2H, d, J = 7.3 Hz), 7.11 (1H, t, J = 8.6 Hz), 7.19-7.30 (5H, m), 7.82 (1H, dd, J = 11.6, 2.5 Hz), 8.46 (1H, s), 8.71 (1H, s), 10.86 (1H, s). ESI-MS (m/z): 630.37 [M+H] ⁺ .

[Example 62] 1-cyclopentyl-N-(3-fluoro-4-((7-(1-methyltetrahydroazan-3-yl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro Pyrimidine-5-formamide [Chem. 135]

1-cyclopentyl-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) as described in Production Example 9-1 )oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.071 mmol ), tertiary-butyl 3-oxotetrahydroazine-1-carboxylate (24.4 mg, 0.143 mmol) and THF (3 mL) were added sodium triacetyloxyborohydride (30.2 mg, 0.143 mmol ), and stirred for 2 hours. To the reaction liquid was added saturated aqueous sodium bicarbonate solution at room temperature, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. Trifluoroacetic acid (550 μL) was added to a mixture of the obtained crude product and dichloromethane (2 mL), followed by stirring for 3 hours. The reaction mixture was concentrated under reduced pressure, and toluene was added to the residue to carry out azeotropy. A 35-37% aqueous formaldehyde solution (15.9 mg) and sodium triacetyloxyborohydride (30.2 mg, 0.143 mmol) were added to a mixture of the obtained residue and THF (1 mL), followed by stirring for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1) to obtain a crude product. A mixture of ethyl acetate and n-heptane was added to the obtained crude product, and the precipitate was collected by filtration to obtain the title compound (19.5 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.71-1.86 (4H, m), 1.87-1.99 (2H, m), 2.17-2.27 (2H, m), 2.37 (3H, s) , 2.66 (2H, t, J = 6.1 Hz), 2.91 (2H, t, J = 5.8 Hz), 2.95 (2H, t, J = 7.0 Hz), 3.17 (1H, quin, J = 5.0 Hz), 3.51 (2H, s), 3.60-3.66 (2H, m), 4.94-5.02 (1H, m), 7.11 (1H, t, J = 10.0 Hz), 7.21-7.27 (5H, m), 7.79-7.85 (1H , m), 8.47 (1H, s), 8.66 (1H, s), 10.88 (1H, s). ESI-MS (m/z): 630.44 [M+H] ⁺ .

[Example 63] 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methyltetrahydroazin-3-yl)methyl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-formamide [Chem. 136]

1-cyclopentyl-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) as described in Production Example 9-1 )oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (40 mg, 0.071 mmol ), tertiary-butyl 3-formyltetrahydroazine-1-carboxylate (26.4 mg, 0.143 mmol) and THF (3 mL) were added sodium triacetyloxyborohydride (30.2 mg, 0.143 mmol ), and stirred for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. Trifluoroacetic acid (550 μL) was added to a mixture of the obtained crude product and dichloromethane (2 mL), followed by stirring for 2 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, and toluene was added to the residue to carry out azeotropy. A 35-37% aqueous formaldehyde solution (15.9 mg) and sodium triacetyloxyborohydride (30.2 mg, 0.143 mmol) were added to a mixture of the obtained residue and THF (1 mL), followed by stirring for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1-0:1) to obtain a crude product. A mixture of ethyl acetate and n-heptane was added to the obtained crude product, and the precipitate was collected by filtration to obtain the title compound (12.4 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.72-1.86 (4H, m), 1.87-1.99 (2H, m), 2.17-2.27 (2H, m), 2.30 (3H, s) , 2.70-2.82 (5H, m), 2.85-2.95 (4H, m), 3.46 (2H, t, J = 7.0 Hz), 3.60 (2H, s), 4.94-5.02 (1H, m), 7.11 (1H , t, J = 10.0 Hz), 7.21-7.28 (5H, m), 7.79-7.85 (1H, m), 8.46 (1H, s), 8.65 (1H, s), 10.88 (1H, s). ESI-MS (m/z): 644.48 [M+H] ⁺ .

[Example 64] 1-cyclopentyl-N-(2-fluoro-4-((7-(1-methyltetrahydroacrin-3-yl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro Pyrimidine-5-formamide [Chem. 137]

To 3-(4-(4-(1-cyclopentyl-3-(4-fluorophenyl)-2,4-diendoxy-1,2) described in Production Example 64-1 at room temperature ,3,4-tetrahydropyrimidine-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)tetrahydro Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl azir-1-carboxylate (22 mg, 0.031 mmol) in dichloromethane (2 mL), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Add 35-37% aqueous formaldehyde (26.4 mg) and sodium triacetyloxyborohydride (13.0 mg, 0.061 mmol) to a THF (2 mL) solution of the residue at room temperature, and stir at room temperature for 3 hours 50 minute. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (9 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.68-1.88 (4H, m), 1.88-2.00 (2H, m), 2.15-2.30 (2H, m), 2.42 (3H, s) , 2.63-2.73 (2H, m), 2.83-2.93 (2H, m), 2.98-3.09 (2H, m), 3.17-3.27 (1H, m), 3.51 (2H, s), 3.63-3.80 (2H, m), 4.92-5.05 (1H, m), 6.87-7.00 (2H, m), 7.16-7.33 (4H, m), 8.41-8.56 (2H, m), 8.65 (1H, s), 10.99 (1H, brs). ESI-MS (m/z): 630.41 [M+H] ⁺ .

[Production Example 64-1] 3-(4-(4-(1-cyclopentyl-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetra Hydropyrimidin-5-carboxamide)-3-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)tetrahydroazia-1-carboxylic acid Tertiary butyl ester[Chem. 138]

1-cyclopentyl-N-(2-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) as described in Production Example 51-1 )oxy)phenyl)-3-(4-fluorophenyl)-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (30 mg, 0.054 mmol ) in THF (3 mL) and acetic acid (0.1 mL) were added tertiary butyl 3-oxotetrahydroazia-1-carboxylate (18.3 mg, 0.107 mmol), sodium triacetyloxyborohydride ( 22.7 mg, 0.107 mmol), stirred at room temperature for 6 hours. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate: methanol = 9: 1) to obtain the title compound (22 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.43 (9H, s), 1.70-1.86 (4H, m), 1.87-1.98 (2H, m), 2.13-2.28 (2H, m) , 2.65-2.77 (2H, m), 2.85-2.94 (2H, m), 3.29-3.40 (1H, m), 3.53-3.62 (2H, m), 3.86-3.95 (2H, m), 3.98-4.08 ( 2H, m), 4.92-5.03 (1H, m), 6.90-7.00 (2H, m), 7.18-7.33 (4H, m), 8.44-8.54 (2H, m), 8.65 (1H, s), 10.99 ( 1H, brs). ESI-MS (m/z): 716.44 [M+H] ⁺ .

[Example 65] 1-cyclopentyl-3-(4-fluorophenyl)-N-(4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4- d] pyrimidin-4-yl)oxy)phenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chemical 139]

The 1-cyclopentyl-3-(4-fluorophenyl)-2,4-dipentoxy-N-(4-((5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (15 mg, 0.028 mmol), 35～ A solution of 37% formaldehyde in water (0.022 mL), sodium triacetyloxyborohydride (11.7 mg, 0.055 mmol) in THF (3 mL) was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (10.6 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.69-1.84 (4H, m), 1.87-1.96 (2H, m), 2.13-2.28 (2H, m), 2.50 (3H, s) , 2.73-2.78 (2H, m), 2.85-2.94 (2H, m), 3.59 (2H, s), 4.94-5.02 (1H, m), 7.09 (2H, d, J = 9.2 Hz), 7.20-7.28 (4H, m), 7.69 (2H, d, J = 9.2 Hz), 8.49 (1H, s), 8.66 (1H, s), 10.80 (1H, brs). ESI-MS (m/z): 557.37 [M+H] ⁺ .

[Example 66] 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(2-(4-methylpiperone-1-yl)acetyl)-5, 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1 ,2,3,4-tetrahydropyrimidine-5-formamide [Chem. 140]

4-(2-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-diendoxy- 1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl )-2-oxoethyl)piperone-1-carboxylic acid tert-butyl ester (42 mg, 0.054 mmol) was dissolved in dichloromethane (4.5 mL), and trifluoroacetic acid (1.5 mL) was added. Thereafter, it was stirred at room temperature for 1 hour. Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, 35-37% aqueous formaldehyde (0.042 mL) and sodium triacetyloxyborohydride (23.0 mg, 0.109 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (15.9 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.43-0.51 (2H, m), 0.65-0.76 (2H, m), 1.25-1.32 (1H, m), 2.22-2.64 (11H, m), 2.89 (1H, t, J = 5.8 Hz), 2.98 (1H, t, J = 5.5 Hz), 3.25-3.31 (2H, m), 3.81 (2H, d, J = 7.3 Hz), 3.87- 3.96 (2H, m), 4.75-4.87 (2H, m), 7.07-7.17 (1H, m), 7.21-7.31 (5H, m), 7.84 (1H, d, J = 12.2 Hz), 8.53 (1H, s), 8.71 (1H, s), 10.89 (1H, brs). ESI-MS (m/z): 687.48 [M+H] ⁺ .

[Production Example 66-1] 4-(2-(4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1, 2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)- 2-oxoethyl) piper-1-carboxylic acid tertiary butyl ester [Chem. 141]

1-(cyclopropylmethyl)-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 5-2 -4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide (30 mg, 0.055 mmol), 2-(4-((tertiary butoxy)carbonyl)piperone-1-yl)acetic acid (20.1 mg, 0.082 mmol), N,N-diisopropylethylamine (0.019 mL, 0.11 mmol), HATU (35.5 mg, 0.093 mmol) in DMF (3 mL) was stirred overnight at room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (42 mg). ESI-MS (m/z): 773.45 [M+H] ⁺ .

[Example 67] N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)benzene Base)-1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Formamide [Chem. 142]

4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1, as described in Production Example 67-1, 2,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (141 mg) in dichloromethane (6 mL) was added trifluoroacetic acid (1.5 mL), and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid, extracted with dichloromethane, and dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (95.2 mg). Part of the obtained crude product (15 mg), cyclopropylformyl chloride (3.89 μL, 0.043 mmol), N,N-diisopropylethylamine (9.71 μL, 0.057 mmol) in dichloromethane ( 3 mL) solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (14.3 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 0.37-0.49 (2H, m), 0.64-0.77 (2H, m), 0.80-0.91 (2H, m), 1.01-1.07 (2H, m), 1.20-1.34 (1H, m), 1.76-1.89 (1H, m), 2.43 (3H, s), 2.82-3.03 (2H, m), 3.79 (2H, brs), 3.88-4.04 (2H, m), 4.75-4.90 (2H, m), 7.03-7.12 (2H, m), 7.21-7.27 (1H, m), 7.65-7.80 (3H, m), 8.50-8.56 (2H, m), 8.70 ( 1H, s), 10.77 (1H, s).

[Production Example 67-1] 4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 143]

The 1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxylic acid (79 mg, 0.263 mmol), 4-(4-aminophenoxy)-5,6-dihydropyrido[3,4-d] described in Production Example 6-1 DMF ( 3 mL) solution was stirred overnight at room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound quantitatively. ESI-MS (m/z): 626.55 [M+H] ⁺ .

[Example 68] 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy- 1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chem. 144]

4-((4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxygen as described in Production Example 68-2 Base-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) Trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (29.9 mg, 0.04 mmol) in dichloromethane (6 mL) and stirred at room temperature for 1 hour. Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, 35-37% formaldehyde aqueous solution (0.031 mL) and sodium triacetyloxyborohydride (17.1 mg, 0.081 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (14.9 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.40-0.47 (2H, m), 0.67-0.75 (2H, m), 1.20-1.34 (3H, m), 1.54-1.63 (1H, m), 1.73-1.82 (2H, m), 1.85-1.95 (2H, m), 2.25 (3H, s), 2.40 (2H, d, J = 7.3 Hz), 2.43 (3H, s), 2.74-2.79 (2H, m), 2.82-2.91 (4H, m), 3.60 (2H, s), 3.79 (2H, brs), 7.10 (1H, t, J = 8.6 Hz), 7.21-7.30 (2H, m), 7.71-7.88 (2H, m), 8.46 (1H, s), 8.52 (1H, s), 8.69 (1H, s), 10.83 (1H, s). ESI-MS (m/z): 655.51 [M+H] ⁺ .

[Production Example 68-1] 4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [chem 145]

The 1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxylic acid (141 mg, 0.468 mmol), 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3, 4-d] pyrimidine-7(8H)-tertiary butyl carboxylate (100 mg, 0.277 mmol), N,N-diisopropylethylamine (0.145 mL, 0.832 mmol), HATU (137 mg, 0.361 mmol ) in DMF (3 mL) was stirred overnight at room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound quantitatively. ESI-MS (m/z): 644.54 [M+H] ⁺ .

[Production Example 68-2] 4-((4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy- 1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl )methyl)piperidine-1-carboxylic acid tertiary butyl ester [chemical 146]

4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1, as described in Production Example 68-1, 2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary Trifluoroacetic acid (1.5 mL) was added to a solution of butyl ester (179 mg, 0.278 mmol) in dichloromethane (6 mL), and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid, extracted with dichloromethane, and dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (132 mg). Part of the obtained crude product (25 mg), tertiary butyl 4-formylpiperidine-1-carboxylate (14.7 mg, 0.069 mmol), sodium triacetyloxyborohydride (19.5 mg, 0.092 mmol ) in THF (3 mL) was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (29.9 mg). ESI-MS (m/z): 741.52 [M+H] ⁺ .

[Example 69] 1-cyclopentyl-N-(3-fluoro-4-((7-(1-methyltetrahydroazan-3-yl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide [Chem. 147]

To 3-(4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-diendoxyl) described in Production Example 69-1 at room temperature -1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- Trifluoroacetic acid (2 mL) was added to a solution of tertiary-butyl tetrahydroacridine-1-carboxylate (20 mg, 0.028 mmol) in dichloromethane (2 mL), and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. To a THF (2 mL) solution of the residue was added 35-37% aqueous formaldehyde (22.8 mg) at room temperature, followed by stirring for 10 minutes. Sodium triacetyloxyborohydride (11.9 mg, 0.056 mmol) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 14 hours and 20 minutes. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=4:1) to obtain the title compound (7 mg). ¹ H-NMR spectrum (400 MHz, CDCl ₃ ) δ (ppm): 1.68-1.83 (4H, m), 1.88-1.98 (2H, m), 2.17-2.24 (2H, m), 2.42-2.48 (6H, m), 2.63-2.70 (2H, m), 2.86-2.94 (2H, m), 3.02-3.15 (2H, m), 3.17-3.28 (1H, m), 3.48-3.54 (2H, m), 3.70- 3.81 (2H, m), 4.94-5.03 (1H, m), 7.06-7.14 (1H, m), 7.18-7.30 (2H, m), 7.72-7.84 (2H, m), 8.47 (1H, s), 8.53 (1H, s), 8.64 (1H, s), 10.85 (1H, brs). ESI-MS (m/z): 627.58 [M+H] ⁺ .

[Production Example 69-1] 3-(4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3 ,4-tetrahydropyrimidin-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)tetrahydroacridine -1-Tertiary butyl carboxylate [Chem. 148]

To 1-cyclopentyl-N-(3-fluoro-4-((5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine) as described in Production Example 1-10 at room temperature -4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-methyl To a solution of amide (20 mg, 0.036 mmol) in THF (2 mL) and acetic acid (0.1 mL) was added tertiary butyl 3-oxotetrahydroazia-1-carboxylate (12.3 mg, 0.072 mmol), and Stir at room temperature for 13 hours 10 minutes. Sodium triacetoxyborohydride (15.2 mg, 0.072 mmol) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 4 hours and 35 minutes. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 3:2 to 1:4) to obtain the title compound (20 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.43 (9H, s), 1.69-1.85 (4H, m), 1.86-1.98 (2H, m), 2.39-2.47 (2H, m) , 2.44 (3H, s), 2.64-2.81 (2H, m), 2.88-2.98 (2H, m), 3.28-3.39 (1H, m), 3.52-3.63 (2H, m), 3.85-3.94 (2H, m), 3.99-4.08 (2H, m), 4.92-5.03 (1H, m), 7.07-7.15 (1H, m), 7.20-7.30 (2H, m), 7.71-7.77 (1H, m), 7.78- 7.85 (1H, m), 8.48 (1H, s), 8.53 (1H, d, J = 2.5 Hz), 8.64 (1H, s), 10.85 (1H, s). ESI-MS (m/z): 713.65 [M+H] ⁺ .

[Example 70] 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrahydroazin-3-yl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1, 2,3,4-tetrahydropyrimidine-5-formamide [Chem. 149]

4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1, as described in Production Example 68-1, 2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary Trifluoroacetic acid (1.5 mL) was added to a solution of butyl ester (179 mg, 0.278 mmol) in dichloromethane (6 mL), and stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, extraction was performed with dichloromethane, and the organic layer was dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (132 mg). Part of the obtained crude product (30 mg), tertiary butyl 3-oxotetrahydroazine-1-carboxylate (37.8 mg, 0.221 mmol), sodium triacetyloxyborohydride (46.8 mg, 0.221 mmol) in THF (3 mL) was stirred overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain a crude product. Trifluoroacetic acid (1 mL) was added to a solution of the obtained crude product in dichloromethane (4 mL), followed by stirring overnight at room temperature. Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, 35-37% aqueous formaldehyde (0.042 mL) and sodium triacetyloxyborohydride (17.3 mg, 0.082 mmol) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (13.5 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.36-0.50 (2H, m), 0.65-0.78 (2H, m), 1.25-1.33 (1H, m), 2.36 (3H, s) , 2.43 (3H, s), 2.61-2.70 (2H, m), 2.86-2.99 (4H, m), 3.12-3.22 (1H, m), 3.50 (2H, s), 3.58-3.69 (2H, m) , 3.79 (2H, brs), 7.10 (1H, t, J = 8.6 Hz), 7.19-7.28 (2H, m), 7.70-7.86 (2H, m), 8.46 (1H, s), 8.52 (1H, d , J = 2.5 Hz), 8.69 (1H, s), 10.83 (1H, s). ESI-MS (m/z): 613.45 [M+H] ⁺ .

[Example 71] N-(4-((7-(tetrahydroazil-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxygen)-3-fluorophenyl)-1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide [Chem. 150]

4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1, as described in Production Example 71-1, 2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4- To a mixture of nitrophenyl ester (29.5 mg, 0.042 mmol) and DMF (2 mL) was added N,N-diisopropylethylamine (14.5 μL, 0.083 mmol) and tetrahydroacridine (5 μL, 0.074 mmol ), stirred at room temperature for 16 hours and 20 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7: 3 to 1: 9) to obtain a crude product. Diethyl ether was added to the obtained crude product, it was ultrasonically pulverized, and the solid was collected by filtration to obtain the title compound (18.6 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.39-0.51 (2H, m), 0.69-0.80 (2H, m), 1.19-1.37 (1H, m), 2.22-2.36 (2H, m), 2.45 (3H, s), 2.91 (2H, t, J = 5.5 Hz), 3.67 (2H, t, J = 5.8 Hz), 3.81 (2H, brs), 4.02-4.17 (4H, m), 4.50 (2H, s), 7.13 (1H, t, J = 8.6 Hz), 7.22-7.30 (2H, m), 7.76 (1H, dd, J = 8.6, 1.8 Hz), 7.83 (1H, dd, J = 12.2, 2.5 Hz), 8.51 (1H, s), 8.54 (1H, d, J = 2.5 Hz), 8.71 (1H, s), 10.85 (1H, s). ESI-MS (m/z): 627.51 [M+H] ⁺ .

[Production Example 71-1] 4-(4-(1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4-nitro Phenyl ester [Chem. 151]

The third grade of 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid described in Production Example 1-4 Butyl ester (20 mg, 0.055 mmol), 1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dipentoxy as described in Production Example 20-2 -1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (25.1 mg, 0.067 mmol), HATU (27.4 mg, 0.072 mmol) and DMF (1 mL) in the Ethylamine (0.030 mL, 0.172 mmol), stirred at room temperature for 66 hours and 20 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7: 3 to 1: 4) to obtain a crude product. Trifluoroacetic acid (1 mL) was added to a mixture of the obtained crude product and dichloromethane (3 mL), followed by stirring at room temperature for 60 minutes. Toluene (3 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the obtained residue, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. 4-Nitrophenyl chloroformate (16.7 mg, 0.083 mmol) and pyridine (0.013 mL, 0.166 mmol) were sequentially added to a mixture of the obtained residue and dichloromethane (3 mL), and stirred at room temperature for 39 hours 30 minutes. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7:3 to 1:4) to obtain the title compound (29.5 mg). ESI-MS (m/z): 709.42 [M+H] ⁺ .

[Example 72] 1-(cyclopropylmethyl)-N-(4-((7-((1-ethylpiperidin-4-yl)methyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2, 3,4-tetrahydropyrimidine-5-carboxamide [Chem. 152]

To 4-((4-(4-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxygen) described in Production Example 15-1 at room temperature Base-1,2,3,4-tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H) Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (42 mg, 0.056 mmol) in dichloromethane (2 mL) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. To a THF (2 mL) solution of the residue was added 90% acetaldehyde (35 μL, 0.565 mmol) at room temperature, and stirred at room temperature for 10 minutes. Sodium triacetyloxyborohydride (23.9 mg, 0.113 mmol) was added to the reaction mixture at room temperature, followed by stirring at room temperature for 20 minutes. Sodium bicarbonate and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. After the organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure. After purification of the residue by NH silica gel column chromatography (ethyl acetate ~ ethyl acetate: methanol = 4: 1), by NH silica gel thin layer chromatography (n-heptane: ethyl acetate = 1: 2 ) to obtain the title compound (25 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.41-0.52 (2H, m), 0.68-0.78 (2H, m), 1.10 (3H, t, J = 7.0 Hz), 1.18-1.45 (4H, m), 1.75-1.85 (2H, m), 1.88-2.00 (2H, m), 2.35-2.51 (4H, m), 2.73-2.82 (2H, m), 2.85-2.93 (2H, m) , 2.94-3.07 (2H, m), 3.57-3.66 (2H, m), 3.81 (2H, d, J = 7.3 Hz), 7.08-7.16 (1H, m), 7.19-7.32 (5H, m), 7.79 -7.88 (1H, m), 8.46 (1H, s), 8.71 (1H, s), 10.87 (1H, s). ESI-MS (m/z): 672.58 [M+H] ⁺ .

[Example 73] 1-(Cyclobutylmethyl)-N-(3-fluoro-4-((7-((1-methyltetrahydroazan-3-yl)methyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-formamide [Chem. 153]

4-(4-(1-(cyclobutylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester (185 mg) Trifluoroacetic acid (1 mL) was added to a solution of dichloromethane (4 mL), and stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, extracted with ethyl acetate, and dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product (131 mg). Part of the obtained crude product (25 mg), tertiary butyl 3-formyl tetrahydroazine-1-carboxylate (16.5 mg, 0.089 mmol), sodium triacetyloxyborohydride (28.4 mg, 0.134 mmol) in THF (3 mL) was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain a crude product. Trifluoroacetic acid (0.500 mL) was added to a dichloromethane (4.5 mL) solution of the obtained crude product, and stirred at room temperature for 1 hour. Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, 35-37% formaldehyde aqueous solution (0.029 mL) and sodium triacetyloxyborohydride (15.8 mg, 0.075 mmol) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (14.3 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.74-1.88 (2H, m), 1.91-2.00 (2H, m), 2.07-2.19 (2H, m), 2.29 (3H, s) , 2.70-2.81 (6H, m), 2.85-2.96 (4H, m), 3.46 (2H, t, J = 7.0 Hz), 3.60 (2H, s), 3.95 (2H, d, J = 7.3 Hz), 7.11 (1H, t, J = 8.6 Hz), 7.18-7.30 (5H, m), 7.81 (1H, dd, J = 12.2, 2.5 Hz), 8.45 (1H, s), 8.55 (1H, s), 10.84 (1H, s). ESI-MS (m/z): 644.50 [M+H] ⁺ .

[Production Example 73-1] 1-(cyclobutylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl Ester [Chem. 154]

3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester (500 mg , 1.80 mmol), (bromomethyl)cyclobutane (0.606 mL, 5.39 mmol), potassium carbonate (745 mg, 5.39 mmol) in DMF (10 mL) was stirred overnight. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (500 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.34 (3H, t, J = 7.3 Hz), 1.75-1.85 (2H, m), 1.88-2.00 (2H, m), 2.07-2.17 (2H, m), 2.68-2.82 (1H, m), 3.89 (2H, d, J = 7.3 Hz), 4.33 (2H, q, J = 6.9 Hz), 7.12-7.18 (4H, m), 8.25 ( 1H, s).

[Production Example 73-2] 4-(4-(1-(cyclobutylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydro Pyrimidine-5-carboxamide)-2-fluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester [Chem. 155]

The 1-(cyclobutylmethyl)-3-(4-fluorophenyl)-2,4-dipentoxy-1,2,3,4-tetrahydropyrimidine-5- Ethyl formate (500 mg, 1.44 mmol), water (2 mL), 4 M hydrogen chloride-1,4-dioxane solution (10 mL, 40.0 mmol) were stirred at 70°C for 4 hours. Water (about 20 mL) was added to the reaction solution, and stirred at 0°C for 30 minutes. The precipitate was collected by filtration to obtain a crude product (377 mg). Part (106 mg) of the obtained crude product, 4-(4-amino-2-fluorophenoxy)-5,6-dihydropyrido[3,4- d] Pyrimidine-7(8H)-tertiary butyl carboxylate (100 mg, 0.277 mmol), N,N-diisopropylethylamine (0.097 mL, 0.555 mmol), HATU (137 mg, 0.361 mmol) The DMF (3 mL) solution was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed twice with water, then washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound quantitatively. ESI-MS (m/z): 661.50 [M+H] ⁺ .

[Example 74] N-(3-fluoro-4-((7-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-5,6,7,8 -Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy- 1,2,3,4-tetrahydropyrimidine-5-carboxamide [Chem. 156]

6-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2) described in Production Example 74-1 ,3,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2,6- Add trifluoroacetic acid (0.500 mL) to a solution of tert-butyl diazaspiro[3.3]heptane-2-carboxylate (23.2 mg, 0.031 mmol) in dichloromethane (3 mL), and stir at room temperature for 1 hour . Toluene was added to the reaction liquid, followed by concentration under reduced pressure. THF (3 mL) was added to the residue, followed by 35-37% formaldehyde aqueous solution (0.024 mL) and sodium triacetyloxyborohydride (13.0 mg, 0.061 mmol), and stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (12.4 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.48 (6H, d, J = 6.7 Hz), 2.27 (3H, s), 2.89 (2H, t, J = 5.5 Hz), 3.31 ( 4H, s), 3.64 (2H, t, J = 5.8 Hz), 4.10 (4H, s), 4.47 (2H, s), 4.90-5.00 (1H, m), 7.12 (1H, t, J = 8.6 Hz ), 7.19-7.29 (5H, m), 7.83 (1H, dd, J = 12.2, 2.5 Hz), 8.49 (1H, s), 8.66 (1H, s), 10.89 (1H, s). ESI-MS (m/z): 673.47 [M+H] ⁺ .

[Production Example 74-1] 6-(4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3 ,4-tetrahydropyrimidine-5-carboxamide)phenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)-2,6-diazepine Heterospiro[3.3]heptane-2-carboxylic acid tertiary butyl ester [Chem. 157]

4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3, 4-tetrahydropyrimidine-5-carboxamido)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid 4-nitrophenyl ester (30 mg, 0.043 mmol), N,N-diisopropylethylamine (0.022 mL, 0.129 mmol), 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl oxalate (41.7 mg , 0.086 mmol) in DMF (3 mL) was stirred overnight at room temperature. The reaction was stirred at 70°C for 8 hours. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (23.2 mg). ESI-MS (m/z): 759.52 [M+H] ⁺ .

[Example 75] 1-cyclopentyl-N-(2,5-difluoro-4-((7-(1-methyltetrahydroazin-3-yl)-5,6,7,8- Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2 ,3,4-tetrahydropyrimidine-5-formamide [Chem. 158]

3-(4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2) described in Production Example 75-2 ,3,4-tetrahydropyrimidine-5-carboxamide)-2,5-difluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl ) Trifluoroacetic acid (0.800 mL) was added to a mixture of tert-butyl tetrahydroacridine-1-carboxylate (13.1 mg, 0.018 mmol) and dichloromethane (2.5 mL), and stirred at room temperature for 3 hours and 45 minutes. Toluene (2 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. To a mixture of the obtained residue and THF (2 mL), 35-37% formaldehyde aqueous solution (4.94 μL) and sodium triacetyloxyborohydride (5.70 mg, 0.027 mmol) were sequentially added, and stirred at room temperature for 2 hours 30 minutes. Saturated aqueous sodium bicarbonate solution and water were added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 4 to ethyl acetate: methanol = 9: 1) to obtain a crude product. Diethyl ether was added to the obtained crude product, it was ultrasonically pulverized, and the solid was collected by filtration to obtain the title compound (6.80 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 1.66-2.11 (6H, m), 2.16-2.33 (2H, m), 2.40 (3H, s), 2.44 (3H, s), 2.65 -2.75 (2H, m), 2.91 (2H, t, J = 5.8 Hz), 2.99 (2H, t, J = 7.0 Hz), 3.20 (1H, quin, J = 6.4 Hz), 3.53 (2H, s) , 3.67 (2H, t, J = 6.7 Hz), 4.99 (1H, quin, J = 7.8 Hz), 7.00 (1H, dd, J = 10.4, 6.7 Hz), 7.21-7.30 (1H, m), 7.75 ( 1H, dd, J = 8.6, 1.8 Hz), 8.41-8.51 (2H, m), 8.52 (1H, d, J = 2.5 Hz), 8.64 (1H, s), 11.07 (1H, d, J = 1.8 Hz ). ESI-MS (m/z): 645.59 [M+H] ⁺ .

[Production Example 75-1] 4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide)-2,5-difluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl ester[ 159]

4-(4-Amino-2,5-difluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)- as described in Production Example 8-2 Tertiary butyl formate (75 mg, 0.198 mmol), 1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dioxo- Add N,N-diisopropyl ethyl amine (0.104 mL, 0.595 mmol), stirred at room temperature for 15 hours and 30 minutes. The mixture was stirred at 60°C for 1 hour. Water was added to the reaction liquid, followed by extraction with ethyl acetate twice. The combined organic layers were filtered using Presep, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=4:1-2:3) to obtain the title compound (113 mg). ESI-MS (m/z): 676.52 [M+H] ⁺ .

[Production Example 75-2] 3-(4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dipentoxy-1,2,3 ,4-tetrahydropyrimidine-5-carboxamide)-2,5-difluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)tetrahydropyrimidin-7(8H)-yl) Tertiary butyl hydroacridine-1-carboxylate [Chem. 160]

4-(4-(1-cyclopentyl-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-carboxamide)-2,5-difluorophenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylic acid tertiary butyl Trifluoroacetic acid (1 mL) was added to a mixture of the ester (113 mg, 0.167 mmol) and dichloromethane (3 mL), and stirred at room temperature for 30 minutes. Toluene (2 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the obtained residue, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain crude product (96 mg). To a mixture of a portion (14 mg) of the obtained crude product and dichloromethane (2.19 mL) were added successively tertiary-butyl 3-oxotetrahydroazine-1-carboxylate (20.8 mg, 0.122 mmol) and Acetic acid (5.47 μL, 0.096 mmol), stirred at room temperature for 16 hours. Sodium triacetyloxyborohydride (7.73 mg, 0.036 mmol) was added to the mixture, followed by stirring at room temperature for 1 hour and 15 minutes. To the mixture was added tertiary-butyl 3-oxotetrahydroazia-1-carboxylate (20.8 mg, 0.122 mmol), and stirred at room temperature for 1 hour and 15 minutes. Sodium triacetyloxyborohydride (7.73 mg, 0.036 mmol) was added to the mixture, followed by stirring at room temperature for 3 hours and 45 minutes. Sodium triacetoxyborohydride was continuously added to the mixture over 15 min at room temperature until disappearance of starting material was confirmed by TLC. Saturated aqueous sodium bicarbonate solution was added to the mixture, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (13.1 mg). ESI-MS (m/z): 731.90 [M+H] ⁺ .

[Example 76] 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(4-(4-methylpiper-1-yl)piper Pyridine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-two-side oxy-1, 2,3,4-tetrahydropyrimidine-5-formamide [Chem. 161]

1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-N-(4-((5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (150 mg, 0.284 mmol ), pyridine (0.069 mL, 0.851 mmol), and 4-nitrophenyl chloroformate (86 mg, 0.426 mmol) in dichloromethane (4.5 mL) were stirred overnight at room temperature. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain a crude product (173 mg). Part of the obtained crude product (50 mg), N,N-diisopropylethylamine (0.025 mL, 0.144 mmol), 1-methyl-4-(piperidin-4-yl)-piperone (15.9 mg, 0.087 mmol) in DMF (3 mL) was stirred at room temperature for 2 hours. Thereafter, the reaction solution was stirred overnight at 70°C. Water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (25.7 mg). ¹ H-NMR spectrum (500 MHz, CDCl ₃ ) δ (ppm): 0.43-0.48 (2H, m), 0.70-0.76 (2H, m), 1.22-1.32 (1H, m), 1.45-1.61 (2H, m), 1.82-1.90 (2H, m), 2.27 (3H, s), 2.35-2.69 (9H, m), 2.82 (2H, t, J = 11.9 Hz), 2.92 (2H, t, J = 5.5 Hz ), 3.56 (2H, t, J = 5.8 Hz), 3.77-3.83 (4H, m), 4.43 (2H, s), 7.03-7.13 (2H, m), 7.21-7.30 (4H, m), 7.70 ( 2H, d, J = 8.6 Hz), 8.50 (1H, s), 8.71 (1H, s), 10.80 (1H, s). ESI-MS (m/z): 738.55 [M+H] ⁺ .

[Pharmacological test example] 1. Axl Kinase Assay This assay measures the inhibitory activity of the test substance on the tyrosine kinase activity of the Axl protein.

Axl protein (Carna Biosciences, Inc. 08-107) solution 5 μL, 5 μL analysis buffer solution containing CSK-tide substrate (AnaSpec Inc 63843) with a final concentration of 1000 nM and ATP (adenosine triphosphate, adenosine triphosphate) (promega V9102) with a final concentration of 6.7 μM, 5 μL of the test substance diluted in assay buffer was reacted at room temperature for 1 hour. Kinase activity was determined using ADP-GloTM Kinase Assay (promega V9102). After the reaction, add ADP-Glo reagent in the form of 15 μL per well, and react at room temperature for 40 minutes to stop the kinase reaction and consume the remaining ATP. Furthermore, 30 μL of kinase detection reagent was added and reacted at room temperature for 40 minutes to carry out conversion of ADP (adenosine diphosphate, adenosine diphosphate) to ATP, luciferase/luciferin coupling reaction, and luminescent reaction using ATP. Enzyme activity was evaluated by measuring the amount of luminescence in each well with Envision ^™ (PerkinElmer Co., Ltd.). The luminescence amount when the test substance was not added but the kinase protein was added was set to 100%, and the luminescence amount when the test substance and the kinase protein were not added was set to 0%, and the luminescence amount in the presence of the test substance was obtained. Luminous rate. The concentration of the test substance required to inhibit the kinase activity by 50% (IC ₅₀ value) was calculated from the luminescence ratio, and is shown in Table 1.

2. Mer Kinase Analysis This assay measures the inhibitory activity of the test substance on the tyrosine kinase activity of the Mer protein.

In the determination of kinase activity, QSS Assist ^TM Mer (MerTK)_TR-FRET analysis kit (08-108TX from Carna Biosciences) was used to implement according to the attached instructions. Add 10 μL of ×4000Mer protein solution diluted 4000 times with 1× assay buffer (15 mM Tris-HCl (pH 7.5), 0.01% Tween20, 2 mM DTT) to a flat-bottomed 384-well black plate (Corning 3573) , 5 μL of 5×ATP/substrate/Metal solution diluted 5 times with 1× assay buffer, 5 μL of the test substance diluted with assay buffer, and react at room temperature for 1 hour (the composition of the solution when used as a phosphorylation reaction , the substrate concentration was 250 nM, the ATP concentration was 3 μM, and the metal ion concentration was 10 mM). Add Eu-labeled anti-phosphorylation antibody (PerkinElmer Co. AD0068), and 60 μL of receptor fluorescent molecular reagent (CR130-100 from PerkinElmer Co., Ltd.) diluted to 33 nM, reacted at room temperature for 30 minutes in the dark. The fluorescence intensity at 620 nm and 665 nm when each well was irradiated with an excitation light of 340 nm was measured by Envision ^TM (PerkinElmer Co., Ltd.). The ratio of the fluorescence intensity at 655 nm to the fluorescence intensity at 620 nm in each well was defined as the TR-FRET ratio, and the TR-FRET ratio when the kinase protein was added without the test substance was defined as 100%, the TR-FRET ratio when no test substance and kinase protein was added was set to 0%, and the TR-FRET ratio in the presence of the test substance was calculated. From this TR-FRET ratio, the concentration of the test substance required to inhibit the kinase activity by 50% (IC ₅₀ value) was calculated and shown in Table 1.

[Table 1] ＜Axl and Mer cell-free kinase inhibitory data＞ Example number Axl IC50 (nM) Mer IC50 (nM) Example number Axl IC50 (nM) Mer IC50 (nM) Example 1 5.2 190 Example 39 5.3 55 Example 2 6.6 530 Example 40 7.4 100 Example 3 3.7 74 Example 41 2.7 44 Example 4 6.3 77 Example 42 3.7 53 Example 5 2.5 32 Example 43 5.9 130 Example 6 4.0 59 Example 44 4.0 65 Example 7 3.5 39 Example 45 2.4 60 Example 8 5.4 130 Example 46 2.7 51 Example 9 2.5 94 Example 47 5.9 290 Example 10 4.3 88 Example 48 2.6 78 Example 11 14 200 Example 49 14 > 1000 Example 12 3.4 120 Example 50 14 430 Example 13 4.0 210 Example 51 8.5 190 Example 14 5.0 170 Example 52 5.4 120 Example 15 1.9 62 Example 53 2.5 100 Example 16 5.0 96 Example 54 9.4 520 Example 17 4.4 64 Example 55 6.7 200 Example 18 4.6 56 Example 56 3.1 90 Example 19 9.9 150 Example 57 5.2 92 Example 20 6.7 120 Example 58 4.3 80 Example 21 3.8 47 Example 59 6.0 300 Example 22 7.8 240 Example 60 2.9 180 Example 23 8.9 120 Example 61 2.8 86 Example 24 7.4 130 Example 62 2.6 62 Example 25 9.5 210 Example 63 2.6 39 Example 26 13 660 Example 64 3.2 61 Example 27 7.5 290 Example 65 9.7 290 Example 28 16 > 1000 Example 66 3.7 150 Example 29 6.0 110 Example 67 7.9 300 Example 30 12 500 Example 68 5.3 270 Example 31 5.3 > 1000 Example 69 4.2 120 Example 32 9.5 490 Example 70 3.7 170 Example 33 4.8 100 Example 71 2.1 190 Example 34 2.9 30 Example 72 2.5 45 Example 35 5.5 260 Example 73 3.1 130 Example 36 3.9 210 Example 74 4.2 160 Example 37 4.1 61 Example 75 3.8 48 Example 38 13 200 Example 76 1.8 82

3. Analysis of Axl-Expressed Ba/F3 Cell Proliferation Inhibition This assay measures the growth inhibitory activity of the test substance in Axl-expressing Ba/F3 cells that proliferate in an Axl activity-dependent manner.

Use RPMI-1640 (WAKO 187-02021) medium containing 10% FBS (Fetal Bovine Serum, fetal bovine serum), penicillin/streptomycin (WAKO 168-23191), in a 5% _CO2 incubator (37°C ) The Ba/F3 cells (Carna Biosciences) introduced with human Axl were cultured and maintained. 20 μL per well was added to each well of a 384-well plate (Greiner's 781080) to prepare a Ba/F3 cell suspension at 2.5 × 10 ⁴ cells/mL in RPMI-1640 medium containing 10% FBS. Then, 20 μL/well of the test substance diluted in RPMI-1640 medium containing 10% FBS was added, and cultured in a 5% CO ₂ incubator (37°C) for 2 days. Add 19.5 μL of CellTiter-Glo ^TM 2.0 (G9243 from Promega) to each well, and incubate at room temperature for 45 minutes. Luminescence was measured by ViewLux ^™ (PerkinElmer) or ENVISION ^™ (PerkinElmer). The luminescence amount in the case where no test substance was added was set to 100%, and the luminescence amount in wells without cells was set to 0%, and the luminescence rate in the presence of the test substance was obtained. The concentration (IC ₅₀ value) of the test substance required to inhibit cell proliferation by 50% was determined and shown in Table 2.

4. Analysis of Mer-Expressed Ba/F3 Cell Proliferation Inhibition This assay measures the growth inhibitory activity of a test substance in Mer-expressing Ba/F3 cells that proliferate in a Mer activity-dependent manner.

Use RPMI-1640 (WAKO 187-02021) medium containing 10% FBS, penicillin/streptomycin (WAKO 168-23191), in a 5% CO ₂ incubator (37°C) for Ba/ F3 cells (Carna Biosciences) were maintained in culture. 20 μL per well was added to each well of a 384-well plate (Greiner's 781080) to add a Ba/F3 cell suspension prepared at 2.5 × 10 ⁴ cells/mL using RPMI-1640 medium containing 10% FBS. Then, 20 μL/well of the test substance diluted in RPMI-1640 medium containing 10% FBS was added, and cultured in a 5% CO ₂ incubator (37°C) for 2 days. Add 19.5 μL of CellTiter-Glo ^TM 2.0 (G9243 from Promega) to each well, and incubate at room temperature for 45 minutes. Luminescence was measured by ViewLux ^™ (PerkinElmer) or ENVISION ^™ (PerkinElmer). The luminescence amount in the case where no test substance was added was set to 100%, and the luminescence amount in wells without cells was set to 0%, and the luminescence rate in the presence of the test substance was obtained. The concentration (IC ₅₀ value) of the test substance required to inhibit cell proliferation by 50% was determined and shown in Table 2.

[Table 2] ＜Axl and Mer expression Ba/F3 cell proliferation inhibition analysis data＞ Example number Axl IC50 (nM) Mer IC50 (nM) Example number Axl IC50 (nM) Mer IC50 (nM) Example 1 28 180 Example 39 37 300 Example 2 110 570 Example 40 57 240 Example 3 15 78 Example 41 8.1 67 Example 4 twenty two 92 Example 42 17 71 Example 5 3.6 twenty three Example 43 34 110 Example 6 15 83 Example 44 18 230 Example 7 18 89 Example 45 9.0 32 Example 8 41 270 Example 46 7.9 34 Example 9 5.3 26 Example 47 44 190 Example 10 29 150 Example 48 17 82 Example 11 66 370 Example 49 67 730 Example 12 20 140 Example 50 72 450 Example 13 27 220 Example 51 41 190 Example 14 29 230 Example 52 38 250 Example 15 8.4 51 Example 53 6.2 61 Example 16 26 200 Example 54 91 1400 Example 17 10 45 Example 55 41 320 Example 18 17 130 Example 56 10 64 Example 19 twenty three 130 Example 57 35 230 Example 20 31 120 Example 58 27 87 Example 21 9.9 63 Example 59 25 210 Example 22 74 290 Example 60 15 140 Example 23 58 270 Example 61 10 55 Example 24 110 490 Example 62 3.1 19 Example 25 78 370 Example 63 8.0 34 Example 26 92 690 Example 64 6.5 26 Example 27 78 320 Example 65 55 390 Example 28 160 800 Example 66 twenty two 230 Example 29 48 240 Example 67 100 1300 Example 30 120 630 Example 68 34 210 Example 31 100 440 Example 69 13 92 Example 32 45 330 Example 70 19 130 Example 33 31 100 Example 71 48 710 Example 34 twenty one 130 Example 72 12 59 Example 35 47 290 Example 73 19 150 Example 36 twenty one 140 Example 74 32 250 Example 37 31 210 Example 75 6.1 26 Example 38 71 430 Example 76 11 140

5. Phosphorylated Axl inhibitory effect of Axl expression in HeLa cell subcutaneous transplantation model The human Axl gene was transfected into HeLa cells (Dainippon Sumitomo Pharmaceutical Co., Ltd.) to obtain an overexpression strain. Using D-PBS (-) (045-29795 of Wako Pure Chemical Industries) to express HeLa cells in Axl cultured in D-MEM (044-29765 of Wako Pure Chemical Industries) containing 10% FBS and penicillin/streptomycin Prepared to a concentration of 2 × 10 ⁸ cells/mL, mixed with MATRIGEL (Corning International's Cat# 354234) at a ratio of 1:1 to prepare a cell suspension of 1 × 10 ⁸ cells/mL. A volume of 100 μL was transplanted into the subcutaneous part of the right abdomen of 6-week-old nude mice (BALB/cAJcl-nu/nu, female, CLEA Japan Co., Ltd.). After 14 days from transplantation, the groups were divided except for individuals with smaller tumors formed. Dissolve the test substance in DMSO, add Tween80 to prepare a 5-fold concentration solution, and store it in cold storage. Just before administration, 5% glucose solution was added to prepare a final administration solution (DMSO: Tween80: 5% glucose solution = 7%: 13%: 80%). The evaluation test system was orally administered at an administration volume of 10 mL/kg. The experiment was carried out with 1 group of 3 rats. The tumor was excised 4 hours after the administration, and was rapidly frozen with liquid nitrogen. For frozen tumors, a cell lysis buffer (Cell Signaling Technology Cat#9803) supplemented with 1 mM PMSF was added and crushed with a homogenizer. The supernatant obtained by centrifuging the cell suspension was used as a protein extract. The total protein amount in the protein extract was quantified using the Pierce ^™ BCA Protein Assay (Thermo Fisher Scientific Cat#23225). The amount of phosphorylated Axl was determined by ELISA method by adding 400 μg of protein extract to each well using PathScan phospho-Axl (panTyr) Sandwich ELISA Kit (Cell Signaling Technology Cat#7042). The amount of total Axl was measured by the ELISA method by adding 2 μg of the protein extract prepared by adding human total Axl Duoset IC ELISA (R&D Systems Cat#DYC1643-2). For each tumor, the amount of phosphorylated Axl corrected by the amount of total Axl was calculated, and the ratio (T/C) (%) of the amount of phosphorylated Axl in the test substance administration group to the amount of phosphorylated Axl in the control group was calculated, and shown in Table 3.

[table 3] ＜Evaluation data of phosphorylated Axl inhibitory effect in HeLa cell subcutaneous transplantation model of Axl expression＞ Example number Dose (mg/kg) T/C (%) Example 1 1.56 44 3.13 37 6.25 29 12.5 18 25 20 50 13

6. Anti-tumor effect in mouse Ba/F3-Axl subcutaneous transplantation model Hanks' balanced salt solution (Cat#084-08965 of Wako Pure Chemical Industries) will be used to contain 10% FBS, penicillin/streptomycin, and the final concentration is 0.5 The mouse myeloid cell line Ba/F3-Axl (Carna Biosciences) cultured in RPMI-1640 medium of μg/mL puromycin was prepared at a concentration of 2 × 10 ⁷ cells/mL. A volume of 100 μL was transplanted into the subcutaneous part of the right abdomen of a 5-week-old mouse (C3H/HeNcrl, female, Charles River Co., Ltd., Japan). Six days after transplantation, the short axis and long axis of the tumor were measured using an electronic digital vernier caliper (digital TM caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following calculation formula. Tumor volume (mm ³ ) = Long diameter (mm) x Short diameter (mm) x Short diameter (mm)/2 Based on the tumor volume on the first day of administration (Day 1), the average value of the tumor volume is approximately equal grouping. Dissolve the test substance in DMSO, add Tween80 to prepare a 5-fold concentration solution, and store it in cold storage. Just before administration, 5% glucose solution was added to prepare a final administration solution (DMSO: Tween80: 5% glucose solution = 7%: 13%: 80%). The evaluation test system was orally administered once a day at an administration volume of 10 mL/kg for 4 consecutive days. In addition, the experiment was carried out with 1 group of 5 animals. For each group of the control group and the test substance administration group, the ratio of the body weight on the last day to the body weight on the first day (relative body weight, RBW) is calculated, and the RBW of the test substance administration group/RBW of the control group is 0.8 or more The test substance-administered group was judged as a group that can be safely administered. For the test substance administration group meeting this determination, the ratio (T/C) (%) of the tumor volume after the test substance administration on the last day to the tumor volume of the control was calculated and shown in Table 4.

[Table 4] ＜Evaluation data of anti-tumor effect in mouse Ba/F3-Axl subcutaneous transplantation model＞ Example number Dose (mg/kg) T/C (%) Example 1 3 73 10 53

7. Histopathological examination of eyes Dissolve the test substance in DMSO, add Tween80, prepare a solution with 5 times the concentration, and store it in cold storage. Add 5% glucose solution just before administration to make the final administration solution (DMSO: Tween80: 5% glucose solution = 7% : 13% : 80%). To 7-week-old mice (BALB/cAjcl, female, CLEA Japan Co., Ltd.), the evaluation samples were orally administered once a day at an administration volume of 20 mL/kg for 14 consecutive days. On the second day after the final administration day, the eyeballs were euthanized by cervical dislocation, and the eyeballs were taken out with glutaraldehyde-formalin solution (25% glutaraldehyde: formaldehyde: phosphate buffer = 12.5 : 2.5 : 85 (v/ v/v)) After being fixed, make pathological specimens embedded in paraffin and stained with hematoxylin-eosin for pathological examination. In addition, the experiment was carried out with 1 group of 5 animals. For each group of the control group and the test substance administration group, the ratio of the body weight on the last day to the body weight on the first day (relative body weight, RBW) is calculated, and the RBW of the test substance administration group/RBW of the control group is 0.8 or more The test substance-administered group was judged as a group that can be safely administered.

In Example 1: No histological change in the retina was observed in the administration group with an administration amount of 100 mg/kg.

8. The combined effect of HCC1806 and eribulin in the subcutaneous transplantation model of mice Using Hanks' balanced salt solution (Cat#084-08965 of Wako Pure Chemical Industries, Ltd.) Human breast cancer cell line HCC1806 cultured in 1640 medium was prepared at a concentration of 9 × 10 ⁷ cells/mL, mixed with MATRIGEL (Cat# 354234 of Corning International Co., Ltd.) at a ratio of 1 : 1 to prepare 4.5 × 10 ⁷ cells/ml cell suspension. A volume of 100 μL was transplanted into the subcutaneous part of the right abdomen of 6-week-old nude mice (CAnN. Cg-Foxnlnu/CrlCrlj, female, Charles River Co., Ltd., Japan). Seven days after transplantation, the short axis and long axis of the tumor were measured using an electronic digital vernier caliper (digital TM caliper, Mitutoyo Co., Ltd.), and the tumor volume was calculated by the following calculation formula. Tumor volume (mm ³ ) = long diameter (mm) x short diameter (mm) x short diameter (mm)/2 Based on the tumor volume on the first day of administration (1st day), the average value of the tumor volume is approximately equal grouping. Dissolve the test substance in DMSO, add Tween80 to prepare a 5-fold concentration solution, and store it in cold storage. Just before administration, 5% glucose solution was added to prepare a final administration solution (DMSO: Tween80: 5% glucose solution = 7%: 13%: 80%). The evaluation sample was administered orally once a day for 28 consecutive days at an administration volume of 20 mL/kg, and 0.15 mg/mL Eribulin solution. For the control group, 0.15 mg/mL Eribulin solution was injected into the caudal vein at an administration volume of 10 mL/kg on the first day and the eighth day. In addition, the experiment was carried out with 1 group of 5 animals. For each of the control group and the test substance administration group, the ratio of the body weight on the last day to the body weight on the first day (relative body weight, RBW) was calculated. The test substance administration group in which the RBW of the test substance administration group/the RBW of the control group was 0.8 or more was determined as a group that could be safely administered. For the test substance administration group meeting this determination, the ratio (T/C) (%) of the tumor volume after the test substance administration on the last day to the tumor volume of the control was calculated and shown in Table 5.

[table 5] ＜Effect of combined use with eribulin in mouse HCC1806 subcutaneous transplantation model＞ Example number Dose (mg/kg) T/C (%) Example 1 25 47 50 twenty four 100 15

Claims (11)

A compound or a pharmaceutically acceptable salt thereof, which is selected from one of the following compound groups: (1) 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide, (2) N-(3-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl) -3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-formamide, (3) N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4- d] pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydro pyrimidine-5-carboxamide, (4) N-(3-fluoro-4-((7-((1-methyltetrahydroazine-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (5) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (6) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methylpiperidin-4-yl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- Formamide, (7) N-(5-((7-(tetrahydroazine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )pyridin-2-yl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5 - formamide, (8) N-(4-((7-(tetrahydroazine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )-2,5-difluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetra Hydropyrimidine-5-carboxamide, (9) 1-cyclopentyl-N-(3-fluoro-4-((7-(1-methylpiperidin-4-yl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5- Formamide, (10) N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)acetyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4 -tetrahydropyrimidine-5-formamide, (11) N-(4-((7-(2-(tetrahydroazine-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3 ,4-tetrahydropyrimidine-5-formamide, (12) N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (13) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-((1-methylpiperidin-4-yl)methyl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydro pyrimidine-5-carboxamide, (14) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine- 4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (15) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-formamide, (16) N-(4-((7-(2-(tetrahydroazine-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two side oxy-1 ,2,3,4-tetrahydropyrimidine-5-formamide, (17) N-(4-((7-(1-ethyltetrahydroazil-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- Base) oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-formamide, (18) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methyltetrahydroazine-3-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-formamide, (19) 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-formyl amine, (20) 1-(cyclopropylmethyl)-N-(2-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide, (21) 1-cyclopentyl-3-(4-fluorophenyl)-N-(4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-formyl amine, (22) N-(3-fluoro-4-((7-(3-(pyrrolidin-1-yl)propionyl)-5,6,7,8-tetrahydropyrido[3,4-d ]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine -5-formamide, (23) (S)-N-(3-fluoro-4-((7-(2-(1-methylpyrrolidin-2-yl)acetyl)-5,6,7,8-tetrahydro Pyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2 ,3,4-tetrahydropyrimidine-5-formamide, (24) N-(3-fluoro-4-((7-(2-(tetrahydro-2H-pyran-4-yl)acetyl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide, (25) N-(3-fluoro-4-((7-(2-(4-methylpiper-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydro Pyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2 ,3,4-tetrahydropyrimidine-5-formamide, (26) N-(4-((7-(cyclopentylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3- Fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (27) N-(4-((7-(2-cyclopropylacetyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-formyl amine, (28) N-(4-((7-(3,3-difluorocyclobutylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Formamide, (29) N-(4-((7-(2,2-difluorocyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Formamide, (30) N-(3-fluoro-4-((7-(1-methylpiperidine-4-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine- 4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Formamide, (31) N-(4-((7-(cyclobutylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3- Fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (32) N-(3-fluoro-4-((7-(2-(4-methylpiper-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4 -tetrahydropyrimidine-5-formamide, (33) N-(3-fluoro-4-((7-((1-methylpiperidin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4- d] pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydro pyrimidine-5-carboxamide, (34) N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3- Fluorophenyl)-1-(2-fluoroethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-formyl amine, (35) N-(3-fluoro-4-((7-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)-5,6,7, 8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy -1,2,3,4-tetrahydropyrimidine-5-formamide, (36) N-(3-fluoro-4-((7-(3-(1-methylpiperidin-4-yl)propionyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4 -tetrahydropyrimidine-5-formamide, (37) N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3- Fluorophenyl)-1-cyclopropyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (38) N-(3-fluoro-4-((7-(oxetane-3-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-methyl Amide, (39) N-cyclopropyl-4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide)phenoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-formamide, (40) N-(4-((7-cyclobutyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl )-3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (41) N-(3-fluoro-4-((7-(4-(4-methylpiper-1-yl)piperidine-1-carbonyl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2, 3,4-tetrahydropyrimidine-5-carboxamide, (42) N-(2,5-difluoro-4-((7-(2-(1-methylpiperidin-4-yl)acetyl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2, 3,4-tetrahydropyrimidine-5-carboxamide, (43) N-(2-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4- d] pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydro pyrimidine-5-carboxamide, (44) N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl) -3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-formamide, (45) N-(2,5-difluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4 -tetrahydropyrimidine-5-formamide, (46) 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydro pyrimidine-5-carboxamide, (47) 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- Formamide, (48) 1-(cyclopropylmethyl)-N-(2-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-formamide, (49) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-methyl-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (50) 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-((1-methyltetrahydroazine-3-yl)methyl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-formamide, (51) 1-cyclopentyl-N-(2-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl) Oxy)phenyl)-3-(4-fluorophenyl)-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (52) N-(4-((7-(2-(tetrahydroazil-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4 -d] pyrimidin-4-yl)-oxyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two side oxy- 1,2,3,4-tetrahydropyrimidine-5-formamide, (53) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide, (54) N-(4-((7-(tetrahydroazine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )-3-fluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-formamide, (55) N-4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3-fluoro Phenyl)-1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide , (56) N-4-((7-(2-(1-ethylpiperidin-4-yl)ethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine -4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetra Hydropyrimidine-5-carboxamide, (57) N-cyclopropyl-4-((6-(1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3 ,4-tetrahydropyrimidine-5-carboxamide)pyridin-3-yl)oxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide, (58) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(5-((7-((1-methylpiperidin-4-yl)methyl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)pyridin-2-yl)-2,4-two-side oxy-1,2,3,4 -tetrahydropyrimidine-5-formamide, (59) 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-formamide, (60) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(2-(1-methylpiperidin-4-yl)ethyl) -5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (61) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methyltetrahydroazine-3-yl)methyl)-5,6,7 ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide, (62) 1-cyclopentyl-N-(3-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-formamide, (63) 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methyltetrahydroazine-3-yl)methyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (64) 1-cyclopentyl-N-(2-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-formamide, (65) 1-cyclopentyl-3-(4-fluorophenyl)-N-(4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d] Pyrimidin-4-yl)oxy)phenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (66) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(2-(4-methylpiper-1-yl)acetyl)-5,6, 7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2 ,3,4-tetrahydropyrimidine-5-formamide, (67) N-(4-((7-(cyclopropylcarbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl) -1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-formyl amine, (68) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1, 2,3,4-tetrahydropyrimidine-5-carboxamide, (69) 1-cyclopentyl-N-(3-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetrahydropyrido[ 3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (70) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide, (71) N-(4-((7-(tetrahydroazine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )-3-fluorophenyl)-1-(cyclopropylmethyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (72) 1-(cyclopropylmethyl)-N-(4-((7-((1-ethylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide, (73) 1-(cyclobutylmethyl)-N-(3-fluoro-4-((7-((1-methyltetrahydroazine-3-yl)methyl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-formamide, (74) N-(3-fluoro-4-((7-(6-methyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine-5-carboxamide, (75) 1-cyclopentyl-N-(2,5-difluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetrahydro Pyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-dioxo-1,2,3 , 4-tetrahydropyrimidine-5-formamide, and (76) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(4-(4-methylpiper-1-yl)piperidine- 1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2, 3,4-tetrahydropyrimidine-5-carboxamide. A compound or a pharmaceutically acceptable salt thereof, which is selected from one of the following compound groups: (1) 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyridine And[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)-2,4-two side oxy-1,2,3, 4-tetrahydropyrimidine-5-formamide, (2) N-(3-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl) -3-(4-fluorophenyl)-1-isopropyl-2,4-diendoxy-1,2,3,4-tetrahydropyrimidine-5-formamide, (3) N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4- d] pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydro pyrimidine-5-carboxamide, (4) N-(3-fluoro-4-((7-((1-methyltetrahydroazine-3-yl)methyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (5) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8-tetra Hydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (6) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methylpiperidin-4-yl)-5,6,7 ,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5- Formamide, (7) N-(5-((7-(tetrahydroazine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )pyridin-2-yl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5 - formamide, (8) N-(4-((7-(tetrahydroazine-1-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy )-2,5-difluorophenyl)-1-isopropyl-3-(5-methylpyridin-2-yl)-2,4-two-side oxy-1,2,3,4-tetra Hydropyrimidine-5-carboxamide, (9) 1-cyclopentyl-N-(3-fluoro-4-((7-(1-methylpiperidin-4-yl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5- Formamide, (10) N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)acetyl)-5,6,7,8-tetrahydropyrido[3 ,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4 -tetrahydropyrimidine-5-formamide, (11) N-(4-((7-(2-(tetrahydroazine-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3 ,4-tetrahydropyrimidine-5-formamide, (12) N-(3-fluoro-4-((7-(2-(1-methylpiperidin-4-yl)ethyl)-5,6,7,8-tetrahydropyrido[3, 4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4- Tetrahydropyrimidine-5-carboxamide, (13) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-((1-methylpiperidin-4-yl)methyl)-5 ,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydro pyrimidine-5-carboxamide, (14) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine- 4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine-5-carboxamide, (15) 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3, 4-tetrahydropyrimidine-5-formamide, (16) N-(4-((7-(2-(tetrahydroazine-1-yl)-2-oxoethyl)-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-(cyclopropylmethyl)-3-(4-fluorophenyl)-2,4-two side oxy-1 ,2,3,4-tetrahydropyrimidine-5-formamide, (17) N-(4-((7-(1-ethyltetrahydroazil-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4- Base) oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetrahydropyrimidine- 5-formamide, (18) 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1-methyltetrahydroazine-3-yl)-5,6 ,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-formamide, and (19) 3-(4-fluorophenyl)-1-isopropyl-N-(4-((7-(1-methyltetrahydroazine-3-yl)-5,6,7,8 -tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-formyl amine. A compound or a pharmaceutically acceptable salt thereof, the compound is 1-cyclopentyl-N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl) represented by the following formula Methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(5-methylpyridin-2-yl)- 2,4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chem. 1]

. A compound or a pharmaceutically acceptable salt thereof, the compound is N-(3-fluoro-4-((7-methyl-5,6,7,8-tetrahydropyrido[3,4 -d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-two-side oxy-1,2,3,4-tetra Hydropyrimidine-5-carboxamide: [Chem. 2]

. A compound or a pharmaceutically acceptable salt thereof, the compound is N-(3-fluoro-4-((7-((1-methylpiperidin-4-yl)methyl)-5 represented by the following formula, 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4- Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chem. 3]

. A compound or a pharmaceutically acceptable salt thereof, which is N-(3-fluoro-4-((7-((1-methyltetrahydroazil-3-yl)methyl)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chem. 4]

. A compound or a pharmaceutically acceptable salt thereof, the compound is 1-(cyclopropylmethyl)-N-(3-fluoro-4-((7-(1-methyltetrahydroazine) represented by the following formula -3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-2, 4-Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chem. 5]

. A compound or a pharmaceutically acceptable salt thereof, the compound is 1-(cyclopropylmethyl)-3-(4-fluorophenyl)-N-(4-((7-(1- Methylpiperidin-4-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)phenyl)-2,4-dioxo -1,2,3,4-tetrahydropyrimidine-5-carboxamide: [Chem. 6]

. A pharmaceutical composition comprising the compound as described in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof. An Axl inhibitor comprising the compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8. The Axl inhibitor according to claim 10, which is an antitumor agent.