Pyrimidino[4,5-d]pyrimidin-2-one derivatives as protein kinase inhibitors

Abstract

Disclosed are a compound selected from novel pyrimido[4,5-d]pyrimidin-2-one derivatives exhibiting excellent antiproliferative activity against cancer cells, its pharmaceutically acceptable salts, its hydrates, and its stereoisomers; a method for preparing said compound; a pharmaceutical composition comprising said compound as an active ingredient for the prevention, mitigation, or treatment of cancer metastasis and proliferative diseases; and an anticancer composition containing said compound as an active ingredient targeting cancer cells. The compound of the present invention exhibits superior selective inhibitory activity against LCK and antiproliferative activity against cancer cells, and is therefore suitable for inhibiting cancer cells and for the prevention or treatment of cancer metastasis and proliferative diseases.

Description

[0001] Cross-references

[0002] This application claims the benefit of priority to Korean Patent Application No. 10-2019-0107018, filed on August 30, 2019, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a compound selected from novel pyrimido[4,5-d]pyrimidin-2-one derivatives having selective inhibitory activity against protein kinases, pharmaceutically acceptable salts thereof, their hydrates and stereoisomers, a method for preparing the compound, and a pharmaceutical composition comprising the compound as an active ingredient for the prevention, relief or treatment of cancer. Background Technology

[0004] Protein kinases are enzymes that catalyze phosphorylation reactions to transfer the γ-phosphate group of ATP to the hydroxyl groups of tyrosine, serine, and threonine residues in proteins. They are responsible for cell metabolism, gene expression, cell growth, cell differentiation, and cell division, and play an important role in cell signaling.

[0005] Protein kinases comprise approximately 2% of the eukaryotic genome, while the human genome contains about 518 protein kinases. Protein kinases are classified into tyrosine protein kinases that phosphorylate tyrosine and serine / threonine kinases that phosphorylate serine and threonine. Of these, about 90 or more are tyrosine kinases, which are further divided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs). Receptor tyrosine kinases are membrane proteins possessing a domain capable of housing growth factors on the cell surface and an active site capable of phosphorylating tyrosine residues in the cytoplasm. Non-receptor tyrosine kinases receive signals to phosphorylate tyrosine residues using a single tyrosine kinase domain present in the cell nucleus and cytoplasm, although they do not possess the shape of a receptor.

[0006] Protein kinases are molecular switches, and the transition between active and inactive states in cells should be smoothly regulated. Abnormal regulation leads to overactivation of intracellular signaling, resulting in uncontrolled cell division and proliferation. Furthermore, aberrant activation of protein kinases due to gene mutations, amplification, and overexpression is associated with the occurrence and development of various tumors, and is therefore crucial for the growth and metastasis of cancer cells. Representative protein kinases with aberrant regulation include EGFR, VEGFR, PDGFRB, c-KIT, ABL1, SRC, BRAF, FGFR, BTK, SYK, ALK, MET, CDK, MEK, mTOR, JAK, LCK, PLK, RSK, LYN, FMS, TIE2, RET, AKT, MAP, FAK, DDR, FLT3, and FES. In particular, receptor tyrosine kinases are primarily involved in signaling pathways related to internal responses and external signals associated with cell growth. Therefore, inhibition of receptor tyrosine kinases can induce inhibition of cancer cell growth and cell death.

[0007] Based on these characteristics, the inhibition of kinase activity has attracted attention as a major target for the development of anticancer drugs, and research and development of low-molecular-weight organic compounds targeting various kinases has been actively carried out.

[0008] Kinase inhibitors include those that act as inhibitors of Bcr-Abl and PDGFR tyrosine kinases. (Imatinib, Novartis), as a Her-2 antibody Trastuzumab (Genentech), as an EGFR inhibitor. Gefitinib (AstraZeneca), as an inhibitor of Raf, VEGFR, KIT, RET, PDGFR-B, and FLT-3. (Sorafenib, Bayer), as a BRAF inhibitor (Vemurafenib, Roche), as an EGFR antibody (Cetuximab, Inclone), as an EGFR inhibitor (Erlotinib, Genentech / Roche), as a KDR inhibitor (Sunitinib, Pfizer). These have been approved by the FDA as anticancer drugs for diseases such as leukemia, breast cancer, non-small cell lung cancer, liver cancer, malignant melanoma, and colorectal cancer, and are widely used as primary standard therapy due to their excellent therapeutic efficacy. In addition, several other compounds are in clinical trials.

[0009] LCK (lymphocyte-specific protein tyrosine kinase) is a member of the Src kinase family. It is a 56 kDa non-receptor tyrosine kinase expressed in T cells, NK cells, and the brain. LCK phosphorylates many kinases, including ZAP-70, ITK, PI3K, and PKC, and affects the cell cycle and cell metabolism. Because LCK plays a crucial role in T cell proliferation, differentiation, and migration, and interacts with the cytoplasmic domains of CD4, CD8, and the β-chain of the IL-2 receptor to induce TCR-mediated T cell activation, proliferation, and differentiation, LCK is an important molecular target for T cell-related diseases. Overexpression of LCK can lead to a variety of diseases and syndromes, including organ transplant rejection, cancer, inflammation, rheumatoid arthritis, asthma, type 1 diabetes, psoriasis, Crohn's disease, and atherosclerosis. LCK may be a molecular target for targeted therapy in colon cancer, chronic lymphocytic leukemia (CLL), thymoma, and glioblastoma.

[0010] [Existing Technical Documents]

[0011] [Patent Documents]

[0012] (Patent Document 1) International Patent Application No.: WO 2005-011597

[0013] [Non-patent literature]

[0014] (Non-patent literature 1) Choi HG, Ren P., Adrian F., et al., A type-II kinase inhibitor capable of inhibiting the T315I "gatekeeper" mutant of Bcr-Abl. J. Med. Chem., 2010; 53(15): 5439-5448.

[0015] (Non-patent document 2) Nonami, A.; Sattler, M.; Weisberg, E.; Liu, Q.; Zhang, J.; Patricelli, MP; Christie, AL; Saur, AM; Kohl, NE; Kung, AL; Yoon, H.; Sim, T.; Gray, NS; Griffin, JD. Identification of novel therapeutic targets in acuteleukemias with NRAS mutations using apharmacologic approach. Blood 2015,125(20),3133-3143.

[0016] (Non-patent literature 3) H Cho, I Shin, E Ju, et al.; First SAR Study for Overriding NRASMutant-Driven Acute Myeloid Leukemia. J. Med. Chem. 2018, 61(18), 8353-8373. Summary of the Invention

[0017] This invention was made to address the aforementioned problems related to the prior art.

[0018] One object of the present invention is to provide a novel pyrimido[4,5-d]pyrimidin-2-one derivative compound with selective inhibitory activity against protein kinases.

[0019] Another object of the present invention is to provide a pharmaceutical composition for treating, preventing and alleviating cancer-related diseases, said pharmaceutical composition comprising a novel pyrimido[4,5-d]pyrimidin-2-one derivative compound as an active ingredient, a pharmaceutically acceptable salt thereof, its hydrate thereof or a stereoisomer thereof.

[0020] Another object of the present invention is to provide a therapeutic agent for cancer-related diseases, inflammatory diseases, and immune diseases caused by overexpression and mutation of LCK, DDR1, FGR, BMX, ABL2, BLX, BLK, LYN, DDR2, RAF1, c-src, CS, and HCK kinases, said therapeutic agent containing a novel pyrimido[4,5-d]pyrimidin-2-one derivative compound as an active ingredient, a pharmaceutically acceptable salt thereof, its hydrate, or a stereoisomer thereof.

[0021] In one aspect, the present invention provides a compound selected from pyrimidine benzo[4,5-d]pyrimidin-2-one derivatives represented by any one of the following formulas 1 to 6, their pharmaceutically acceptable salts, their hydrates, and their stereoisomers: [Formula 1]

[0022]

[0023] [Equation 2]

[0024]

[0025] [Formula 3]

[0026]

[0027] [Formula 4]

[0028]

[0029] [Formula 5]

[0030]

[0031] [Formula 6]

[0032]

[0033] in

[0034] R1 is hydrogen; C1-C 13 Alkyl; C3-C 10 Cyclic groups; or C3-C 10 Heterocyclic groups;

[0035] A is hydrogen; C1-C 13 Alkyl; C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; C3-C 10 Heterocyclic group; or -C(O)-(C1-C 13 alkyl);

[0036] Y is C6-C 10 Aryl; or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S);

[0037] L1, L2, L3, and L4 are each independently selected from -NR5-; -NR5CH2-; -NR5C(O)-; -C(O)NR5-; -NR5C(O)NR5-; -S(O)2-; -NR5S(O)2-; -S(O)2NR5-; -O-; -CH2-; -CH(CH3-); -C(O)O-; -C(O-); The group formed;

[0038] L5 and L6 are each independently -C(O)NR5R6; -CR5R6R7; -OR5; -CCl3; C1-C6 alkyl; C3-C 10 Cycloyl; -substituted or unsubstituted benzene; -substituted or unsubstituted indole; -substituted or unsubstituted phenyl; -substituted or unsubstituted hexane; -substituted or unsubstituted furan; -substituted or unsubstituted thiophene; -substituted or unsubstituted pyridine; -substituted or unsubstituted benzofuran; -substituted or unsubstituted naphthalene; -substituted or unsubstituted anthracene; or -substituted or unsubstituted phenanthrene;

[0039] R2, R3, and R4 are each independently -O-; -CH2-; -CH(CH3)-; -CR5R6-; -NR5-; -NR5CH2-; -NR5C(O)-; -C(O)NR5-; -NR5C(O)NR5-; -S(O)2-; -NR5S(O)2-; or -C3-C 10 Cyclic group -;

[0040] R5, R6, and R7 are each independently hydrogen; halogen; C1-C6 alkyl; C3-C 10 Cyclic group; C6-C 10 Aryl; or -CH2(Ph);

[0041] R 10 R 11 and R 12 Each is independently hydrogen; C1-C 13 Alkyl; C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; C3-C 10 Heterocyclic group; -C(O)-(C1-C 13 Alkyl); -CH2(Ph); -CH2(Ph)R5; benzyl; or -CH2CH=CH2; and

[0042] N is 0, 1, 2, 3, or 4.

[0043] The C1-C6 alkyl group, C1-C 13 Alkyl or C3-C 10 The cycloyl group includes at least one substituent, said substituent being selected from hydrogen; hydroxyl; halogen group; C1-C. 13 Alkyl; C1-C6 alkoxy; amino (-NR8R9); nitro (-N(O2); amide (-(C=O)NR8R9); carboxyl (-C(O)OH); nitrile (-CN); urea (-NR8(C=O)NR9-); sulfonamide (-NHS(O)2-); thio (-S-); sulfone (-S(O)2-); phosphoryl (-P(O)R8R9); C6-C 10 Aryl; C3-C 10 heteroaryl; and C3-C 10 A group composed of heterocyclic groups.

[0044] The C6-C 10 Aryl, C3-C 10 heteroaryl or C3-C 10 The heterocyclic group includes at least one substituent selected from hydrogen; hydroxyl; halogen group; carbonyl group (-(C=O)R8R9); or a halogen or C3-C group. 10Heterocyclic substituted or unsubstituted C1-C3 alkyl groups; derived from halogens or C3-C 10 Heterocyclic substituted or unsubstituted C1-C3 alkoxy groups; C6-C 10 Phenoxy; amino (-NR8R9); nitro (-N(O)2); amide (-(C=O)NR8R9); carboxyl (-C(O)OH); nitrile (-CN); urea (-NR8(C=O)NR9-); sulfonamide (-NHS(O)2-); thio (-S-); sulfone (-S(O)2-); phosphoryl (-P(O)R8R9); C6-C 10 Aryl; C3-C 10 heteroaryl and C3-C 10 A group composed of heterocyclic groups.

[0045] R8 and R9 above include at least one selected from hydrogen; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C 10 Aryl; C3-C 10 heteroaryl and C3-C 10 The group composed of heterocyclic groups, and

[0046] The C3-C 10 heteroaryl and C3-C 10 Heterocyclic groups include at least one heteroatom selected from the group consisting of N, O, and S.

[0047] Other aspects and preferred embodiments of the invention are discussed below. Detailed Implementation

[0048] Unless the context clearly indicates otherwise, all figures, data, and / or expressions representing components, reaction conditions, polymer composition, and mixture amounts in this specification are approximate values, reflecting various uncertainties inherent in the measurements other than those obtained when these data were obtained. For this reason, it should be understood that, in all cases, the term "approximately" should be construed as modifying all figures, data, and / or expressions. Furthermore, when numerical ranges are disclosed in a statement, unless otherwise defined, these ranges are continuous and include all figures from the minimum to the maximum value within each range. Additionally, when the range is an integer, unless otherwise defined, it includes all integers from the minimum to the maximum value, including the maximum value within the range.

[0049] It should be understood that, in the specification, when referring to the range of a parameter, the parameter encompasses all numbers including the endpoints disclosed within the range. For example, the range "5-10" includes the numbers 5, 6, 7, 8, 9, and 10, as well as any subranges, such as 6-10, 7-10, 6-9, and 7-9, and any numbers between suitable integers within the range, such as 5.5, 6.5, 7.5, 5.5-8.5, and 6.5-9. Furthermore, for example, the range "10%-30%" encompasses all integers, including numbers of 10%, 11%, 12%, and 13% and 30%, as well as any subranges, such as 10%-15%, 12%-18%, or 20%-30%, and any numbers between suitable integers within the range, such as 10.5%, 15.5%, and 25.5%.

[0050] The present invention will be described in detail below.

[0051] As a result of ongoing research to address the aforementioned problems, the inventors have developed novel pyrimido[4,5-d]pyrimidin-2-one derivatives that are useful as anticancer compounds for the prevention and treatment of cancer, exhibiting excellent inhibitory activity against cancer cells, particularly as selective kinase activity inhibitors, as well as pharmaceutically acceptable salts, hydrates and stereoisomers thereof, methods for their preparation, and pharmaceutical compositions comprising them as active ingredients for the prevention or treatment of cancer.

[0052] In one aspect, the present invention provides a compound selected from pyrimidino[4,5-d]pyrimidin-2-one derivatives represented by any one of the following formulas 1 to 6, its pharmaceutically acceptable salt, its hydrate, and its stereoisomer: [Formula 1]

[0053]

[0054] [Equation 2]

[0055]

[0056] [Formula 3]

[0057]

[0058] [Formula 4]

[0059]

[0060] [Formula 5]

[0061]

[0062] [Formula 6]

[0063]

[0064] in

[0065] R1 is hydrogen; C1-C 13 Alkyl; C3-C 10 Cyclic groups; or C3-C 10 Heterocyclic groups;

[0066] A is hydrogen; C1-C 13 Alkyl; C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; C3-C 10 Heterocyclic group; or -C(O)-(C1-C 13 alkyl);

[0067] Y is C6-C 10 Aryl; or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S);

[0068] L1, L2, L3, and L4 are each independently selected from -NR5-; -NR5CH2-; -NR5C(O)-; -C(O)NR5-; -NR5C(O)NR5-; -S(O)2-; -NR5S(O)2-; -S(O)2NR5-; -O-; -CH2-; -CH(CH3-); -C(O)O-; -C(O-); The group formed;

[0069] L5 and L6 are each independently -C(O)NR5R6; -CR5R6R7; -OR5; -CCl3; C1-C6 alkyl; C3-C 10 Cycloyl; -substituted or unsubstituted benzene; -substituted or unsubstituted indole; -substituted or unsubstituted phenyl; -substituted or unsubstituted hexane; -substituted or unsubstituted furan; -substituted or unsubstituted thiophene; -substituted or unsubstituted pyridine; -substituted or unsubstituted benzofuran; -substituted or unsubstituted naphthalene; -substituted or unsubstituted anthracene; or -substituted or unsubstituted phenanthrene;

[0070] R2, R3, and R4 are each independently -O-; -CH2-; -CH(CH3)-; -CR5R6-; -NR5-; -NR5CH2-; -NR5C(O)-; -C(O)NR5-; -NR5C(O)NR5-; -S(O)2-; -NR5S(O)2-; or -C3-C 10 Cyclic group -;

[0071] R5, R6, and R7 are each independently hydrogen; halogen; C1-C6 alkyl; C3-C 10Cyclic group; C6-C 10 Aryl; or -CH2(Ph);

[0072] R 10 R 11 and R 12 Each is independently hydrogen; C1-C 13 Alkyl; C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; C3-C 10 Heterocyclic group; -C(O)-(C1-C 13 Alkyl); -CH2(Ph); -CH2(Ph)R5; benzyl; or -CH2CH=CH2; and

[0073] N is 0, 1, 2, 3, or 4.

[0074] The C1-C6 alkyl group, C1-C 13 Alkyl or C3-C 10 The cycloyl group includes at least one substituent, said substituent being selected from hydrogen; hydroxyl; halogen group; C1-C. 13 Alkyl; C1-C6 alkoxy; amino (-NR8R9); nitro (-N(O2); amide (-(C=O)NR8R9); carboxyl (-C(O)OH); nitrile (-CN); urea (-NR8(C=O)NR9-); sulfonamide (-NHS(O)2-); thio (-S-); sulfone (-S(O)2-); phosphoryl (-P(O)R8R9); C6-C 10 Aryl; C3-C 10 heteroaryl; and C3-C 10 A group composed of heterocyclic groups.

[0075] The C6-C 10 Aryl, C3-C 10 heteroaryl or C3-C 10 The heterocyclic group includes at least one substituent selected from hydrogen; hydroxyl; halogen group; carbonyl group (-(C=O)R8R9); or a halogen or C3-C group. 10 Heterocyclic substituted or unsubstituted C1-C3 alkyl groups; derived from halogens or C3-C 10 Heterocyclic substituted or unsubstituted C1-C3 alkoxy groups; C6-C 10Phenoxy; amino (-NR8R9); nitro (-N(O)2); amide (-(C=O)NR8R9); carboxyl (-C(O)OH); nitrile (-CN); urea (-NR8(C=O)NR9-); sulfonamide (-NHS(O)2-); thio (-S-); sulfone (-S(O)2-); phosphoryl (-P(O)R8R9); C6-C 10 Aryl; C3-C 10 heteroaryl and C3-C 10 A group composed of heterocyclic groups.

[0076] R8 and R9 above include at least one selected from hydrogen; C1-C6 alkyl; C1-C6 alkenyl; C1-C6 alkynyl; C6-C 10 Aryl; C3-C 10 heteroaryl and C3-C 10 The group composed of heterocyclic groups, and

[0077] The C3-C 10 heteroaryl and C3-C 10 Heterocyclic groups include at least one heteroatom selected from the group consisting of N, O, and S.

[0078] In one embodiment of the present invention, in formulas 1 to 6 above, R1 is hydrogen; or C1-C 13 Alkyl; A is hydrogen; C1-C 13 Alkyl; C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; C3-C 10 Heterocyclic group; or -C(O)-(C1-C 13 Alkyl); and Y is C6-C 10 Aryl.

[0079] In one embodiment of the invention, the compound is the compound of Formula 1, and in Formula 1 above, R1 is hydrogen; or C1-C 13 Alkyl group; A is C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; or C3-C 10 Heterocyclic group; Y is C6-C 10 Aryl; L1, L3, and L4 are each independently selected from the group consisting of -NR5C(O)- and -C(O)NR5-; and L2 is...

[0080] In one embodiment of the invention, the compound is the compound of Formula 1, and in Formula 1 above, R1 is hydrogen; or C1-C 13Alkyl group; A is C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; or C3-C 10 Heterocyclic group; Y is C6-C 10 Aryl; L1 and L2 are each independently selected from the group consisting of -NR5C(O)- and -C(O)NR5-; and L3 is...

[0081] In one embodiment of the present invention, the compound is the compound of Formula 2, and in Formula 2 above, R1 is hydrogen; or C1-C 13 Alkyl group; A is C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; or C3-C 10 Heterocyclic group; Y is C6-C 10 Aryl; L1 is selected from the group consisting of -NR5C(O)- and -C(O)NR5-.

[0082] In one embodiment of the invention, the compound is the compound of formula 3, and in formula 3 above, R1 is hydrogen; or C1-C 13 Alkyl group; A is C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; or C3-C 10 Heterocyclic group; Y is C6-C 10 Aryl; L1 is selected from the group consisting of -NR5C(O)- and -C(O)NR5-, and R2 is -CH2-.

[0083] In one embodiment of the invention, the compound is the compound of Formula 4, and in Formula 4 above, R1 is hydrogen; or C1-C 13 Alkyl group; A is C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; or C3-C 10 Heterocyclic group; Y is C6-C 10 Aryl; L1 and L2 are each independently selected from the group consisting of -NR5C(O)- and -C(O)NR5-; and R2 and R3 are -CH2-.

[0084] In one embodiment of the invention, the compound is the compound of formula 5, and in formula 5 above, R1 is hydrogen; or C1-C 13 Alkyl group; A is C6-C 10 Aryl; C3-C 10Cyclic group; C3-C 10 heteroaryl; or C3-C 10 Heterocyclic group; and Y is C6-C 10 Aryl.

[0085] In one embodiment of the invention, the compound is the compound of Formula 6, and in Formula 6 above, R1 is hydrogen; or C1-C 13 Alkyl group; A is C6-C 10 Aryl; C3-C 10 Cyclic group; C3-C 10 heteroaryl; or C3-C 10 Heterocyclic group; and Y is C6-C 10 Aryl.

[0086] In another aspect, the present invention provides a compound selected from pyrimidino[4,5-d]pyrimidin-2-one derivatives represented by any one of the following formulas 1 to 6, their pharmaceutically acceptable salts, their hydrates, and their stereoisomers, wherein the compound is selected from the group consisting of compounds 1 to 57:

[0087] (Compound 1) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0088] (Compound 2) (R)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0089] (Compound 3) (R)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclopropyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0090] (Compound 4) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclopropyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0091] (Compound 5) (R)-N-(2-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide;

[0092] (Compound 6) (S)-N-(2-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide;

[0093] (Compound 7) (R)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-phenylalanyl)pyrrolidine-2-carboxamide;

[0094] (Compound 8) (R)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0095] (Compound 9) (S)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0096] (Compound 10) (R)-N-(1-(((R)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-D-valine)pyrrolidine-2-carboxamide;

[0097] (Compound 11) (S)-N-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)1-oxo-3-phenylpropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0098] (Compound 12) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclobutyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0099] (Compound 13) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)piperidine-2-carboxamide;

[0100] (Compound 14) (S)-N-(1-((2-(dimethylamino)-2-oxoethyl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0101] (Compound 15) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)azacyclobutane-2-carboxamide;

[0102] (Compound 16) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-isoleucyl)pyrrolidine-2-carboxamide;

[0103] (Compound 17) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-alanyl)pyrrolidine-2-carboxamide;

[0104] (Compound 18) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)glycyl)pyrrolidine-2-carboxamide;

[0105] (Compound 19) (S)-1-((S)-2-cyclohexyl-2-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzamido)acetyl)-N-(1-(((S)-1-dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)pyrrolidine-2-carboxamide;

[0106] (Compound 20) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-leucyl)pyrrolidine-2-carboxamide;

[0107] (Compound 21) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((S)-2-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzamido)pentanoyl)pyrrolidine-2-carboxamide;

[0108] (Compound 22) (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0109] (Compound 23) (R)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0110] (Compound 24) (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-phenylalanyl)pyrrolidine-2-carboxamide;

[0111] (Compound 25) (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-alanyl)pyrrolidine-2-carboxamide;

[0112] (Compound 26) (S)-3-benzyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0113] (Compound 27) (S)-3-(3-fluorobenzyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0114] (Compound 28) (S)-3-(4-fluorobenzyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0115] (Compound 29) (S)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(2-methylbenzyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0116] (Compound 30) (S)-3-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0117] (Compound 31)(S)-1-benzyl-3-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0118] (Compound 32) (R)-3-((R)-sec-butyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0119] (Compound 33)(S)-1-benzyl-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0120] (Compound 34)(S)-3-benzyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0121] (Compound 35)(R)-3-benzyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0122] (Compound 36)(R)-3-benzyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0123] (Compound 37)(S)-3-isobutyl-1-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0124] (Compound 38)(S)-1-allyl-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0125] (Compound 39)(S)-1,3-diisobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0126] (Compound 40) (S)-3-isobutyl-1,5-dimethyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0127] (Compound 41)(S)-1-benzyl-3-isobutyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0128] (Compound 42) (S)-3-isobutyl-1-(2-methoxyethyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0129] (Compound 43)(S)-1-(2-(benzylamino)-2-oxoethyl)-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0130] (Compound 44) ​​(S)-2-(5-(but-3-en-1-yl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide;

[0131] (Compound 45) (S)-2-(5-(but-3-en-1-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazapentan-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide;

[0132] (Compound 46) (S)-2-(1-benzyl-5-(but-3-en-1-yl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyridino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide;

[0133] (Compound 47)(3S,4S)-N 3 -Benzyl-N 4 -(4-chlorobenzyl)-1-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)pyrrolidine-3,4-dicarboxamide;

[0134] (Compound 48)(3S,4S)-N 3 -(2-(1H-indol-3-yl)ethyl)-N 4 -(4-chlorobenzyl)-1-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)pyrrolidine-3,4-dicarboxamide;

[0135] (Compound 49) 3-Isobutoxy-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide;

[0136] (Compound 50) 3-(2-(1H-indol-3-yl)ethoxy)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide;

[0137] (Compound 51) 3-(4-methoxyphenethoxy)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide;

[0138] (Compound 52) 3-Isobutoxy-N-(2-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-2-oxoethyl)-4-nitrobenzamide;

[0139] (Compound 53) (S)-3-isobutoxy-N-(1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-2-oxopropan-2-yl)-4-nitrobenzamide;

[0140] (Compound 54) (S)-3-isobutoxy-N-(4-methyl-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopentane-2-yl)-4-nitrobenzamide;

[0141] (Compound 55) (S)-N-3-(1H-indol-3-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopropane-2-yl)-3-isobutoxy-4-nitrobenzamide;

[0142] (Compound 56) (S)-3-(4-methoxyphenethoxy)-N-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopropan-2-yl)-4-nitrobenzamide; and

[0143] (Compound 57) 2,2,2-Trichloroethyl(3S,4S)-3-((4-chlorobenzyl)carbamoyl)-4-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate.

[0144] In the definition of substituents in this invention, the term "alkane" refers to an aliphatic hydrocarbon radical. The alkyl group can be a "saturated alkyl group" that does not contain an alkenyl or ynyl moiety, or an "unsaturated alkyl group" that contains at least one alkenyl or ynyl moiety. The term "alkenyl" refers to a group containing at least one carbon-carbon double bond, and the term "ynyl" refers to a group containing at least one carbon-carbon triple bond. The alkyl group, when used alone or in combination, can be cyclic, branched, or linear.

[0145] The term "aryl" refers to a carbocyclic aromatic monocyclic group containing six carbon atoms, which may be further fused individually or with another group having a second 5- or 6-membered carbocyclic group, which may be aromatic, saturated, or unsaturated. Examples of aryl groups include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, etc. The aryl group may be attached to another group at an appropriate position on the aromatic ring.

[0146] The term "alkoxy" refers to an alkyl group (i.e., -O-alkyl) linked to another group via an oxygen atom. The alkoxy group may or may not be substituted with at least one suitable substituent. Examples of alkoxy groups include, but are not limited to, (C1-C6) alkoxy groups, such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O-2-methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl-1-propyl, -O-2-methyl-1-pentyl, -3-O -Methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O-3-methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl-1-butyl, -O-butyl, -O-isobutyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

[0147] The term "phenoxy" refers to a phenyl group (i.e., -O-aryl) linked to another group via an oxygen atom. The phenoxy group may or may not be substituted with at least one halogen, alkyl, aryl, or heteroaryl group, but is not limited thereto.

[0148] The term "amino" refers to an alkyl group (i.e., -NH- or -N-alkyl) linked to another group via a nitrogen atom. The amino group may or may not be substituted with at least one suitable substituent. Examples of amino groups include, but are not limited to, (C1-C6) amino groups, such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl-2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2-dimethyl-1-propyl, -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, etc. -NH-2-methyl-2-pentyl, -NH-3-methyl-2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2-ethyl-1-butyl, -NH-butyl, -NH-isobutyl, -NH-tert-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N,N-dimethyl, -N-methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, - N-Methyl-N-butyl, -N-methyl-N-isobutyl, -N-methyl-N-pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N-propyl, -N-ethyl-N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N-hexyl, -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl- N-Isopropyl, -N-propyl-N-butyl, -N-propyl-N-isobutyl, -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N-butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N-dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl and -N,N-dihexyl.

[0149] The term "halogen atom" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0150] Unless otherwise stated, the term "heterocyclic group" refers to a heteroaromatic compound containing at least one heteroatom selected from N, O, and S. Preferably, the heterocyclic group may include pyrrolyl, furanyl, morpholinyl, piperazine, and piperidinyl, and more preferably, pyrrolidine, piperidinyl, piperazine, and morpholinyl, but is not limited thereto.

[0151] Unless otherwise stated, the term "heteroaryl" refers to a heteroaromatic compound containing at least one heteroatom selected from N, O, and S. Preferably, the heteroaryl group is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, isoxazolyl, oxazolyl, thiazolyl, and pyrroleyl, but is not limited thereto.

[0152] Specific examples of preferred compounds according to the present invention are as follows:

[0153] (Compound 1) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0154]

[0155] (Compound 2) (R)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0156]

[0157] (Compound 3) (R)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclopropyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0158]

[0159] (Compound 4) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclopropyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0160]

[0161] (Compound 5) (R)-N-(2-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide;

[0162]

[0163] (Compound 6) (S)-N-(2-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide;

[0164]

[0165] (Compound 7) (R)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-phenylalanyl)pyrrolidine-2-carboxamide;

[0166]

[0167] (Compound 8) (R)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0168]

[0169] (Compound 9) (S)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0170]

[0171] (Compound 10) (R)-N-(1-(((R)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-D-valine)pyrrolidine-2-carboxamide;

[0172]

[0173] (Compound 11) (S)-N-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)1-oxo-3-phenylpropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0174]

[0175] (Compound 12) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclobutyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0176]

[0177] (Compound 13) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)piperidine-2-carboxamide;

[0178]

[0179] (Compound 14) (S)-N-(1-((2-(dimethylamino)-2-oxoethyl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0180]

[0181] (Compound 15) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)azacyclobutane-2-carboxamide;

[0182]

[0183] (Compound 16) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-isoleucyl)pyrrolidine-2-carboxamide;

[0184]

[0185] (Compound 17) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-alanyl)pyrrolidine-2-carboxamide;

[0186]

[0187] (Compound 18) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)glycyl)pyrrolidine-2-carboxamide;

[0188]

[0189] (Compound 19) (S)-1-((S)-2-cyclohexyl-2-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzamido)acetyl)-N-(1-(((S)-1-dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)pyrrolidine-2-carboxamide;

[0190]

[0191] (Compound 20) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-leucyl)pyrrolidine-2-carboxamide;

[0192]

[0193] (Compound 21) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((S)-2-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzamido)pentanoyl)pyrrolidine-2-carboxamide;

[0194]

[0195] (Compound 22) (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0196]

[0197] (Compound 23) (R)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide;

[0198]

[0199] (Compound 24) (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-phenylalanyl)pyrrolidine-2-carboxamide;

[0200]

[0201] (Compound 25) (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-alanyl)pyrrolidine-2-carboxamide;

[0202]

[0203] (Compound 26) (S)-3-benzyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0204]

[0205] (Compound 27) (S)-3-(3-fluorobenzyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0206]

[0207] (Compound 28) (S)-3-(4-fluorobenzyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0208]

[0209] (Compound 29) (S)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(2-methylbenzyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0210]

[0211] (Compound 30) (S)-3-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0212]

[0213] (Compound 31)(S)-1-benzyl-3-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0214]

[0215] (Compound 32) (R)-3-((R)-sec-butyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0216]

[0217] (Compound 33)(S)-1-benzyl-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0218]

[0219] (Compound 34)(S)-3-benzyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0220]

[0221] (Compound 35)(R)-3-benzyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0222]

[0223] (Compound 36)(R)-3-benzyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0224]

[0225] (Compound 37)(S)-3-isobutyl-1-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0226]

[0227] (Compound 38)(S)-1-allyl-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0228]

[0229] (Compound 39)(S)-1,3-diisobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0230]

[0231] (Compound 40) (S)-3-isobutyl-1,5-dimethyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0232]

[0233] (Compound 41)(S)-1-benzyl-3-isobutyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0234]

[0235] (Compound 42) (S)-3-isobutyl-1-(2-methoxyethyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0236]

[0237] (Compound 43)(S)-1-(2-(benzylamino)-2-oxoethyl)-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide;

[0238]

[0239] (Compound 44) ​​(S)-2-(5-(but-3-en-1-yl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide;

[0240]

[0241] (Compound 45) (S)-2-(5-(but-3-en-1-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazapentan-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide;

[0242]

[0243] (Compound 46) (S)-2-(1-benzyl-5-(but-3-en-1-yl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyridino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide;

[0244]

[0245] (Compound 47)(3S,4S)-N 3 -Benzyl-N 4 -(4-chlorobenzyl)-1-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)pyrrolidine-3,4-dicarboxamide;

[0246]

[0247] (Compound 48)(3S,4S)-N 3 -(2-(1H-indol-3-yl)ethyl)-N 4 -(4-chlorobenzyl)-1-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)pyrrolidine-3,4-dicarboxamide;

[0248]

[0249] (Compound 49) 3-Isobutoxy-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide;

[0250]

[0251] (Compound 50) 3-(2-(1H-indol-3-yl)ethoxy)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide;

[0252]

[0253] (Compound 51) 3-(4-methoxyphenethoxy)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide;

[0254]

[0255] (Compound 52) 3-Isobutoxy-N-(2-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-2-oxoethyl)-4-nitrobenzamide;

[0256]

[0257] (Compound 53) (S)-3-isobutoxy-N-(1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-2-oxopropan-2-yl)-4-nitrobenzamide;

[0258]

[0259] (Compound 54) (S)-3-isobutoxy-N-(4-methyl-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopentane-2-yl)-4-nitrobenzamide;

[0260]

[0261] (Compound 55) (S)-N-3-(1H-indol-3-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopropane-2-yl)-3-isobutoxy-4-nitrobenzamide;

[0262]

[0263] (Compound 56) (S)-3-(4-methoxyphenethoxy)-N-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopropan-2-yl)-4-nitrobenzamide; and

[0264]

[0265] (Compound 57) 2,2,2-Trichloroethyl(3S,4S)-3-((4-chlorobenzyl)carbamoyl)-4-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate

[0266]

[0267] The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, and preferably the pharmaceutically acceptable salts can comprise at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.

[0268] The compound represented by any one of formulas 1 to 6 according to the invention, or a pharmaceutically acceptable salt thereof, may comprise hydrates and solvates. The hydrates may be formed by combining the compound represented by any one of formulas 1 to 6 with water molecules.

[0269] In another aspect, the present invention provides a pharmaceutical composition for the prevention, mitigation or treatment of cancer, the pharmaceutical composition containing a compound as an active ingredient, the compound being selected from compounds represented by any one of formulas 1 to 6 according to the present invention, pharmaceutically acceptable salts thereof, hydrates thereof and stereoisomers thereof.

[0270] The pharmaceutical composition according to the present invention has excellent ability to inhibit protein kinase activity. The protein kinases may specifically include ABL1, ABL2 / ARG, ARAF, BLK, BMX / ETK, BRAF, c-Src, CSK, DDR1, DDR2, EPHA2, EPHA4, ERBB4 / HER2, ERBB4 / HER4, EPHB1, FGR, FRK / PTK5, FYN, FGFR1, FMS, HCK, LCK, LIMK1, LYN, LYN B, MEK5, MLK1 / MAP3K9, MLK3 / MAP3K11, P38a / MAPK14, PDGFRa, PDGFRb, PEAK1, RAF1, YES / YES1, ARK5 / NUAK1, Aurora C, BMPR2, BRSK2, BTK, c-Kit, CAMK1b, CAMK1d, CAMKK2, CK1d, CK2a, CK2a2, CLK1, CLK3, CTK / MATK, DAPK1, DY RK1 / DYRK1A, DYRK1B, DYRK3, EGRF, EPHA2, EPHA3, EPHA4, EPHA5, EPHA8, EPHB1, EPHA3, EPHA5, EPHA8, EPHB2 , EPHB4, ERBB2 / HER2, ERK1, ERN1 / IRE1, FLT4 / VEGFR3, GRK4, HIPK3, IKKa / CHUK, IRAK1, KDR / VEGFR2, KHS / M AP4K5, MAPKAPK5 / PRAK, MASTL, MEK2, MEKK3, MKK6, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MSK1 / RPS6 KA5, MSK2 / RPS6KA4, MSSK1 / STK23, MST4, MUSK, NEK11, NEK8, p38b / MAPK11, PAK5, PKCd, PKCeta, PKCG, PKMY T1, PKN3 / PRK3, PLK3, PYK2, RET, RIPK4, RON / MST1R, ROS / ROS1, SIK1, ZAK / MLTK, WNK3, WNK2, TRKC, STK32B / The group consisting of YANK2, SNRK, SLK / STK2, SIK3, RSK1, ROCK1, PKG2 / PRKG2, MRCKa / CDC42BPA, LIMK2, JAK2, JAK1, ITK, IRAK1, GSK3a, GCK / MAP4K2, FGFR2, FGFR1, FES / FPS, c-MET, c-Kit, ARAF, ALK6 / BMPR1B, ALK1 / ACVRL1, AKT3, etc.

[0271] Therefore, the pharmaceutical compositions of the present invention can be used to treat, prevent, and alleviate cancer-related diseases caused by abnormal cell growth. Examples of cancer-related diseases that can be prevented, treated, or alleviated by treatment with the pharmaceutical compositions of the present invention include gastric cancer, lung cancer, liver cancer, colorectal cancer, small bowel cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, hematologic malignancies (including leukemia, multiple myeloma, myelodysplastic syndrome), lymphomas (including Hodgkin's disease, non-Hodgkin's lymphoma), psoriasis, fibroadenoma, etc.

[0272] In particular, the pharmaceutical compositions of the present invention can be used as therapeutic agents for cancer-related diseases, inflammatory diseases, and immune diseases caused by overexpression and mutation of LCK, DDR1, FGR, BMX, ABL2, BLX, BLK, LYN, DDR2, RAF1, c-src, CS, and HCK kinases.

[0273] Preferably, the cancer is mediated and caused by a protein kinase. Preferably, the protein kinase may include one or more selected from LCK, c-Src, p38a / MAPK14, ABL1, DDR1, and FGR. More preferably, the protein kinase may be LCK.

[0274] In another aspect, the present invention provides a pharmaceutical composition comprising any one of the said compounds as an active ingredient for the prevention, relief or treatment of cancer.

[0275] In another aspect, the present invention provides a pharmaceutical composition for the prevention, mitigation or treatment of cancer, wherein the cancer is caused by an LCK mutation.

[0276] In another aspect, the present invention provides a pharmaceutical composition for use as a therapeutic agent for cancer-related diseases, inflammatory diseases, and immune diseases, wherein the pharmaceutical composition is applied to patients with LCK overexpression.

[0277] In another embodiment of the invention, the cancer includes one or more selected from the group consisting of colorectal cancer, thymic cancer, brain cancer, prostate cancer, leukemia, lung cancer, breast cancer, thyroid cancer, bladder cancer, stomach cancer, and blood cancer.

[0278] The pharmaceutical composition can be applied to laboratory animals, such as mice, rabbits, rats, guinea pigs, or hamsters, or primates including humans, but is not limited thereto. Preferably, the pharmaceutical composition can be applied to primates including humans, more preferably humans.

[0279] As used herein, the term “treatment” includes the reduction or improvement of symptoms, the reduction of the severity of the disease, the delay or reduction of the progression of the disease, the improvement, mitigation or stabilization of the condition of the disease, partial or complete recovery, prolongation of survival and other beneficial therapeutic outcomes.

[0280] Additionally, as used herein, the treatment of cancer refers to the treatment of all cancer cells, and the cancers include angiogenesis and mitosis of endothelial cells (solid tumors, tumor metastases, and benign tumors). For example, the cancers include, but are not limited to, breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, urogenital tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, carcinogenic cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, normal hematoma, melanoma, sarcoma, bladder cancer, liver cancer, bile duct cancer, kidney cancer, myeloid diseases, lymphatic diseases, Hodgkin's disease, pilomatric carcinoma, oral cancer, pharyngeal (oral) cancer, lip cancer, tongue cancer, small intestine cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancers, leukemia, hemangioma, trachoma, and pyogenic sarcoma.

[0281] The content of the active ingredient, i.e., the compound represented by any one of formulas 1 to 6 above, its pharmaceutically acceptable salt, its hydrate, and its stereoisomer, is appropriately adjusted and selected by those skilled in the art through the mode of use and method of use of the pharmaceutical composition according to the present invention.

[0282] For example, the amount of the compound present, based on the total weight of the pharmaceutical composition, is 0.1-10% by weight, more preferably 0.5-5% by weight, and the compound is selected from compounds represented by any one of formulas 1 to 6, their pharmaceutically acceptable salts, their hydrates, and their stereoisomers.

[0283] The compound selected from any one of formulas 1 to 6, the pharmaceutically acceptable salt thereof, the hydrate thereof, and the stereoisomer thereof may be present alone in the pharmaceutical composition or in combination with a pharmaceutically acceptable carrier, excipient, diluent, or adjuvant.

[0284] Examples of one or more of the pharmaceutically acceptable carriers, excipients, and diluents include, but are not limited to, those selected from the group consisting of lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylparaben, propylparaben, talc, magnesium stearate, mineral oil, dextrin, calcium carbonate, propylene glycol, liquid paraffin, and physiological saline, as well as any commonly used carriers, excipients, or diluents. Additionally, the pharmaceutical composition may also contain common fillers, expanders, binders, disintegrants, anticoagulants, lubricants, wetting agents, pH adjusters, nutrients, vitamins, electrolytes, alginate and its salts, pectic acid and its salts, protective colloids, glycerin, fragrances, emulsifiers, preservatives, etc.

[0285] The compound represented by any one of formulas 1 to 6, or a pharmaceutically acceptable salt thereof, may be administered in combination with another anticancer agent used to treat cancer or tumors to improve the therapeutic effect of the anticancer agent.

[0286] Specifically, in addition to the active ingredient, the pharmaceutical composition may further contain at least one known anticancer agent or therapeutic agent that is effective in treating or preventing cancer, and therefore can be used as a combination therapy, either simultaneously or separately. Other anticancer agents or therapeutic agents that can be used in combination therapy may include, but are not limited to, for example, selected... (Imatinib) (sunitinib) (trastuzumab) (bortezomib), dexamethasone, At least one compound from the group consisting of sorafenib, aromatase inhibitors, or kinase inhibitors.

[0287] The pharmaceutical composition can be administered orally or parenterally, and, for example, via various routes, including oral, transdermal, subcutaneous, intravenous, or intramuscular routes. Furthermore, the dosage form of the composition can vary depending on the method of use and can be formulated using methods known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to mammals. Typically, solid dosage forms for oral administration include tablets, lozenges, soft or hard capsules, pills, powders, granules, etc. These dosage forms can be prepared, for example, by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used. Liquid dosage forms for oral administration include suspensions, liquids and solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavorings, and preservatives can also be included. Parenteral drug delivery dosage forms include creams, lotions, ointments, plasters, liquids and solutions, aerosols, liquid extracts, elixirs, infusions, sachets, patches, and injections. Injectable preparations are preferably in the form of isotonic aqueous solutions or suspensions.

[0288] The pharmaceutical composition may further comprise adjuvants, such as bactericides, preservatives, stabilizers, hydrating agents or emulsifying agents, salts and / or buffers for controlling osmotic pressure, and other therapeutically useful substances. Alternatively, the pharmaceutical composition may be formulated according to conventional mixing, granulation or coating methods or using suitable methods known in the art.

[0289] Furthermore, the dosage of the pharmaceutical composition may take into account the method of administration, the patient's age, sex, disease severity, and condition, the absorption rate of the active ingredient in the body, the inactivation rate of the active ingredient and drugs used in combination therewith, and whether the pharmaceutical composition is administered once or in multiple doses. The active ingredient of the pharmaceutical composition is administered, preferably orally or parenterally, to mammals, including humans, at a dose of 0.001-100 mg / kg body weight, preferably 0.01-35 mg / kg body weight, once daily or in multiple doses.

[0290] In another aspect, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of the compound represented by any one of formulas 1 to 6, a pharmaceutically acceptable salt thereof, its hydrate thereof or a stereoisomer thereof.

[0291] Preferably, the treatment method may further include identifying the patient's need for cancer prevention or treatment prior to administration.

[0292] As used herein, the term "therapeutic effective amount" refers to the amount of an active ingredient effective for the prevention or treatment of cancer in mammals, and this therapeutic effective amount can be controlled by a variety of factors, such as the type of disease, the severity of the disease, the type and amount of the active ingredient and other components contained in the composition, the dosage form, the age, weight, general health status, the patient's sex and diet, the time of administration, the route of administration, the clearance of the composition in the blood, the duration of treatment, and any drugs used concurrently. However, preferably, as described above, the compound can be administered orally or parenterally in doses of 0.001-100 mg / kg body weight, preferably 0.01-35 mg / kg body weight, once or more daily.

[0293] In another aspect, the present invention provides a method for preparing the compound represented by any one of formulas 1 to 6, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0294] In the following description, the invention will be presented in more detail with reference to preparation examples, examples, and experimental examples. However, the following preparation examples, examples, and experimental examples are provided only to better understand the invention and should not be construed as limiting the scope of the invention.

[0295] [Preparation Example 1]

[0296]

[0297] As shown in the reaction scheme above, in the first reaction, tert-butanol is added to the carboxylic acid as a starting material to introduce a protecting group into the carboxyl group via esterification. In the second reaction, the resulting product is reacted with palladium / carbon and cyclohexene at 80°C to reduce the nitro group to an amino group. In the third reaction, N,N-diisopropylethylamine and phosphoryl chloride are added to replace the hydroxyl group of the pyrimidine starting material with a chloro group. In the fourth reaction, sodium iodide and potassium carbonate are added to the benzoate skeleton to introduce a protecting group into the carboxyl group via S... N 2. Reactions were performed to prepare compounds incorporating pyrimidines. In the fifth reaction, methylamine was added to the resulting compound in the presence of dioxane solvent to prepare the compound via amination. In the sixth reaction, triphosgene was added to the resulting product to induce cyclization via urea formation, thereby preparing the compound. In the seventh reaction, Buchwald-Hartwig amination was performed using a ligand in the presence of a palladium catalyst to prepare a compound incorporating an amine. In the eighth reaction, trifluoroacetic acid was added to the resulting compound to induce deprotection, thereby preparing a carboxylic acid compound.

[0298] Furthermore, the intermediate compounds synthesized during the preparation process according to the above reaction scheme include novel compounds, which are also within the scope of this invention.

[0299] Specific examples of 4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,d]pyrimidin-3(2H)-yl)benzoic acid and its novel intermediate compounds, represented by Formula 1 according to the present invention, are shown below.

[0300] 4-Methyl-3-nitrobenzene tert-butyl ester

[0301] tert-butyl 3-amino-4-methylbenzoate

[0302] 2,4-Dichloro-5-(chloromethyl)pyrimidine

[0303] 3-(((2,4-dichloropyridin-5-yl)methyl)amino)-4-methylbenzoate tert-butyl ester

[0304] 3-(((2-chloro-4-(methylamino)pyrimidin-5-yl)methyl)amino)-4-methylbenzoate tert-butyl

[0305] 3-(7-chloro-1-methyl-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)-4-methylbenzoate tert-butyl ester

[0306] 4-Methyl-3-(1-Methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidinyl[4,5-d]pyrimidin-3(2H)-yl)tert-butyl benzoate

[0307] 4-Methyl-3-(1-Methyl-7-(((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,d]pyrimidin-3(2H)-yl)benzoic acid

[0308] Step 1: tert-butyl 4-methyl-3-nitrobenzene

[0309]

[0310] 4-Methyl-3-nitrobenzoic acid (5 g, 27.6 mmol) was placed in a round-bottom flask and dissolved in dichloromethane (138 mL). Then, 4-dimethylaminopyridine (0.34 g, 27.6 mmol), tert-butanol (2.98 mL, 33.1 mmol), and N,N′-dicyclohexylcarbodiimide (6.83 g, 33.1 mmol) were added at 0 °C. After stirring at room temperature for two days, the reaction was complete, and the resulting product was extracted with dichloromethane and water. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, distilled under reduced pressure, dried, and the resulting residue was purified by column chromatography (ethyl acetate:hexane = 1:6) to give tert-butyl 4-methyl-3-nitrobenzoate (4.97 g, 76%).

[0311] 1 H NMR (400MHz, CDCl3) δ 8.52 (d, J = 1.8 Hz, 1H), 8.09 (dd, J = 7.9, 1.8 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 2.65 (s, 3H), 2.17 (s, 2H), 1.61 (s, 9H).

[0312] Step 2: tert-butyl 3-amino-4-methylbenzoate

[0313]

[0314] 112.70 g (0.475 mmol) of tert-butyl 4-methyl-3-nitrobenzoate was placed in a round-bottom flask and dissolved in ethanol / cyclohexene (1 / 1, 0.2 M, 2.38 mL). Palladium / carbon (24.1 mg, 0.574 mmol) was then added. After stirring at 80 °C for 16 hours, the floating material was filtered through diatomaceous earth. The collected organic layer was distilled under reduced pressure, and the resulting residue was purified by column chromatography (ethyl acetate:hexane = 1:4) to give tert-butyl 3-amino-4-methylbenzoate (91 mg, 92%).

[0315] 1 H NMR (400MHz, CDCl3) δ7.33 (dd, J=7.7, 1.7Hz, 1H), 7.29 (d, J=1.7Hz, 1H), 7.07 (d, J=7.7Hz, 1H), 3.72 (s, 2H), 2.20 (s, 3H), 1.57 (s, 9H).

[0316] Step 3: 2,4-Dichloro-5-(chloromethyl)pyrimidine

[0317]

[0318] 5-(hydroxymethyl)pyrimidine (15 g, 105.6 mmol) was placed in a round-bottom flask and dissolved in toluene (52.8 mL, 2 M). N,N-diisopropylethylamine was added at 0 °C, followed by slow dropwise addition of phosphoryl chloride (49.21 mL, 528 mmol), and the mixture was stirred at 110 °C. The solvent was removed by vacuum distillation, and the resulting residue was purified by column chromatography (ethyl acetate:hexane = 1:6) to give 2,4-dichloro-5-(chloromethyl)pyrimidine (14.81 g, 71%).

[0319] 1 H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 4.64 (s, 2H).

[0320] Step 4: 3-(((2,4-dichloropyridin-5-yl)methyl)amino)-4-methylbenzoate tert-butyl ester

[0321]

[0322] 3-Amino-4-methylbenzoate tert-butyl ester (5.32 g, 25.65 mmol) and 2,4-dichloro-5-(chloromethyl)pyrimidine (6.08 g, 30.8 mmol) were placed in a round-bottom flask and dissolved in acetone (32.06 mL, 0.8 M). Sodium iodide (5.77 g, 38.5 mmol) and potassium carbonate (6.74 g, 48.7 mmol) were then added. The resulting mixture was stirred at 50 °C for 10 hours until the reaction was complete. The product was then extracted with dichloromethane and water. The collected organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The residue was then purified by column chromatography (ethyl acetate:hexane = 1:4) to give 3-(((2,4-dichloropyridin-5-yl)methyl)amino)-4-methylbenzoate tert-butyl ester (7.17 g, 76%).

[0323] 1 H NMR (400MHz, CDCl3) δ8.50 (s, 1H), 7.36 (dd, J=7.5, 1.6Hz, 1H), 7.13 (d, J=7.7H z, 1H), 7.07 (d, J = 1.6Hz, 1H), 4.55 (d, J = 6.0Hz, 2H), 2.25 (s, 4H), 1.55 (s, 9H).

[0324] Step 5: 3-(((2-chloro-4-(methylamino)pyrimidin-5-yl)methyl)amino)-4-methylbenzoate tert-butyl ester

[0325]

[0326] 7.17 g (19.5 mmol) of tert-butyl 3-(((2,4-dichloropyridin-5-yl)methyl)amino)-4-methylbenzoate was placed in a round-bottom flask and dissolved in 1,4-dioxane (64.9 mL, 0.3 M). Methylamine (3.97 mL, 38.9 mmol) and N,N-diisopropylethylamine (10.17 mL, 58.41 mmol) were added, and the resulting mixture was stirred at 60 °C for 1 hour and 30 minutes. When the reaction was complete, the product was extracted with dichloromethane and water. The collected organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by vacuum distillation, and the resulting residue was purified by column chromatography (ethyl acetate:hexane = 1:1) to give tert-butyl 3-(((2-chloro-4-(methylamino)pyrimidin-5-yl)methyl)amino)-4-methylbenzoate (6.72 g, 95%).

[0327] 1 H NMR (400MHz, CDCl3) δ7.96 (s, 1H), 7.45 (dd, J = 7.7, 1.5Hz, 1H), 7.40 (d, J = 1.3Hz, 1H), 7.15 (d, J = 7.7Hz, 1H) , 6.02(s,1H), 4.20(d,J=5.5Hz,2H), 3.36(d,J=5.6Hz,1H), 3.04(d,J=4.9Hz,3H), 2.18(s,3H), 1.55(s,9H).

[0328] Step 6: tert-butyl 3-(7-chloro-1-methyl-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)-4-methylbenzoate

[0329]

[0330] 4.26 g (11.7 mmol) of tert-butyl 3-(((2-chloro-4-(methylamino)pyrimidin-5-yl)methyl)amino)-4-methylbenzoate was added to a round-bottom flask and dissolved in tetrahydrofuran (39.1 mL, 0.3 M). Then, triphosgene (1.74 g, 5.86 mmol) and triethylamine (8.13 mL, 58.6 mmol) were added at 0 °C. The mixture was stirred at 70 °C for 1 hour until the reaction was complete. The reaction product was then extracted with dichloromethane and water. The collected organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by vacuum distillation, and the resulting residue was purified by column chromatography (ethyl acetate:hexane = 1:6 → 1:2) and cured with hexane to obtain tert-butyl 3-(7-chloro-1-methyl-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)-4-methylbenzoate (1.75 g, 48%).

[0331] 1 H NMR (400MHz, CDCl3) δ8.12(s,1H), 7.90(dd,J=7.9,1.8Hz,1H), 7.85(d,J=1.7Hz,1H), 7.36(d,J=8.0Hz, 1H), 4.83(dd,J=14.8,1.1Hz,1H), 4.55(dd,J=14.8,0.9Hz,1H), 3.47(s,3H), 2.28(s,3H), 1.58(s,9H).

[0332] Step 7: 4-Methyl-3-(1-Methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidinyl[4,5-d]pyrimidin-3(2H)-yl)tert-butyl benzoate

[0333]

[0334] 1.75 g (4.50 mmol) of tert-butyl 3-(7-chloro-1-methyl-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)-4-methylbenzoate was placed in a round-bottom flask and dissolved in 2-butanol (22.47 mL, 0.2 M). Then, 0.49 g (4.54 mmol) of 5-amino-2-methylpyridine, 3.11 g (22.48 mmol) of potassium carbonate, 0.43 g (0.899 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, and 0.82 g (0.90 mmol) of tris(dibenzylideneacetone)dipalladium(O) (0.82 g, 0.90 mmol) were added, and the mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the floating matter was filtered through diatomaceous earth. The collected organic layer was distilled under reduced pressure and dried, and the resulting residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1), and then cured with diethyl ether and hexane to give tert-butyl 4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidinyl[4,5-d]pyrimidin-3(2H)-yl)benzoate (1.55 g, 75%).

[0335] 1 H NMR (400MHz, CDCl3) δ8.72 (s, 1H), 8.00 (m, J = 7.7Hz, 2H), 7.88 (dd, J = 7.9, 1.8Hz, 1H), 7.86 (d, J = 1.7Hz, 1H), 7.34 (d, J = 8.0Hz, 1H), 7. 16(d,J=8.4Hz,1H), 7.04(s,1H), 4.76(d,J=14.2Hz,1H), 4.46(d,J=14.0Hz,1H), 3.45(s,3H), 2.56(s,3H), 2.29(s,3H), 1.58(s,9H).

[0336] Step 8: 4-Methyl-3-(1-Methyl-7-(((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,d]pyrimidin-3(2H)-yl)benzoic acid

[0337]

[0338] 0.11 g (0.2386 mmol) of tert-butyl 4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidinyl[4,5-d]pyrimidin-3(2H)-yl)benzoate was placed in a round-bottom flask and dissolved in dichloromethane (2.39 mL, 0.1 M). Trifluoroacetic acid (0.36 mL, 4.77 mmol) was then added, and the mixture was stirred at room temperature for one day. After the reaction was complete, the reaction solution was distilled under reduced pressure and dried. The resulting residue was cured with diethyl ether and hexane to obtain 0.09 g (95%) of 4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,d]pyrimidin-3(2H)-yl)benzoate.

[0339] 1 H NMR (400MHz, DMSO) δ10.32(s,1H), 9.20(s,1H), 8.43(d,J=9.0Hz,1H), 8.23(s,1H), 7.93(d,J=1.8Hz,1H), 7.84(dd,J=7.9,1.8Hz,1H) , 7.74(d,J=8.1Hz,1H), 7.46(d,J=8.0Hz,1H), 4.85(d,J=14.1Hz,1H), 4.55(d,J=14.1Hz,1H), 3.37(s,3H), 2.61(s,3H), 2.22(s,3H).

[0340] The following are methods for preparing the compounds of Examples 1 to 6 and the compounds of Examples 10 to 25.

[0341] The corresponding target compounds and various peptide compounds can be synthesized via amide coupling reactions using HATU from 4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,d]pyrimidin-3(2H)-yl)benzoic acid (compound 23) synthesized through the preparation process of the intermediate in step 8, as shown in the following chemical reaction schemes:

[0342]

[0343] Benzoic acid 21 (1.0 equivalent) and peptide 22 (1.0 equivalent) (synthesized according to the following reference: J. Am. Chem. Soc. 2017, 139, 492-516) were placed in a round-bottom flask and dissolved in dimethylformamide (0.2 M). Then, HATU (2.0 equivalent) and N,N-diisopropylethylamine (10.0 equivalent) were added, and the mixture was stirred for one day. When the reaction was complete, the resulting product was extracted with an aqueous solution of dichloromethane and sodium bicarbonate. The collected organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the resulting residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 1 (yield 10-20%).

[0344] The following describes methods for preparing the compounds of Examples 7 to 9.

[0345] The target compounds can be synthesized via amide coupling reactions using 4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,d]pyrimidin-3(2H)-yl)benzoic acid (compound 23), synthesized from the intermediates synthesized in step 8, and various peptide compounds, as shown in the following chemical reaction scheme:

[0346]

[0347] Benzoic acid 21 (1.0 equivalent) and peptide 23 (1.0 equivalent) (synthesized according to the following reference: J. Am. Chem. Soc. 2007, 129, 8710-8711) were placed in a round-bottom flask and dissolved in dimethylformamide (0.2 M). Then, HATU (2.0 equivalent) and N,N-diisopropylethylamine (10.0 equivalent) were added, and the mixture was stirred for one day. When the reaction was complete, the product was extracted with an aqueous solution of dichloromethane and sodium bicarbonate. The collected organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 2 (yield 10-20%).

[0348] Example 1:

[0349] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0350]

[0351] C 43 H 60 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 826.4728; the measured value is 826.4734.

[0352] Example 2:

[0353] (R)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0354]

[0355] C 43 H 60 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 826.4728; the measured value is 826.4738.

[0356] Example 3:

[0357] (R)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)carbamoyl)cyclopropyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0358]

[0359] C 43 H 58 N11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 824.4572; the measured value is 824.4574.

[0360] Example 4:

[0361] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)carbamoyl)cyclopropyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0362]

[0363] C 43 H 58 N 11 O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 824; the measured value is 824.

[0364] Example 5:

[0365] (R)-N-(2-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0366]

[0367] C 41 H 56 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 798.4415; the measured value is 798.4425.

[0368] Example 6:

[0369] (S)-N-(2-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0370]

[0371] C 41 H 56 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 798.4415; the measured value is 798.4420.

[0372] Example 7:

[0373] (R)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-phenylalanyl)pyrrolidine-2-carboxamide

[0374]

[0375] C 48 H 55 N 10 O5[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 851.4357; the measured value is 851.4377.

[0376] Example 8:

[0377] (R)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0378]

[0379] C 44 H 55 N 10 O5[M+H] +The calculated LRMS(MM:ESI-APCI+) m / z is 803; the measured value is 803.

[0380] Example 9:

[0381] (S)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0382]

[0383] C 44 H 55 N 10 O5[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 803.4357; the measured value is 803.4371.

[0384] Example 10:

[0385] (R)-N-(1-(((R)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-D-valine)pyrrolidine-2-carboxamide

[0386]

[0387] C 43 H 60 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 826.4728; the measured value is 826.4733.

[0388] Example 11:

[0389] (S)-N-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)1-oxo-3-phenylpropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide

[0390]

[0391] C 48 H 62 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 888.4885; the actual measured value is 888.4888.

[0392] Example 12:

[0393] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)carbamoyl)cyclobutyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0394]

[0395] C 44 H 60 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 838.4728; the measured value is 838.4726.

[0396] Example 13:

[0397] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)piperidin-2-carboxamide

[0398]

[0399] C 44 H 62 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 840.4885; the measured value is 840.4897.

[0400] Example 14:

[0401] (S)-N-(1-((2-(dimethylamino)-2-oxoethyl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide

[0402]

[0403] C 39 H 52 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 770.4102; the measured value is 770.4101.

[0404] Example 15:

[0405] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)azacyclobutane-2-carboxamide

[0406]

[0407] C 42 H 58 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 812.4572; the measured value is 812.4561.

[0408] Example 16:

[0409] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-isoleucyl)pyrrolidine-2-carboxamide

[0410]

[0411] C 44 H 62 N11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 840.4885; the actual measured value is 840.4885.

[0412] Example 17:

[0413] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-alanyl)pyrrolidine-2-carboxamide

[0414]

[0415] C 41 H 56 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 798.4415; the measured value is 798.4418.

[0416] Example 18:

[0417] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)glycyl)pyrrolidine-2-carboxamide

[0418]

[0419] C 40 H 54 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 784.4259; the measured value is 784.4257.

[0420] Example 19:

[0421] (S)-1-((S)-2-cyclohexyl-2-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzamido)acetyl)-N-(1-(((S)-1-dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)pyrrolidine-2-carboxamide

[0422]

[0423] C 46 H 64 N 11 O6[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 866.5041; the measured value is 866.5021.

[0424] Example 20:

[0425] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-leucyl)pyrrolidine-2-carboxamide

[0426]

[0427] C 44 H 61 N 11 O6Na[M+Na] + The calculated LRMS(MM:ESI-APCI+) m / z is 862; the measured value is 862.

[0428] Example 21:

[0429] (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((S)-2-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzamido)pentanoyl)pyrrolidine-2-carboxamide

[0430]

[0431] C 43 H60 N 11 O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 826; the measured value is 826.

[0432] Example 22:

[0433] (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0434]

[0435] C 42 H 58 N 11 O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 812; the measured value is 812.

[0436] Example 23:

[0437] (R)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valyl)pyrrolidine-2-carboxamide

[0438]

[0439] C 42 H 58 N 11 O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 812; the measured value is 812.

[0440] Example 24:

[0441] (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-phenylalanyl)pyrrolidine-2-carboxamide

[0442]

[0443] C 46 H 58 N 11 O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 860; the measured value is 860.

[0444] Example 25:

[0445] (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-alanyl)pyrrolidine-2-carboxamide

[0446]

[0447] C 40 H 54 N 11 O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 784; the measured value is 784.

[0448] [Preparation Example 2]

[0449] The process for preparing the compounds in Examples 26-43 is as follows:

[0450]

[0451] Aniline 25 (1.0 equivalent) and carboxylic acid 26 (1.0 equivalent) (synthesized according to the following reference: Bioorg. Med. Chem. 2015, 23, 7095-7109) were placed in a round-bottom flask and dissolved in dimethylformamide (0.2 M). Then, HATU (2.0 equivalent) and N,N-diisopropylethylamine (10.0 equivalent) were added, and the mixture was stirred for one day. When the reaction was complete, the product was extracted with an aqueous solution of dichloromethane and sodium bicarbonate. The collected organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 4 (yield 10-20%).

[0452] Example 26:

[0453] (S)-3-benzyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0454]

[0455] 1 H NMR (400MHz, DMSO) δ10.83 (s, 1H), 10.50 (s, 1H), 9.64 (s, 1H), 8.80 (d, J = 2.6Hz, 1H), 8.16 (d, J = 1.6Hz, 1H), 8.05 (dd, J = 8. 4,2.6Hz,1H), 7.83(dd,J=4.0,2.1Hz,1H), 7.76(s,1H), 7.69(dd,J=8.2,1.7Hz,1H), 7.59(dd,J=8.4,2.2Hz,1H), 7.51(dt ,J=8.6,4.2Hz,1H), 7.44(d,J=4.4Hz,4H), 7.40-7.24(m,6H)), 7.18(dd,J=8.0,5.8Hz,2H), 4.71(d,J=14.0Hz,1H), 4.52( d,J=14.0Hz,1H), 3.73(dd,J=8.1,5.5Hz,1H), 3.42(td,J=18.2,16.0,6.9Hz,2H), 3.32(s,3H), 2.40(s,3H), 2.13(s,3H); 13C NMR (101MHz, DMSO) δ170.58, 167.78, 164.89, 159.42, 157.49, 153.73, 152.56, 150.6 9,141.65, 140.51, 139.76, 139.67, 139.01, 138.21, 135.18, 131.35, 131.25, 131.20 ,130.93,130.19,129.78,129.14,128.81,128.55,126.71,126.51,122.93,121.84, 121.21, 120.08, 119.52, 119.49, 103.42, 65.58, 47.12, 37.61, 28.71, 23.71, 17.28; C 43 H 38 N9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 728.3098; the measured value is 728.3102.

[0456] Example 27:

[0457] (S)-3-(3-fluorobenzyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0458]

[0459] C 43 H 36 FN9O3Na[M+Na] + The calculated LRMS(MM:ESI-APCI+) m / z is 768; the measured value is 768.

[0460] Example 28:

[0461] (S)-3-(4-fluorobenzyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0462]

[0463] 1H NMR (600MHz, DMSO) δ10.83(s,1H), 10.51(s,1H), 9.64(s,1H), 8.88-8.72(m,1H), 8.16(s,1H), 8.08-8.03(m ,1H), 7.84(d,J=5.8Hz,1H), 7.77(s,1H), 7.70(d,J=8.3Hz,1H), 7.60(d,J=8.3Hz,1H), 7.51(t,J=7.0Hz,2H ), 7.47-7.35(m,8H), 7.30(d,J=8.4Hz,1H), 7.18(d,J=8.4Hz,1H), 7.10(t,J=8.7Hz,3H), 4.71(d,J=14.0Hz ,1H), 4.53(d,J=14.0Hz,1H), 3.73(t,J=6.8Hz,1H), 3.41(dd,J=13.2,5.3Hz,2H), 2.40(s,3H), 2.13(s,3H); 13 C NMR (151MHz, DMSO) δ170.46, 167.77, 164.76, 161.98, 160.38, 159.30, 157.38, 153.62, 152.4 5. 150.58, 141.53, 140.39, 139.64, 138.89, 138.09, 135.62, 135.60, 135.07, 131.90, 131.85 ,131.23, 131.14, 131.11, 130.83, 129.66, 129.03, 128.71, 126.59, 122.83, 121.73, 121.12, 119.98, 119.39, 115.15, 115.02, 103.31, 65.36, 47.00, 38.61, 36.62, 28.61, 23.60, 17.17; C 43 H 37 FN9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 746.3003; the measured value is 746.3035.

[0464] Example 29:

[0465] (S)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(2-methylbenzyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0466]

[0467] C 44 H 40 N9O3[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 742; the measured value is 742.

[0468] Example 30:

[0469] (S)-3-Methyl-N-(4-Methyl-3-(1-Methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0470]

[0471] C 37 H 34 N9O3[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 652; the measured value is 652.

[0472] Example 31:

[0473] (S)-1-Benzyl-3-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0474]

[0475] 1H NMR (600MHz, DMSO) δ10.47 (s, 1H), 9.64 (s, 1H), 8.80 (d, J = 2.7Hz, 1H), 8.21 (d, J = 1.7Hz, 1H), 8.16 (s, 1H), 8.06 (dd, J = 8.4, 2.7Hz, 1H), 7 .81(dd,J=4.7,2.2Hz,1H), 7.75(dd,J=8.1,1.7Hz,1H), 7.61(ddd,J=7.3,4.6,2.1Hz,1H), 7.51(t,J=7.4Hz,1H), 7.42(t,J=7.6Hz,2H), 7 .31(dq,J=6.7,2.4,1.6Hz,4H), 7.18(d,J=8.5Hz,1H), 7.15-7.08(m,3H), 7.00-6.95(m,2H), 5.58(d,J=15.6Hz,1H), 5.04(d,J=15.6Hz, 1H), 4.70(d,J=14.0Hz,1H), 4.53(d,J=14.0Hz,1H), 3.86(q,J=6.2Hz,1H), 3.34(s,3H), 2.41(s,3H), 2.14(s,3H), 1.61(d,J=6.3Hz,3H); 13 CNMR (151MHz, DMSO) δ169.71, 167.06, 164.08, 158.93, 157.02, 153.24, 152.11, 150.17, 141.4 8. 141.18, 139.94, 137.86, 137.59, 137.45, 137.08, 134.72, 132.49, 130.96, 130.78, 130.44, 129.61, 129.00, 128.38, 128.25, 127.10, 127.04, 126.29, 123.54, 122.49, 122.28, 119.79, 11 9.29, 102.95, 58.37, 53.60, 48.93, 46.63, 41.84, 28.23, 23.18, 18.08, 17.48, 16.79, 16.72; C 44 H 40 N9O3[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 742; the measured value is 742.

[0476] Example 32:

[0477] (R)-3-((R)-sec-butyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0478]

[0479] C 40 H 40 N9O3[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 694; the measured value is 694.

[0480] Example 33:

[0481] (S)-1-Benzyl-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0482]

[0483] C 47 H 46 N9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 784.3724; the measured value is 784.3715.

[0484] Example 34:

[0485] (S)-3-benzyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide

[0486]

[0487] 1H NMR (600MHz, DMSO) δ 10.66 (s, 1H), 10.44 (s, 1H), 9.66 (s, 1H), 8.81 (d, J = 2.7Hz, 1H), 8.15 (d, J = 3.0Hz, 1H), 8. 06(dd,J=8.5,2.6Hz,1H), 7.88-7.79(m,2H), 7.75-7.71(m,1H), 7.64(s,1H), 7.59(d,J=8.2Hz,1H), 7.29(d,J= 8.4Hz,1H), 7.27-7.16(m,5H), 7.14(t,J=7.3Hz,1H), 4.70(d,J=13.7Hz,1H), 4.55-4.45(m,1H), 3.55(d,J=14. 0Hz,1H), 3.52(s,3H), 3.44-3.40(m,1H), 3.34(s,3H), 3.16(dt,J=15.0,7.5Hz,1H), 2.41(s,6H), 2.13(s,3H); 13 C NMR (151MHz, DMSO) δ169.93, 167.27, 164.76, 159.28, 157.37, 153.59, 152.45, 150 .45, 141.52, 140.14, 139.58, 138.08, 137.61, 137.59, 135.14, 131.19, 131.12, 13 0.88, 129.90, 129.87, 129.14, 128.40, 126.75, 126.30, 122.93, 122.23, 120.87, 1 19.95, 119.42, 119.38, 103.34, 64.85, 46.99, 37.34, 28.61, 25.86, 23.49, 17.16; C 38 H 36 N9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 666.2941; the measured value is 666.2943.

[0488] Example 35:

[0489] (R)-3-benzyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0490]

[0491] 1 H NMR (600MHz, DMSO) δ10.66 (s, 1H), 10.44 (s, 1H), 9.66 (s, 1H), 8.81 (d, J = 2.7Hz, 1H), 8.15 (d, J = 3.0Hz, 1H), 8. 06(dd,J=8.5,2.6Hz,1H), 7.88-7.79(m,2H), 7.75-7.71(m,1H), 7.64(s,1H), 7.59(d,J=8.2Hz,1H), 7.29(d,J= 8.4Hz,1H), 7.27-7.16(m,5H), 7.14(t,J=7.3Hz,1H), 4.70(d,J=13.7Hz,1H), 4.55-4.45(m,1H), 3.55(d,J=14. 0Hz,1H), 3.52(s,3H), 3.44-3.40(m,1H), 3.34(s,3H), 3.16(dt,J=15.0,7.5Hz,1H), 2.41(s,6H), 2.13(s,3H); 13 C NMR (151MHz, DMSO) δ169.93, 167.27, 164.76, 159.28, 157.37, 153.59, 152.45, 150 .45, 141.52, 140.14, 139.58, 138.08, 137.61, 137.59, 135.14, 131.19, 131.12, 13 0.88, 129.90, 129.87, 129.14, 128.40, 126.75, 126.30, 122.93, 122.23, 120.87, 1 19.95, 119.42, 119.38, 103.34, 64.85, 46.99, 37.34, 28.61, 25.86, 23.49, 17.16; C 38 H 36 N9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z is 666.2941; the measured value is 666.2947.

[0492] Example 36:

[0493] (R)-3-benzyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0494]

[0495] C 43 H 38 N9O3[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 728; the measured value is 728.

[0496] Example 37:

[0497] (S)-3-Isobutyl-1-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0498]

[0499] 1 H NMR (600MHz, DMSO) δ10.53 (s, 1H), 9.76 (s, 1H), 8.87 (t, J = 2.5Hz, 1H), 8.18 (s, 1H), 8.12 (d, J = 8.5Hz, 1H), 8.06 (s, 1H), 7.85-7.81 (m, 1H) , 7.80(d,J=8.2Hz,1H), 7.65-7.61(m,1H), 7.55(d,J=7.6Hz,2H), 7.52(d,J=7.3Hz,1H), 7.46(dd,J=11.7,7.8Hz,3H), 7.33(d,J=8.4Hz,1 H), 7.27(d,J=8.5Hz,1H), 4.72(d,J=14.0Hz,1H), 4.55(d,J=14.0Hz,1H), 3.62(ddq,J=9.6,6.8,3.4,2.8Hz,1H), 3.57(dt,J=8.9,5.4Hz, 1H), 3.35(s,3H), 3.14(qd,J=7.4,4.1Hz,2H), 2.44(s,3H), 2.15(s,4H), 1.92-1.78(m,2H), 0.94(d,J=6.4Hz,3H), 0.76(d,J=6.3Hz,3H); 13CNMR (151MHz, DMSO) δ170.28, 167.36, 164.71, 159.15, 157.42, 153.61, 152.45, 149.85 ,143.69,141.53,138.36,138.03,137.98,135.53,131.31,131.17,130.91,130.80,13 0.16, 129.57, 128.76, 123.56, 123.31, 121.38, 120.16, 119.61, 103.59, 61.52, 53.96, 46.99, 42.21, 35.10, 28.64, 24.53, 23.74, 22.93, 22.14, 18.45, 17.17, 17.09, 12.86; C 41 H 42 N9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 708.3411; the measured value is 708.3407.

[0500] Example 38:

[0501] (S)-1-Allyl-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0502]

[0503] 1H NMR (600MHz, DMSO) δ10.51 (s, 1H), 9.65 (s, 1H), 8.89-8.64 (m, 1H), 8.14 (d, J = 31.3Hz, 2H), 8.08-8.01 (m ,1H), 7.81(m,2H), 7.62(d,J=8.3Hz,1H), 7.57-7.39(m,6H), 7.32(d,J=8.3Hz,H), 7.18(d,J=8.3Hz,1H), 5.76(ddt,J=16.1,10.3,5.0Hz,1H), 5.04(d,J=10.4Hz,1H), 4.98(d,J=17.3Hz,1H), 4.73(dd,J=18.1,7 .8Hz,2H), 4.60-4.50(m,2H), 3.64(dd,J=8.8,4.5Hz,1H), 3.34(s,3H), 2.40(s,3H), 2.14(s,3H), 2.11(m 1H), 1.88(dd,J=12.9,7.1Hz,2H), 0.94(d,J=5.7Hz,3H), 0.77(d,J=5.6Hz,3H); 13 C NMR (151MHz, DMSO) δ169.22, 167.53, 164.63, 159.31, 157.38, 153.62, 152.48, 150.58, 142. 44, 141.56, 140.39, 138.37, 138.02, 138.00, 135.06, 133.77, 131.85, 131.33, 131.16, 130. 93, 130.15, 129.45, 128.84, 126.59, 123.70, 122.83, 122.08, 120.15, 120.13, 119.63, 119. 60, 116.64, 103.31, 61.69, 49.16, 47.00, 40.42, 28.61, 24.63, 23.66, 23.60, 22.30, 17.17; C 43 H 44 N9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 734.3567; the measured value is 734.3565.

[0504] Example 39:

[0505] (S)-1,3-Diisobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazazo-8-carboxamide

[0506]

[0507] 1 H NMR (600MHz, DMSO) δ10.48 (s, 1H), 9.65 (s, 1H), 8.80 (d, J = 2.6Hz, 1H), 8.17 ( d,J=3.0Hz,2H), 8.05(dd,J=8.6,2.7Hz,1H), 7.86-7.77(m,2H), 7.64(dt,J=5 .9,2.9Hz,1H), 7.57-7.51(m,3H), 7.48(t,J=7.4Hz,2H), 7.44(d,J=8.1Hz,1 H), 7.33(d,J=8.4Hz,1H), 7.18(d,J=8.5Hz,1H), 4.71(d,J=13.9Hz,1H), 4.54 (d,J=14.0Hz,1H), 4.21(dd,J=13.8,8.9Hz,1H), 3.66(dd,J=13.8,5.9Hz,1H ), 3.57(dd,J=8.9,4.4Hz,1H), 3.34(s,3H), 2.41(s,3H), 2.15(s,3H), 2.14-2 .09(m,1H), 1.83(tt,J=13.0,7.4Hz,2H), 1.66(p,J=6.7Hz,1H), 0.93(d,J=6. 1Hz,3H), 0.75(d,J=6.1Hz,3H), 0.71(d,J=6.6Hz,3H), 0.53(d,J=6.6Hz,3H); 13C NMR (151MHz, DMSO) δ170.12, 167.31, 164.54, 159.31, 157.39, 153.63, 152.48, 150.58, 142. 48, 141.55, 140.39, 138.16, 137.97, 135.06, 132.44, 131.34, 131.15, 130.93, 130.09, 129.3 5. 128.88, 126.59, 123.91, 122.83, 122.41, 120.25, 119.77, 119.73, 103.31, 61.72, 52.75, 4 7.01, 31.32, 28.61, 27.11, 24.59, 23.71, 23.60, 22.43, 22.24, 20.23, 19.50, 17.18, 14.33; C 44 H 48 N9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 750.3880; the measured value is 750.3883.

[0508] Example 40:

[0509] (S)-3-Isobutyl-1,5-dimethyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0510]

[0511] 1H NMR (600MHz, DMSO) δ10.45(s,1H), 9.64(s,1H), 8.80(d,J=2.7Hz,1H), 8.16(s,1H), 8.05(dd,J=8.5,2.7Hz,1H), 7.95(s ,1H), 7.88(d,J=8.1Hz,1H), 7.85-7.77(m,2H), 7.68-7.61(m,1H), 7.32(d,J=8.4Hz,1H), 7.17(d,J=8.4Hz,1H), 4.70(d, J=13.9Hz,1H), 4.53(d,J=14.0Hz,1H), 3.40(m,1H), 3.36(s,3H), 3.34(s,3H), 2.43(s,3H), 2.40(s,3H), 2.14(s,3H), 1. 93(ddd,J=13.5,8.4,5.2Hz,1H), 1.72(ddp,J=33.0,13.6,6.6,6.1Hz,2H), 0.85(d,J=6.4Hz,3H), 0.70(d,J=6.3Hz, 3H); 13 C NMR (151MHz, DMSO) δ170.07, 167.18, 164.65, 159.31, 157.39, 153.61, 152.48 ,150.57,141.77,141.54,140.39,138.00,137.50,135.06,132.63,131.27,1 31.14, 128.14, 126.59, 123.59, 122.82, 121.23, 121.20, 120.14, 119.66, 103 .31, 60.66, 47.00, 35.06, 28.61, 25.44, 24.23, 23.60, 23.58, 22.11, 17.17; C 36 H 40 N9O3[M+H] + The calculated HRMS (MM: ESI-APCI+) m / z value is 646.3254; the measured value is 646.3265.

[0512] Example 41:

[0513] (S)-1-Benzyl-3-isobutyl-5-methyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0514]

[0515] C 42 H 44 N9O3[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 722; the measured value is 722.

[0516] Example 42:

[0517] (S)-3-Isobutyl-1-(2-methoxyethyl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0518]

[0519] 1 H NMR (600MHz, DMSO) δ10.51 (s, 1H), 9.65 (s, 1H), 8.80 (d, J = 2.7Hz, 1H), 8.16 (d, J = 2.8Hz, 2H), 8.05 (dd, J = 8.5, 2.7Hz, 1H), 7.85-7.76 (m, 2H), 7.6 4(dd,J=8.4,2.2Hz,1H), 7.55-7.50(m,3H), 7.49-7.44(m,2H)), 7.39(d ,J=8.1Hz,1H), 7.33(d,J=8.4Hz,1H), 7.18(d,J=8.5Hz,1H), 4.71(d,J=1 4.0Hz,1H), 4.54(d,J=14.0Hz,1H), 4.40(dt,J=14.5,5.6Hz,1H), 3.99(ddd,J=14.4,6.5,4.2Hz,1H), 3.58(dd,J=8.7,4.5Hz,1H), 3.42-3.35(m, 2H), 3.34(s,3H), 2.95(s,3H), 2.41(s,3H), 2.14(s,3H), 2.11(q,J=8.8 Hz,1H), 1.86-1.80(m,2H), 0.93(d,J=5.9Hz,3H), 0.76(d,J=5.9Hz,3H); 13C NMR (151MHz, DMSO) δ169.32, 167.58, 164.67, 159.31, 157.39, 153.62, 152.48, 150.58, 142. 78, 141.56, 140.39, 138.48, 138.04, 138.03, 137.81, 135.06, 132.37, 131.29, 131.16, 131. 14, 130.78, 129.81, 129.42, 128.69, 126.59, 123.91, 122.86, 122.83, 120.16, 120.14, 119. 64, 119.60, 103.31, 69.70, 61.57, 58.27, 47.01, 28.61, 24.63, 23.67, 23.60, 22.29, 17.18; C 43 H 46 N9O4[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 752.3673; the measured value is 752.3667.

[0520] Example 43:

[0521] (S)-1-(2-(benzylamino)-2-oxoethyl)-3-isobutyl-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazaphen-8-carboxamide

[0522]

[0523] 1H NMR(600MHz,DMSO)δ10.54(s,1H)、9.65(s,1H)、8.81(d,J=2.8Hz,1H)、8.67(t,J=6.0Hz,1H)、8.17(s,1H)、8.09-7.99(m,2H)、7.82(q,J=2.4Hz,1H)、7.80-7.77(m,1H)、7.63(dd,J=8.1,2.4Hz,1H)、7.56-7.53(m,2H)、7.51(t,J=7.3Hz,1H)、7.45(t,J=7.5Hz,2H)、7.40(d,J=8.1Hz,1H)、7.34(d,J=8.5Hz,1H)、7.25(dt,J=15.7,7.6Hz,4H)、7.18(dd,J=8.1,4.6Hz,2H)、4.66(dtd,J=46.8,16.2,15.1,3.8Hz,3H)、4.55(d,J=14.0Hz,1H)、4.34(dd,J=15.4,6.0Hz,1H)、4.26(dd,J=15.4,5.7Hz,1H)、3.66(qd,J=4.5,1.9Hz,1H)、3.35(s,3H)、2.41(s,3H)、2.15(s,3H)、2.13(d,J=8.8Hz,1H)、1.90-1.82(m,2H)、0.95(d,J=6.1Hz,3H)、0.78(d,J=5.9Hz,3H); 13 CNMR(151MHz,DMSO)δ169.56、167.99、167.90、164.84、159.32、157.39、153.62、152.49、150.55、143.08、141.58、140.35、139.43、138.73、138.07、138.05、137.94、135.08、131.62、131.32、131.19、130.70、130.04、129.66、128.61、128.59、127.44、127.08、126.63、123.43、122.84、122.13、122.12、120.09、119.60、119.56、103.30、63.16、61.40、50.68、47.02、42.48、40.22、28.61、24.61、23.73、23.57、22.25、17.18;C 49 H 49 N 10 O4[M+H] +The calculated HRMS (MM:ESI-APCI+) m / z value is 841.3938; the measured value is 841.3947.

[0524] [Preparation Example 3]

[0525] The preparation methods of the compounds in Examples 44 to 46 are as follows:

[0526]

[0527] Aniline 25 (1.0 equivalent) and carboxylic acid 27 (1.0 equivalent) (benzodiazepine 27 derivative synthesized according to the following reference: Org. Lett. 2015, 17, 3592-3595) were placed in a round-bottom flask and dissolved in dimethylformamide (0.2 M). Then, HATU (2.0 equivalent) and N,N-diisopropylethylamine (10.0 equivalent) were added, and the mixture was stirred for one day. When the reaction was complete, the product was extracted with an aqueous solution of dichloromethane and sodium bicarbonate. The collected organic layer was washed several times with water, dried with anhydrous magnesium sulfate, filtered, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 5 (yield 10-20%).

[0528] Example 44:

[0529] (S)-2-(5-(but-3-en-1-yl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide

[0530]

[0531] C 35 H 36 N9O3[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 630; the measured value is 630.

[0532] Example 45:

[0533] (S)-2-(5-(but-3-en-1-yl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide

[0534]

[0535] 1 H NMR (600MHz, DMSO) δ10.18(s,1H), 9.69(s,1H), 8.83(s,1H), 8.13(s,1H), 8.08(d,J=8.5Hz,1H), 7.71(d,J=7.8Hz,1H), 7.67(d,J=14.5 Hz,1H), 7.60(t,J=7.9Hz,1H), 7.50(d,J=8.4Hz,1H), 7.32(t,J=8.2Hz,2H), 7.22(dd,J=14.1,8.4Hz,2H), 5.67(dt,J=16.6,8.4Hz,1H) , 4.84(d,J=13.6Hz,2H), 4.63(d,J=14.0Hz,1H), 4.47(d,J=14.1Hz,1H), 3.90(d,J=7.2Hz,1H), 3.31(s,3H), 3.25(s,3H), 3.12(td,J=1 5.8,6.9Hz,1H), 2.97(ddt,J=30.1,14.6,7.4Hz,2H), 2.75(dt,J=15.4,7.9Hz,1H), 2.42(s,3H), 2.21(m,1H), 2.14(m,1H), 2.08(s,3H); 13 C NMR (151MHz, DMSO) δ170.61, 169.82, 169.67, 159.18, 157.39, 153.53, 152.3 9. 150.08, 142.17, 141.47, 138.45, 137.66, 131.59, 131.07, 130.00, 129.83, 127.62, 127.32, 124.88, 123.29, 122.25, 118.45, 118.04, 115.54, 103.48, 59 .82, 46.92, 39.00, 36.78, 34.93, 31.22, 31.20, 28.58, 23.16, 18.45, 17.04; C 36 H 38 N9O3[M+H] + The calculated HRMS (MM: ESI-APCI+) m / z value is 644.3098; the measured value is 644.3099.

[0536] Example 46:

[0537] (S)-2-(1-benzyl-5-(but-3-en-1-yl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazaphen-3-yl)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyridino[4,5-d]pyrimidin-3(2H)-yl)phenyl)acetamide

[0538]

[0539] 1 H NMR (400MHz, DMSO) δ10.20 (s, 1H), 9.63 (s, 1H), 8.79 (d, J = 2.6Hz, 1H), 8.13 (d, J = 1.7Hz, 1H), 8.05 (dd, J = 8.4, 2.7Hz, 1H), 7.72-7.6 2(m,2H), 7.62-7.48(m,2H), 7.34(td,J=8.3,2.2Hz,1H), 7.27(t,J=7.4Hz,1H), 7.24-7.13(m,5H), 7.03(d,J=7.3Hz,2H), 5.79-5.66 (m,1H), 5.33(dd,J=15.7,3.8Hz,1H), 4.97-4.85(m,3H), 4.63(d,J=14.1Hz,1H), 4.48(d,J=14.1Hz,1H), 4.02(t,J=7.1Hz,1H), 3.3 4(s,3H), 3.22(ddd,J=16.8,9.9,7.4Hz,1H), 3.10-2.99(m,1H), 2.79-2.70(m,2H), 2.40(s,3H), 2.09(s,3H), 1.98(q,J=7.5Hz,2H); 13 C NMR (101MHz, DMSO) δ170.79, 169.79, 169.35, 169.33, 159.41, 157.50, 153.66, 152.53, 15 0.67, 141.62, 140.53, 140.51, 138.54, 138.04, 137.62, 135.18, 131.66, 131.18, 131.14, 1 30.15, 128.79, 127.72, 127.61, 127.56, 126.69, 125.49, 122.98, 122.91, 118.63, 118.27 ,115.55,103.42,59.96,49.63,47.06,39.01,36.96,31.09,31.07,28.67,23.70,17.16;C 42 H 42N9O3[M+H] + The calculated HRMS (MM:ESI-APCI+) m / z value is 720.3411; the measured value is 720.3410.

[0540] [Preparation Example 4]

[0541] The preparation methods of the compounds in Examples 47 and 48 are as follows:

[0542]

[0543] Benzoic acid 21 (1.0 equivalent) and amine 31 (1.0 equivalent) (amine 31 derivative synthesized according to the following reference: J. Am. Chem. Soc. 2011, 133, 10184-10194) were placed in a round-bottom flask and dissolved in dimethylformamide (0.2 M). Then, COMU (1.2 equivalent) and N,N-diisopropylethylamine (2.5 equivalent) were added, and the mixture was stirred for one day. When the reaction was complete, the resulting product was extracted with dichloromethane and an aqueous solution of sodium bicarbonate. The collected organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the resulting residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 8 (yield 10-42%).

[0544] Example 47:

[0545] (3S,4S)-N 3 -Benzyl-N 4 -(4-Chlorobenzyl)-1-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)pyrrolidine-3,4-dicarboxamide

[0546]

[0547] C 41 H 41 ClN9O4[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 758; the measured value is 758.

[0548] Example 48:

[0549] (3S,4S)-N 3 -(2-(1H-indol-3-yl)ethyl)-N 4-(4-Chlorobenzyl)-1-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)pyrrolidine-3,4-dicarboxamide

[0550]

[0551] C 44 H 44 ClN 10 O4[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 811; the measured value is 811.

[0552] [Preparation Example 5]

[0553] The preparation methods of the compounds in Examples 49 to 51 are as follows:

[0554]

[0555] Aniline 25 (1.0 equivalent) and benzoic acid 32 (1.0 equivalent) (benzoic acid 32 derivatives were synthesized according to the following reference: J. Am. Chem. Soc. 2009, 131, 5564-5572) were placed in a round-bottom flask and dissolved in dimethylformamide (0.2 M). Then, COMU (2.0 equivalent) and N,N-diisopropylethylamine (5.0 equivalent) were added, and the mixture was stirred for one day. When the reaction was complete, the product was extracted with an aqueous solution of dichloromethane and sodium bicarbonate. The collected organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 9 (yield 10-54%).

[0556] Example 49:

[0557] 3-Isobutoxy-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide

[0558]

[0559] C 31 H 32 N8O5Na[M+Na] + The calculated LRMS(MM:ESI-APCI+) m / z is 619; the measured value is 619.

[0560] Example 50:

[0561] 3-(2-(1H-indol-3-yl)ethoxy)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide

[0562]

[0563] C 37 H 34 N9O5[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 684; the measured value is 684.

[0564] Example 51:

[0565] 3-(4-methoxyphenethoxy)-N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)-4-nitrobenzamide

[0566]

[0567] C 36 H 34 N8O6Na[M+Na] + The calculated LRMS(MM:ESI-APCI+) m / z is 697; the measured value is 697.

[0568] [Preparation Example 6]

[0569] The preparation methods of the compounds in Examples 52 to 56 are as follows:

[0570]

[0571] Acid 34 (1.5 equivalents) (acid 34 derivatives were synthesized according to the following reference: J. Am. Chem. Soc. 2009, 131, 5564-5572) and NMM (1.6 equivalents) were placed in a round-bottom flask and dissolved in dimethylformamide (0.1 M). Isobutyl chloroformate (1.6 equivalents) was then slowly added at 0 °C. After stirring at 0 °C for 30 min, aniline 33 was added and the mixture was refluxed for 20 h. The reaction was terminated with an aqueous ammonium chloride solution, and the resulting product was extracted with ethyl acetate and water. The collected organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 35 (yield 70-84%).

[0572] Amide 35 (1.0 equivalent), potassium carbonate (5.0 equivalent), 5-amino-2-methylpyridine (1.01 equivalent), 2-dicyclohexylphospho-2',4',6'-triisopropylbiphenyl (0.2 equivalent), and Pd2(dba)3 (0.2 equivalent) were placed in a round-bottom flask and dissolved in 2-butanol (0.2 M). The resulting solution was then stirred at 100 °C for 2 hours and cooled to room temperature. After filtration, the solvent was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 10 (yield 61-85%).

[0573] Example 52:

[0574] 3-Isobutoxy-N-(2-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-2-oxoethyl)-4-nitrobenzamide

[0575]

[0576] C 33 H 36 N9O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 654; the measured value is 654.

[0577] Example 53:

[0578] (S)-3-Isobutoxy-N-(1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-2-oxopropane-2-yl)-4-nitrobenzamide

[0579]

[0580] C 34 H 38 N9O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 668; the measured value is 668.

[0581] Example 54:

[0582] (S)-3-Isobutoxy-N-(4-methyl-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopentane-2-yl)-4-nitrobenzamide

[0583]

[0584] C 37 H 43 N9O6Na[M+Na] + The calculated LRMS(MM:ESI-APCI+) m / z is 732; the measured value is 732.

[0585] Example 55:

[0586] (S)-N-3-(1H-indol-3-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopropane-2-yl)-3-isobutoxy-4-nitrobenzamide

[0587]

[0588] C 42 H 43 N 10 O6[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 783; the measured value is 783.

[0589] Example 56:

[0590] (S)-3-(4-methoxyphenethoxy)-N-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)amino)-1-oxopropan-2-yl)-4-nitrobenzamide

[0591]

[0592] C 39 H 40 N9O7[M+H] + The calculated LRMS(MM:ESI-APCI+) m / z is 746; the measured value is 746.

[0593] [Preparation Example 7]

[0594] The preparation method of the compound in Example 57 is as follows:

[0595]

[0596] Aniline 2 (1.0 equivalent) and acid 36 (1.0 equivalent) (acid 36 derivative synthesized according to the following reference: J. Am. Chem. Soc. 2009, 131, 5564-5572) were placed in a round-bottom flask and dissolved in dimethylformamide (0.1 M). Then, HATU (2.0 equivalent) and N,N-diisopropylethylamine (5.0 equivalent) were added, and the mixture was stirred for one day. When the reaction was complete, the resulting product was extracted with an aqueous solution of dichloromethane and sodium bicarbonate. The collected organic layer was washed several times with water, dried over anhydrous magnesium sulfate, filtered, and the resulting residue was purified by column chromatography (dichloromethane:methanol = 20:1 → 10:1) to give amide 11 (yield 47%).

[0597] Example 57:

[0598] 2,2,2-Trichloroethyl(3S,4S)-3-((4-chlorobenzyl)carbamoyl)-4-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)phenyl)carbamoyl)pyrrolidine-1-carboxylate

[0599]

[0600] C 36 H 35 Cl4N9O5Na[M+Na] + The calculated LRMS(MM:ESI-APCI+) m / z is 836; the measured value is 836.

[0601] [Experimental Example]

[0602] Experimental Example 1. Determination of Kinase Inhibitory Activity

[0603] To measure the inhibitory activity (inhibitory capacity %) of the compounds of the present invention against protein kinases, a complete kinase assay was performed.

[0604] The experimental compounds used in this paper are compounds 1 and 33. Residual enzyme activity (%) was calculated by measuring the inhibitory activity against kinases after treatment with the experimental compounds at a single concentration of 1 μM. Kinases with a calculated residual enzyme activity (%) of 30% or less (i.e., inhibition rate greater than 70%) are shown below.

[0605] <Kinetic inhibitors with an activity of 70% or higher>

[0606] LCK, DDR1, FGR, BMX, ABL2, BLX, BLK, LYN, DDR2, RAF1, c-Src, CSK, HCK

[0607] Experimental Example 2. Inhibitory activity against LCK, c-Src, p38a / MAPK14, ABL1, DDR1 and FGR kinases

[0608] IC50 was calculated by measuring the inhibitory activity of the compounds of the present invention against LCK, c-Src, p38a / MAPK14, ABL1, DDR1, and FGR kinases. 50 The calculated IC value. 50 The values ​​are shown in Tables 1 to 3 below:

[0609] IC 50 active

[0610] A = 1 - 200nM

[0611] B = 200-400nM

[0612] C = 400-600nM

[0613] D≥600nM

[0614] Table 1

[0615]

[0616]

[0617] Table 2

[0618]

[0619]

[0620] Table 3

[0621] LCK c-Src p38a / MAPK14 ABL1 ABL1(T315I) Example 47 A A A A - Example 48 A A C A - Example 49 A - A A D Example 50 A - B A - Example 51 A - A A - Example 52 A - C A D Example 53 C - D D - Example 54 A - D A D Example 55 D - - D - Example 56 A - D A - Example 57 A A A A -

[0622] [Preparation Example]

[0623] Furthermore, the novel compounds represented by any one of formulas 1 to 6 according to the present invention can be formulated in various forms according to their intended purpose. Examples of some formulation methods including incorporating the compounds represented by any one of formulas 1 to 6 according to the present invention as active ingredients are as follows, but the present invention is not limited thereto.

[0624] Formulation Example 1: Tablets (Direct Compression)

[0625] 5.0 mg of the active ingredient was sieved, and 14.1 mg of lactose, 0.8 mg of cropovidone USNF and 0.1 mg of magnesium stearate were mixed therein, and the mixture was compressed into tablets.

[0626] Formulation Example 2: Tablets (Wet Granulation)

[0627] 5.0 mg of the active ingredient was sieved and mixed with 16.0 mg of lactose and 4.0 mg of starch. 0.3 mg of polysorbate-80 was dissolved in pure water, and an appropriate amount of the resulting solution was added to the mixture, followed by granulation. The granules were dried, sieved, and mixed with 2.7 mg of silica gel and 2.0 mg of magnesium stearate. The granules were then compressed into tablets.

[0628] Formulation Example 3: Powders and Capsules

[0629] 5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone, and 0.2 mg of magnesium stearate. The resulting mixture was then filled into No. 5 hard gelatin capsules using a suitable apparatus.

[0630] Preparation Example 4: Injection

[0631] The injection was prepared by incorporating 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na2HPO4·12H2O, and 2.974 mg of distilled water.

[0632] As is evident from the foregoing, the compounds according to the present invention possess excellent inhibitory properties against protein kinases such as ABL1, ABL2 / ARG, ARAF, BLK, BMX / ETK, BRAF, c-Src, CSK, DDR1, DDR2, EPHA2, EPHA4, ERBB4 / HER2, ERBB4 / HER4, EPHB1, FGR, FRK / PTK5, FYN, FGFR1, FMS, HCK, LCK, LIMK1, LYN, LYN B, MEK5, MLK1 / MAP3K9, MLK3 / MAP3K11, P38a / MAPK14, PDGFRa, PDGFRb, PEAK1, RAF1, YES / YES1, ARK5 / NUAK1, and Aurora. C, BMPR2, BRSK2, BTK, c-Kit, CAMK1b, CAMK1d, CAMKK2, CK1d, CK2a, CK2a2, CLK1, CLK3, CTK / MATK, DAPK1, DY RK1 / DYRK1A, DYRK1B, DYRK3, EGRF, EPHA2, EPHA3, EPHA4, EPHA5, EPHA8, EPHB1, EPHA3, EPHA5, EPHA8, EPHB2 , EPHB4, ERBB2 / HER2, ERK1, ERN1 / IRE1, FLT4 / VEGFR3, GRK4, HIPK3, IKKa / CHUK, IRAK1, KDR / VEGFR2, KHS / M AP4K5, MAPKAPK5 / PRAK, MASTL, MEK2, MEKK3, MKK6, MLK1 / MAP3K9, MLK2 / MAP3K10, MLK3 / MAP3K11, MSK1 / RPS 6KA5, MSK2 / RPS6KA4, MSSK1 / STK23, MST4, MUSK, NEK11, NEK8, p38b / MAPK11, PAK5, PKCd, PKCeta, PKCG, PKM YT1, PKN3 / PRK3, PLK3, PYK2, RET, RIPK4, RON / MST1R, ROS / ROS1, SIK1, ZAK / MLTK, WNK3, WNK2, TRKC, STK32B The ability to activate / YANK2, SNRK, SLK / STK2, SIK3, RSK1, ROCK1, PKG2 / PRKG2, MRCKa / CDC42BPA, LIMK2, JAK2, JAK1, ITK, IRAK1, GSK3a, GCK / MAP4K2, FGFR2, FGFR1, FES / FPS, c-MET, c-Kit, ARAF, ALK6 / BMPR1B, ALK1 / ACVRL1 and AKT3.Therefore, the compounds of the present invention can be used to treat, prevent, and alleviate cancer-related diseases caused by abnormal cell growth.

[0633] The compounds according to the present invention, their pharmaceutically acceptable salts, their hydrates, their stereoisomers, and pharmaceutical compositions comprising the above as active ingredients for the prevention or treatment of cancer exhibit low cytotoxicity and have excellent inhibitory activity against cancer cells and selective antiproliferative activity, and are therefore suitable for the prevention or treatment of cancer.

[0634] Examples of cancer-related diseases that can be prevented, treated, or alleviated by treatment with the compounds described in this invention include stomach cancer, lung cancer, liver cancer, colorectal cancer, small bowel cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenosis, uterine cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, bladder cancer, blood cancers (including leukemia, multiple myeloma, and myelodysplastic syndrome), lymphomas (including Hodgkin's disease and non-Hodgkin's lymphoma), psoriasis, fibroadenoma, etc.

[0635] In particular, the compounds according to the present invention have excellent selective inhibitory activity against LCK kinases, and are therefore effective for the treatment of cancer-related diseases that require LCK kinase inhibition.

[0636] Although embodiments of the invention have been described above, it will be apparent to those skilled in the art that the invention can be implemented in other specific embodiments without altering the technical concept or essential characteristics of the invention. Therefore, it should be understood that the foregoing embodiments are illustrative in all respects and not restrictive.

Claims

1. A compound and a pharmaceutically acceptable salt thereof, said compound being selected from pyrimidino[4,5-d]pyrimidin-2-one derivatives represented by Formula 1: [Formula 1] ； in R1 is hydrogen; A is ; Y is ; L1, L3 and L4 are all -C(O)NH-; L2 is , where n is 1, 2 or 3; L5 is -C(O)NMe2 or phenyl; R2 is -CH(CH(CH3)2)-; -CR5R6-; -CH(CH(CH2CH3)CH3)-; -CH(CH3)-; -CH2-; -CH(CH2(CH(CH3)2))-; or -CH(CH2CH2CH3)-; R3 can be -C(CH3)2-; -C3 cyclo-; -CH2-; -CH(CH(CH3)2)-; -CH(CH2(Ph))-; or -C4 cyclo-; R4 is -CH(CH2(CH(CH3)2))-; -CH(CH3)-; -CH2-; or -CH(CH(CH3)2)-; R5 is hydrogen; R6 is a C6 cyclic group or -CH2(Ph); And among them, R2, R3, and R4 are not simultaneously -CH(CH(CH3)2)-, -C(CH3)2-, or -CH(CH(CH3)2)-.

2. The compound of claim 1 and its pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of compounds 1 to 21 and 24-25: (Compound 1) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 2) (R)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 3) (R)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclopropyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 4) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclopropyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 5) (R)-N-(2-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-oxoethyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 6) (S)-N-(2-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-oxoethyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 7) (R)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-phenylalanyl)pyrrolidine-2-carboxamide; (Compound 8) (R)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 9) (S)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 10) (R)-N-(1-(((R)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-D-valine)pyrrolidine-2-carboxamide; (Compound 11) (S)-N-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)1-oxo-3-phenylpropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 12) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)carbamoyl)cyclobutyl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 13) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)piperidine-2-carboxamide; (Compound 14) (S)-N-(1-((2-(dimethylamino)-2-oxoethyl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)pyrrolidine-2-carboxamide; (Compound 15) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-valine)azacyclobutane-2-carboxamide; (Compound 16) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-isoleucyl)pyrrolidine-2-carboxamide; (Compound 17) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopent-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-alanyl)pyrrolidine-2-carboxamide; (Compound 18) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)glycyl)pyrrolidine-2-carboxamide; (Compound 19) (S)-1-((S)-2-cyclohexyl-2-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzamido)acetyl)-N-(1-(((S)-1-dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)pyrrolidine-2-carboxamide; (Compound 20) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-leucyl)pyrrolidine-2-carboxamide; (Compound 21) (S)-N-(1-(((S)-1-(dimethylamino)-4-methyl-1-oxopentane-2-yl)amino)-2-methyl-1-oxopropane-2-yl)-1-((S)-2-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzamido)valoyl)pyrrolidine-2-carboxamide; (Compound 24) (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-phenylalanyl)pyrrolidine-2-carboxamide; (Compound 25) (S)-N-(1-(((S)-1-(dimethylamino)-3-methyl-1-oxobutan-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-1-((4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino))-2-oxo-1,4-dihydropyrimidino[4,5-d]pyrimidin-3(2H)-yl)benzoyl)-L-alanyl)pyrrolidine-2-carboxamide.

3. The compound according to claim 1 and its pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is a salt of an inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid.

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