BR112017025356B1 - COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE FOR THE MANUFACTURE OF A MEDICINE - Google Patents

Abstract

COMPOUND, PHARMACEUTICAL COMPOSITION, AND, USE FOR THE MANUFACTURE OF A MEDICINE. The purpose of the present invention is to provide a compound having excellent CDK4/6 inhibition activity. The present invention is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD

[001] The present invention relates to a pyrido[3,4]pyrimidine derivative and a pharmaceutically acceptable salt thereof. In particular, the present invention relates to a compound which exhibits cyclin-dependent kinase-4 and/or cyclin-dependent kinase-6 (hereinafter referred to as “CDK4/6”) inhibitory activity and which is useful for the prevention or treatment of rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer.

PREVIOUS TECHNIQUE

[002] Cell growth, which is a process involving the proliferation and division of cells, occurs in response to various stimuli.

[003] Pathological conditions caused by the hyperproliferation of cells, such as cancer, are characterized by uncontrollable cell cycle progression, and thus excessive cell cycle progression, for example, resulting from abnormalities in genes and proteins that directly or indirectly regulate cell cycle progression. Substances that regulate cell hyperproliferation through cell cycle control can be used to treat various pathological conditions characterized by uncontrollable or unwanted cell growth.

[004] Cell cycle progression is a complicated process that involves highly regulated transcription phases and multiple checkpoints.

[005] Cyclin-dependent kinases and serine/threonine protein kinases are important intracellular enzymes that play essential roles in regulating cell division and proliferation. The catalytic subunits of cyclin-dependent kinases are activated by regulatory subunits known as cyclins, and multiple cyclins have been identified in mammals (Non-Patent Literature 1).

[006] The retinoblastoma protein (Rb) is a checkpoint protein for the transition from the G1 phase to the S phase of the cell cycle. The Rb protein associates with the E2F transcription factor family and inhibits its activity in the absence of appropriate growth stimulation (Non-Patent Literature 2 and 3). A cell stimulated by a mitogen enters the S phase through the synthesis of cyclin D, which is an activator of CDK4/6. CDK4/6 bound to cyclin-D inactivates the Rb protein upon phosphorylation. Phosphorylation of the Rb protein releases E2F in order to prevent transcription of a gene required for S phase. Complete inactivation of the Rb protein requires the phosphorylation of both cyclin-D-dependent CDK4/6 and cyclin-E-dependent CDK2 . The phosphorylation of the Rb protein by CDK4/6 at a specific site is essential for the cyclin-E-dependent phosphorylation of CDK2 (Non-Patent Literature 4). Thus, cyclin-D-dependent CDK4/6 is an important enzyme complex that controls the transition from the G1 phase to the S phase.

[007] CDK2 forms a complex with cyclin-E and also forms a complex with cyclin-A. CDK2 also acts in the steps subsequent to the S phase and is responsible for DNA replication. Inhibition of CDK2 likely results in the expression of genotoxicity (Non-Patent Literature 5).

[008] Cyclin-S has a molecular mechanism that positively regulates CDK4/6 activity. In contrast, p16 encoded by the INK4a gene negatively regulates CDK4/6 activity (Non-Patent Literature 6).

[009] CDK inhibitors can be used to treat various diseases caused by abnormal cell growth, such as cancer, cardiovascular disorders, kidney disease, specific infections, and autoimmune diseases. CDK inhibitors are also expected to be effective for the treatment of diseases including but not limited to rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, and cancer. Inhibition of cell cycle progression and cell growth through CDK inhibition is predicted to be effective for such a disease based on the technical findings described below.

[0010] Rheumatoid arthritis involves the formation of pannus through hyperproliferation of synovial cells. This hyperproliferation can be reduced by introducing p16 into an affected area of a model animal or by administering a CDK4/6 inhibitor to the animal (Non-Patent Literature 7 to 9). A CDK4-cyclin-D complex regulates MMP3 production in synovial cells derived from a patient with rheumatoid arthritis. Downregulation of CDK4/6 activity inhibits not only proliferation but also MMP3 production (Non-Patent Literature 10).

[0011] Therefore, CDK4/6 inhibitors are predicted to have an inhibitory effect on the proliferation of synovial cells and a protective effect on cartilage in rheumatoid arthritis.

[0012] A pathway for regulating cell growth including genes responsible for checkpoints in the G1 and S phases of the cell cycle is associated with the progression of plaque, stenosis, and restenosis after angiogenesis. Overexpression of the inhibitory protein p21 against CDK inhibits angiogenesis and the subsequent growth of vascular smooth muscle and intimal hyperplasia (Non-Patent Literature 11 and 12).

[0013] Abnormal regulation of the cell cycle is also associated with polycystic kidney disease, which is characterized by the growth of cysts filled with fluid in the renal tubule. A small molecular CDK inhibitor is effective for treating the disease (Non-Patent Literature 13).

[0014] Induction of expression of the cell cycle inhibitory protein p21 with an adenoviral vector is effective in a murine pulmonary fibrosis model (Non-Patent Literature 14).

[0015] It is known that the content of cyclin-D1/CDK4 increases in a rat model of cerebral infarction in association with neuronal death caused by local ischemia. Neuronal death is reduced by administration of flavopiridol, which is a non-selective CDK inhibitor (Non-Patent Literature 15).

[0016] The cyclin-D-CDK4/6-INK4a-Rb pathway is frequently detected in human cancer caused by the abnormality of many factors that contribute to the growth of cancer cells, such as loss of functional p16INK4a, overexpression of cyclin- D1, overexpression of CDK4, or loss of functional Rb (Non-Patent Literature 16 to 18). Such an abnormality stimulates cell cycle progression from the G1 phase to the S phase, and this pathway certainly plays an important role in oncogenic transformation or the abnormal growth of cancer cells.

[0017] CDK4/6 inhibitors may be effective, particularly for some tumors that involve abnormality in genes that activate CDK4/6 kinase activity, such as cancers that involve cyclin-D translocation, cancers that involve cyclin amplification -D, cancers involving amplification or overexpression of CDK4 or CDK6, and cancers involving inactivation of p16. CDK4/6 inhibitors may be effective for the treatment of cancers that involve a genetic abnormality in the upstream regulator of cyclin-D, the amount of which increases due to defects in the upstream regulator.

[0018] In fact, many compounds that inhibit CDK4/6 activity have been synthesized and disclosed in the art, and such compounds have been clinically tested for the treatment of cancers, such as breast cancer (Non-Patent Literature 19).

[0019] The most acute and severe radiotherapeutic and chemotherapeutic toxicities are caused by effects on stem cells and progenitor cells. A CDK4/6 inhibitor causes temporary cell cycle arrest of hematopoietic stem and progenitor cells, and protects them from radiotherapeutic and chemotherapeutic cytotoxicity. After treatment with the inhibitor, hematopoietic stem and progenitor cells (HSPCs) return from temporary dormancy and then function normally. Thus, it is assumed that chemotherapeutic resistance with the use of a CDK4/6 inhibitor provides significant protection of the bone marrow (Non-Patent Literature 20).

[0020] Consequently, CDK4/6 inhibitors are supposed to be effective for the treatment of rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer, and the protection of the bone marrow, in particular, for the treatment of rheumatoid arthritis or cancer and bone marrow protection.

[0021] Patent Literature 1 and Non-Patent Literature 21 disclose CDK4 inhibitors, Patent Literature 2 and 3 and Non-Patent Literature 22 to 24 reveal CDK inhibitors containing CDK4/6, and Non-Patent Literature 25 disclose CDK4/FLT3 inhibitors.

[0022] Pyrido [3,4-d]pyrimidine derivatives have an inhibitory effect on Mps1 (also known as TTK) (Patent Literature 4). This inhibitory effect is completely different from the CDK4/6 inhibitory effect disclosed herein.

[0023] Non-Patent Literature 26 and Non-Patent Literature 27 disclose that various pyrido [3,4-d]pyrimidine derivatives exhibit an inhibitory activity against CDK2, which is completely different from the superior CDK4/6 inhibitory effect presented by the present invention. LIST OF CITATIONS Patent Literature: [Patent Literature 1] WO2003/062236 [Patent Literature 2] WO2010/020675 [Patent Literature 3] WO2010/075074 [Patent Literature 4] WO2014/037750

Non-Patent Literatures:

[0024] [Non-Patent Literature 1] Johnson D. G. and Walker C. L., Annual Review of Pharmacology and Toxicology 1999; 39: p.295-312 [Non-Patent Literature 2] Ortega et al., Biochimica et Biophysica Acta- Reviews on Cancer 2002; 1602 (1): p.73-87 [Non-Patent Literature 3] Shapiro, Journal of Clinical Oncology 2006; 24 (11): p.1770-1783 [Non-Patent Literature 4] Lundberg et al., Molecular and Cellular Biology 1998; 18 (2): p.753-761 [Non-Patent Literature 5] Andrew J. Olaharski, PLoS Computational Biology 2009; 5 (7): e1000446 [Non-Patent Literature 6] Kamb et al., Science 1994; 264 (5157): p.436-440 [Non-Patent Literature 7] Taniguchi, K et al., Nature Medicine, Vol.5, p.760-767 (1999) [Non-Patent Literature 8] Sekine, C et al. , Journal of Immunology 2008, 180: p.1954-1961 [Non-Patent Literature 9] Hosoya, T et al., Annals of the Rheumatic Diseases 2014, Aug 27 Epub, in press. [Non-Patent Literature 10] Nonomura Y et al., Arthritis & Rheumatology 2006, Jul; 54 (7): p.2074-83 [Non-Patent Literature 11] Chang M.W. et al., Journal of Clinical Investigation, 1995, 96: p.2260 [Non-Patent Literature 12] Yang Z-Y. et al., Proceedings of the National Academy of Sciences (USA) 1996, 93: p.9905 [Non-Patent Literature 13] Bukanov N.O. et al., Nature, 2006, 4444: p.949-952 [Non-Patent Literature 14] American Journal Physiology: Lung Cellular and Molecular Physiology, 2004, Vol. 286, p.L727-L733 [Non-Patent Literature 15] Proceedings of the National Academy of Sciences of the United States of America, 2000, Vol.97, p.10254 -10259 [Non-Patent Literature 16] Science, Vol. 254, p.1138-1146 (1991) [Non-Patent Literature 17] Cancer Research, 1993, Vol. 53, p.5535-5541 [Non-Patent Literature 18] Current Opinion in Cell Biology, 1996, Vol.8, p.805-814 [Non-Patent Literature 19] Guha M, Nature Biotechnology 2013, Mar; 31 (3): p.187 [Non-Patent Literature 20] Journal of Clinical Investigation 2010; 120 (7): p.2528-2536 Soren M. Johnson p.3430-3449 [Non-Patent Literature 26] Organic & Biomolecular Chemistry, 2015, 13, p.893-904

[0025] [Non-Patent Literature 27] “Rapid Discovery of Pyrido [3,4- d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach”, Paolo Innocenti et al., J. Med. Chem., Article ASAP,Publication Date (Web): April 7, 2016, DOI: 10.1021/acs.jmedchem.5b01811.

SUMMARY OF THE INVENTION Problem to be solved by the invention:

[0026] An objective of the present invention is to provide a compound that exhibits superior CDK4/6 inhibitory activity. Ways to solve the problem:

[0027] The present inventors conducted extensive studies to solve the problems described above and discovered that a new pyrido [3,4-d]pyrimidine derivative represented by Formula (I) exhibits CDK4/6 inhibitory activity. The present invention was made based on this discovery. The present invention includes the following aspects:

[0028] Aspect (1): A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof: [Formula 1] [in which L represents -NR5-, -O-, or -S-; R5 represents a hydrogen atom or a C1-6 alkyl group substituted with zero to two -OH groups, zero to two C1-8 alkoxyl groups, and zero to six fluorine atoms; R1 represents a C1-8-alkyl, C3-12-cycloalkyl, (C3-12-cycloalkyl)-C1-6-alkyl, 4- to 12-membered heterocyclyl, (4- to 12-membered heterocyclyl)-C1-alkyl group 6, C6-10-aryl, (C6-10-aryl)-C1-6-alkyl, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C1-6-alkyl, C1-8-alkyl sulfonyl, or acyl-C1-8; each of the heteroatom-containing groups represented by R1 contains one to four heteroatoms selected from oxygen, sulfur, and nitrogen atoms; R1 is optionally substituted with one to six substituents selected from the group consisting of a halogen atom, =O, -OH, -CN, -COOH, -COOR6, -R7, a zero-substituted C3-6-cycloalkyl group to two groups - OH, zero to two C1-8-alkoxyl groups, and zero to six fluorine atoms, a 3- to 10-membered heterocyclyl group substituted with zero to two -OH groups, zero to two C1-8-alkoxyl groups, and zero to six fluorine atoms, one C1-8-acyl group substituted with zero to two -OH groups, zero to two C1-8-alkoxyl groups, and zero to six fluorine atoms, and one C1-8-alkoxyl group substituted with zero to two -OH groups, zero to two C1-8-alkoxyl groups, and zero to six fluorine atoms; R6 and R7 each independently represent a C1-6-alkyl group substituted with zero to two -OH groups, zero to two C1-8-alkoxyl groups, and zero to six fluorine atoms; R2 represents a C1-8-alkyl, C3-8-cycloalkyl, 4- to 6-membered heterocyclyl, or C1-8-acyl, -COOR8, or -CONR9R10 group; each of the C1-8 alkyl and C3-8 cycloalkyl groups represented by R2 is substituted with zero or one -OH group, zero to two C1-8 alkoxy groups substituted with zero or one -OH group, zero or one alkoxy group -C1-4, and zero to three fluorine atoms, and zero to five fluorine atoms; R2 is not an unsubstituted C1-8 alkyne group, nor an unsubstituted C1-8 cycloalkyl group, nor trifluoromethyl group; R8, R9, and R10 each independently represent a hydrogen atom or a C1-8 alkyl group; the 4 to 6 membered heterocyclyl group represented by R2 is optionally substituted with one to four substituents selected from the group consisting of a fluorine atom, -OH, and C1-4-alkyl and C1-4-alkoxyl groups; each of the C1-8 acyl group, -COOR8, and -CONR9R10 represented by R2 is optionally substituted with one to four substituents selected from the group consisting of a fluorine atom, -OH, a C1-4 alkoxy group; R9 and R10 of -CONR9R10 represented by R2 are optionally linked via a single bond or -O- to form a ring including the nitrogen atom attached to R9 and R10; the heterocyclyl group represented by R2 having a 4- or 5-membered ring contains an oxygen heteroatom, and the heterocyclyl group having a 6-membered ring contains one or two oxygen heteroatoms; R3 represents a hydrogen atom, a C1-8 alkyl group, or a halogen atom; X represents CR11 or a nitrogen atom; Y represents CR12 or a nitrogen atom; Z represents CR13 or a nitrogen atom; R11 to R13 each independently represent an atom of hydrogen, fluorine, chlorine, a C1-6 alkyl group, or C1-6 alkoxyl group; R4 represents -A1-A2-A3; A1 represents a single bond, a C1-8 alkylene, C2-8 alkenylene, or C2-8 alkynylene group; one or two sp3 carbon atoms at any of the positions of A1 are optionally substituted by one or two structures selected from the group consisting of -O-, -NR14-, -C(=O)-, -C(=O)-O -, -O- C(=O)-, -OC(=O)-O-, -C(=O)-NR15-, -OC(=O)-NR16-, -NR17-C(=O) -, - NR18-C(=O)-O-, -NR19-C(=O)-NR20-, -S(=O)p-, -S(=O)2-NR21-, -NR22- S (=O)2-, and -NR23-S(=O)2-NR24-, and a structure of -OO-, -O-NR14-, -NR14- O-, -O-CH2-O-, - O-CH2-NR14-, or -NR14-CH2-O- is not formed in the case of substitution of two sp3 carbon atoms; A2 represents a single bond, a C1-7-alkylene, C3-12-cycloalkylene, C3-12-cycloalkylidene, 4- to 12-membered heterocyclylene, 4- to 12-membered heterocyclylene, C6-10-arylene, or 5-membered heteroarylene group. to 10 members; A3 represents a halogen atom, -CN, -NO2, -R25, -OR26, 27 28 29 30 31 32 33 -NR R , -C(=O)R , -C(=O)-OR , -OC( =O)R , -OC(=O)-NR R , - C(=O)-NR34R35, -NR36-C(=O)R37, -NR38-C(=O)-OR39, -S(=O )2-R40, -S(=O)2- NR41R42, or -NR43-S(=O)2R44; A3 represents -R25, if the A1 end next to A2 has a structure selected from the group consisting of -O-, -NR14-, -C(=O)-, -C(=O)- O-, -OC( =O)-, -OC(=O)-O-, -C(=O)-NR15-, -OC(=O)-NR16-, -NR17-C(=O)- , -NR18-C( =O)-O-, -NR19-C(=O)-NR20-, -S(=O)p-, -S(=O)2-NR21-, -NR22- S(=O)2-, and -NR23-S(=O)2-NR24- and A2 is a single bond; R 14 32 34 36 38 41 43 , R , R , R , R , R , and R each independently represent a hydrogen atom, a C1-8-alkyl group, a C1-8 acyl group, a C1-alkyl group 8-sulfonyl, 4- to 12-membered heterocyclyl, C3-12-cycloalkyl, C6-10-aryl, 5- to 10-membered heteroaryl, (4- to 12-membered heterocyclyl)-C1-3-alkyl, (C3-cycloalkyl) 12)-C1-3-alkyl, (C6-10-aryl)-C1-3-alkyl, or (5- to 10-membered heteroaryl)-C1-3-alkyl; R 15 31 33 35 37 39 40 42 44 to R, R, R, R, R, R, R, and R each independently represent a hydrogen atom or a C1-8-alkyl group, heterocyclyl of 4 to 12-membered, C3-12-cycloalkyl, C6-10-aryl, 5-10 membered heteroaryl, (4-12 membered heterocyclyl)-C1-3-alkyl, (C3-12-cycloalkyl)-C1-3-alkyl , (C6-10-aryl)-C1-3-alkyl, or (5- to 10-membered heteroaryl)-C1-3-alkyl; A1, A2, A3, and R14 to R44 in A1, A2, and A3 are each independently substituted with one to four substituents selected from the group consisting of -OH, =O, -COOH, -SO3H, -PO3H2, -CN , -NO2, one halogen atom, one zero-substituted C1-8-alkyl group to two -OH groups, zero to two -OR45 groups, and zero to six fluorine atoms, one zero-substituted C3-12-cycloalkyl group to two -OH groups, zero to two -OR46 groups, and zero to six fluorine atoms, one C1-8 alkoxy group substituted with zero to two -OH groups, zero to two -OR47 groups, and zero to six fluorine atoms. fluorine, and a 4 to 12 membered heterocyclyl group substituted with zero to two -OH groups, zero to two -OR49 groups, and zero to six fluorine atoms; R14 to R44 are optionally connected to A1, A2, or A3 or between A1 and A2, between A1 and A3, or between A2 and A3 via a single connection, -O-, -NR50-, or -S(=O)p- to form a ring; R11 or R13 is optionally linked to A1, A2, or A3 via a single bond, -O-, -NR51-, or -S(=O)p- to form a ring; R45 to R51 each represent one hydrogen atom or a zero-substituted C1-4 alkyl group or one -OH group and zero to six fluorine atoms; p represents an integer from 0 to 2; and each of the heteroatom-containing groups represented by A1, A2, and A3 contains one to four heteroatoms selected from oxygen, sulfur, and nitrogen atoms].

[0029] Aspect (2): The compound or pharmaceutically acceptable salt thereof according to Aspect (1), wherein L represents -NH-.

[0030] Aspect (3): The compound or pharmaceutically acceptable salt thereof according to Aspect (1) or (2), wherein R1 represents a C1-8-alkyl, C3-12-cycloalkyl, (cycloalkyl- C3-12)-C1-6-alkyl, 4- to 12-membered heterocyclyl, or (4- to 12-membered heterocyclyl)-C1-6-alkyl.

[0031] Aspect (4): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (3), wherein R2 is a C1-8 alkyl group substituted with one to four fluorine atoms.

[0032] Aspect (5): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (3), wherein R2 is a zero-substituted C1-8 alkyl group or an -OH group and zero to two C1-8 alkoxy groups substituted with zero or one -OH group, zero or one C1-4 alkoxy group, and zero to three fluorine atoms.

[0033] Aspect (6): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (3), wherein R2 is a 4 to 6 membered heterocyclyl group optionally substituted with one to four selected substituents of the group consisting of a fluorine atom, -OH, and C1-4-alkyl and C1-4-alkoxyl groups.

[0034] Aspect (7): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (3), wherein R2 is - COOR8, -CONR9R10, or a C1-8 acyl group, each group being optionally substituted with one to four substituents selected from the group consisting of a fluorine atom, -OH, and a C1-8 alkoxy group.

[0035] Aspect (8): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (7), wherein X represents CR11, Y represents CR12, and Z represents CR13.

[0036] Aspect (9): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (7), wherein X represents a nitrogen atom, Y represents CR12, and Z represents CR13.

[0037] Aspect (10): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (7), wherein X represents CR11, Y represents a nitrogen atom, and Z represents CR13.

[0038] Aspect (11): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (7), wherein X represents CR11, Y represents CR12, and Z represents a nitrogen atom.

[0039] Aspect (12): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (11), wherein A1 is a single bond.

[0040] Aspect (13): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (11), wherein A1 represents a C1-8 alkylene group, and no sp3 carbon atom in A1 is replaced by another structure.

[0041] Aspect (14): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (11), wherein A1 represents a C1-8 alkylene group, and an sp3 carbon atom in Any position of A1 is replaced by -O-.

[0042] Aspect (15): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (11), wherein A1 represents a C1-8 alkylene group, and an sp3 carbon atom in any position of A1 is replaced by -NR14-.

[0043] Aspect (16): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (11), wherein A1 represents a C1-8 alkylene group, an sp3 carbon atom at any position of A1 is replaced by -NR14-, and an sp3 carbon atom in any other position of A1 is optionally replaced by -O-.

[0044] Aspect (17): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (16), wherein A2 represents a 4 to 12 membered heterocyclylene group; and A2 is optionally substituted with one to four substituents selected from the group consisting of -OH, -COOH, -SO3H, -PO3H2, -CN, -NO2, a halogen atom, a C1-8 alkyl group optionally substituted with zero to two -OH groups, zero to two -OR45 groups, and zero to six fluorine atoms, one C3-12-cycloalkyl group optionally substituted with zero to two -OH groups, zero to two -OR46 groups, and zero to six fluorine atoms , a C1-8-alkoxy group optionally substituted with zero to two -OH groups, zero to two -OR47 groups, and zero to six fluorine atoms, and a 4 to 12-membered heterocyclyl group substituted with zero to two -OH groups , zero to two groups - OR49, and zero to six fluorine atoms.

[0045] Aspect (18): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (16), wherein A2 represents a 4 to 12 membered heterocyclylene group substituted with =O; and A2 is optionally substituted with one to four substituents selected from the group consisting of -OH, =O, -COOH, -SO3H, -PO3H2, -CN, -NO2, a halogen atom, a zero-substituted C1-8 alkyl group to two -OH groups, zero to two -OR45 groups, and zero to six fluorine atoms, one C3-12-cycloalkyl group substituted with zero to two -OH groups, zero to two -OR46 groups, and zero to six fluorine atoms. fluorine, a C1-8 alkoxy group substituted with zero to two -OH groups, zero to two -OR47 groups, and zero to six fluorine atoms, and a 4 to 12 membered heterocyclyl group substituted with zero to two -OH groups , zero to two -OR49 groups, and zero to six fluorine atoms.

[0046] Aspect (19): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (18), wherein X represents CR11, Y represents CR12, Z represents CR13, and R11 or R13 is linked to A1, A2, or A3 via a single bond, -O-, -NR51-, or -S(=O)p- to form a ring.

[0047] Aspect (20): The compound or pharmaceutically acceptable salt thereof according to any of Aspects (1) to (19), wherein A3 is a hydrogen atom.

[0048] Aspect (21): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (19), wherein A3 is a 25 26 27 28 29 30 halogen atom, -CN, -R , -OR , -NR R , -C(=O)R , or -C(=O)-OR , and R25 to R30 each independently represent a hydrogen atom, an optionally substituted C1-8-alkyl group , an optionally substituted 4- to 12-membered heterocyclyl group, an optionally substituted C3-12-cycloalkyl group, an optionally substituted (4- to 12-membered heterocyclyl)-C1-3-alkyl group, or a (C3-12-cycloalkyl) group )-C1-3-alkyl optionally substituted.

[0049] Aspect (22): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (21), wherein R3 is a hydrogen atom.

[0050] Aspect (23): The compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (21), wherein R3 represents a C1-4 alkyl group, a fluorine atom, or a chlorine atom.

[0051] Aspect (24): The compound, or pharmaceutically acceptable salt thereof, selected from: 6-(difluoromethyl)-N8-isopropyl-N2-(5-piperazin-1-yl-2-pyridyl)pyrido [3, 4-d]pyrimidine-2,8-diamine (1R)-1- [8-(isopropylamino)-2- [(5-piperazin-1-yl-2-pyridyl)amino]pyrido [3,4-d] pyrimidin-6-yl]ethanol 1- [2- [(5-piperazin-1-yl-2-pyridyl)amino]-8-(tetrahydrofuran-3-ylamino)pyrido [3,4-d]pyrimidin- 6-yl]ethanol 1-[2-[(5-piperazin-1-yl-2-pyridyl)amino]-8-(tetrahydropyran-3-ylamino)pyrido [3,4-d]pyrimidin-6- yl]ethanol N8-isopropyl-6-[(1R)-1-methoxyethyl]-N2-(6-piperazin-1-ylpyridazin-3-yl)pyrido [3,4-d]pyrimidine-2,8-diamine N8 -isopropyl-6- [(1R)-1-methoxyethyl]-N2- [5-(piperazin-1-ylmethyl)-2-pyridyl]pyrido [3,4-d]pyrimidine-2,8-diamine 1- [ 6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one 1- [ 6- [ [5-chloro-6- [(1R)-1-hydroxyethyl]-8- (isopropylamino)pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2- one (1R)-1-[2-[(6-piperazin-1-ylpyridazin-3-yl)amino]-8-(tetrahydropyran-4-ylamino)pyrido [3,4-d]pyrimidin-6- yl]ethanol (1R)-1- [2- [(6-piperazin-1-ylpyridazin-3-yl)amino]-8- [ [(3S)-tetrahydropyran-3-yl]amino]pyrido [3 ,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [(6-piperazin-1-ylpyridazin-3-yl)amino]-8- [ [(3R)-tetrahydropyran- 3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[5-(piperazin-1-ylmethyl)-2-pyridyl]amino]-8 -(tetrahydropyran-4-ylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [[5-(piperazin-1-ylmethyl)-2-pyridyl] amino]-8- [ [(3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [ [5-( piperazin-1-ylmethyl)-2-pyridyl]amino]-8- [ [(3R)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [ 6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]pyridazin-3-yl]piperidin-4-ol (1R )-1- [8-(isopropylamino)-2- [(6-piperazin-1-ylpyridazin-3-yl)amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [ [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-2-one 6- [ (1R)-1-methoxyethyl]-N2-[5-(piperazin-1-ylmethyl)-2-pyridyl]-N8-[(3S)-tetrahydropyran-3-yl]pyrido[3,4-d] pyrimidine-2,8-diamine 6-[(1R)-1-methoxyethyl]-N2-(6-piperazin-1-ylpyridazin-3-yl)-N8-[(3S)-tetrahydropyran-3-yl] pyrido [3,4-d]pyrimidine-2,8-diamine 6-[(1R)-1-methoxyethyl]-N2-[5-(piperazin-1-ylmethyl)-2-pyridyl]-N8-(tetra- hydropyran-4-ylmethyl)pyrido[3,4-d]pyrimidine-2,8-diamine N8-isopropyl-6-[(1R)-1-methoxyethyl]-N2-(5-piperazin-1-ylpyrazin-2- il)pyrido [3,4-d]pyrimidine-2,8-diamine N8-isopropyl-6-[(1R)-1-methoxyethyl]-N2-[6-[(2S)-2-methylpiperazin-1-yl ]pyridazin-3-yl]pyrido [3,4-d]pyrimidine-2,8-diamine N8-isopropyl-6- [(1R)-1-methoxyethyl]-N2- [6- [(2R)-2- methylpiperazin-1-yl]pyridazin-3-yl]pyrido [3,4-d]pyrimidine-2,8-diamine (1R)-1- [2- [ [6-(4,7-diazaspiro [2.5]octan -7-yl)pyridazin-3-yl]amino]-8-(isopropylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [ [5-(4, 7-diazaspiro [2.5]octan-7-ylmethyl)-2-pyridyl]amino]-8-(isopropylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol 2- [1- [ [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]-4-piperidyl]propan-2- ol (1R)-1- [2- [ [5- [ [4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino]-8-(isopropylamino)pyrido [3,4- d]pyrimidin-6-yl]ethanol (1R)-1- [2- [ [5- [2-(dimethylamino)ethoxy]-2-pyridyl]amino]-8- [ [(3S)-tetrahydropyran- 3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino ]-8- [ [(3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 2-hydroxy-1- [4- [6- [ [6 - [(1R)-1-hydroxyethyl]-8- (isopropylamino)pyrido [3,4-d]pyrimidin-2-yl]amino]pyridazin-3-yl]piperazin-1-yl]ethanone 1- [6- [ [8-(isopropylamino)-6- [(2S)-tetrahydrofuran-2-yl]pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one ( 1R)-1-[8-(isopropylamino)-2-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)pyrido [3,4-d]pyrimidin-6-yl ]ethanol 2- [4- [ [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl ]methyl]piperazin-1-yl]-2-methyl-propan-1-ol 4- [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido [3,4- d ]pyrimidin-2-yl]amino]-3-pyridyl]-1- [(2S)-2-hydroxypropyl]-1,4-diazepan-5-one 4- [6- [ [6- [(1R)- 1-hydroxyethyl]-8-(isopropylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]-1- [(2R)-2-hydroxypropyl]-1,4-diazepan- 5-one N8-isopropyl-N2-[5-(piperazin-1-ylmethyl)-2-pyridyl]-6-[(2S)-tetrahydrofuran-2-yl]pyrido[3,4-d]pyrimidine- 2,8-diamine 1- [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-2-methyl- 3-pyridyl]piperazin-2-one 1-[6-[[8-(isopropylamino)-6-[(3S)-tetrahydrofuran-3-yl]pyrido[3,4-d]pyrimidin-2-yl ]amino]-3-pyridyl]piperazin-2-one (1R)-1- [2-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-8- [ [ (3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 1-[6-[[8-(isopropylamino)-6-(3-methyloxetan-3 -yl)pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (1R)-1-[2-[[5-[4-(dimethylamino)cyclo- hexoxy]-2-pyridyl]amino]- 8- [ [(3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 6- [(1R)- 1-methoxyethyl]-N2-[5-(piperazin-1-ylmethyl)-2-pyridyl]-N8-propyl-pyrido [3,4-d]pyrimidine-2,8-diamine 6-[(1R)-1 -methoxyethyl]-N2-(6-piperazin-1-ylpyridazin-3-yl)-N8-propyl-pyrido [3,4-d]pyrimidine-2,8-diamine acid 1- [ [6- [ [6- (difluoromethyl)-8-[(4-methylcyclohexyl)amino]pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperidine-4-carboxylic (1R)-1- [8-(ethylamino)-2- [ [5- [ [4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl ]ethanol (1R)-1- [2- [ [5- [ [4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino]-8-(propylamino)pyrido [3,4 -d]pyrimidin-6-yl]ethanol N8-isopropyl-6-(3-methyloxetan-3-yl)-N2-(6-piperazin-1-ylpyridazin-3-yl)pyrido [3,4-d]pyrimidine -2,8-diamine N8-isopropyl-6-(3-methyloxetan-3-yl)-N2-[5-(piperazin-1-ylmethyl)-2-pyridyl]pyrido [3,4-d]pyrimidine-2 ,8-diamine 6-(3-methyloxetan-3-yl)-N2-[5-(piperazin-1-ylmethyl)-2-pyridyl]-N8-[(3S)-tetrahydropyran-3-yl]pyrido [3,4-d]pyrimidine-2,8-diamine 4- [6- [ [6- [(1R)-1-hydroxyethyl]-8- [isopropyl(methyl)amino]pyrido [3,4-d] pyrimidin-2-yl]amino]-3-pyridyl]-1,4- diazepan-5-one (1R)-1- [8-(isopropylamino)-2- [(6-methyl-5-piperazin-1- yl-2-pyridyl)amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[6-(2-hydroxyethyl)-7,8-dihydro- 5H-1,6-naphthyridin-2-yl]amino]-8-(isopropylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [8-(isopropylamino)-2- [[6-[2-(methylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol N2-(6-piperazin-1-ylpyridazin-3-yl)-6-[(3S)-tetrahydrofuran-3-yl]-N8-[(3S)-tetrahydropyran-3-yl]pyrido [3 ,4-d]pyrimidine-2,8-diamine N2-[5-(piperazin-1-ylmethyl)-2-pyridyl]-6-[(3R)-tetrahydrofuran-3-yl]-N8-[( 3S)-tetrahydropyran-3-yl]pyrido [3,4-d]pyrimidine-2,8-diamine (1R)-1-[2-[[6-[2-(dimethylamino)ethyl]-7, 8-dihydro-5H-1,6-naphthyridin-2-yl]amino]-8-(isopropylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol (2S)-1- [4- [ [6- [ [8-(ethylamino)-6- [(1R)-1-hydroxyethyl]pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-1- yl]propan-2-ol (2R)-1- [4- [ [6- [ [8-(ethylamino)-6- [(1R)-1-hydroxyethyl]pyrido [3,4- d]pyrimidin-2 -yl]amino]-3-pyridyl]methyl]piperazin-1-yl]propan-2-ol (1R)-1-[8-(isopropylamino)-2-[[5-[(2R)-2-methylpiperazin -1-yl]- 2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [8-(isopropylamino)-2- [ [5- [(2S) -2-methylpiperazin-1-yl]-2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol N8-isopropyl-N2-(5-piperazin-1-yl-2-pyridyl) -6- [(2S)-tetrahydrofuran-2-yl]pyrido [3,4-d]pyrimidine-2,8-diamine (1R)-1- [8-(cyclobutylamino)-2- [ [5- [[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[8-(cyclopropylmethylamino )-2- [ [5- [ [4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 6-( 3-methyloxetan-3-yl)-N2-(5-piperazin-1-yl-2-pyridyl)-N8-propyl-pyrido [3,4-d]pyrimidine-2,8-diamine 6-(3-methyloxetan -3-yl)-N2- [5-(piperazin-1-ylmethyl)-2-pyridyl]- N8-propyl-pyrido [3,4-d]pyrimidine-2,8-diamine N2-(5-piperazin- 1-yl-2-pyridyl)-N8-propyl-6-tetrahydrofuran-3-yl-pyrido[3,4-d]pyrimidine-2,8-diamine N2-[5-(piperazin-1-ylmethyl) -2-pyridyl]-N8-propyl-6-tetrahydrofuran-3-yl-pyrido [3,4-d]pyrimidine-2,8-diamine N8-isopropyl-6-(3-methyloxetan-3-yl) -N2-(5-piperazin-1-yl-2-pyridyl)pyrido [3,4-d]pyrimidine-2,8-diamine N8-isopropyl-N2-(5-piperazin-1-yl-2-pyridyl) -6-tetrahydrofuran-3-yl-pyrido [3,4-d]pyrimidine-2,8-diamine 2- [4- [ [6- [ [8-(isopropylamino)-6-tetrahydrofuran-3 -yl-pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-1-yl]ethanol 2- [4- [ [6- [ [6-tetrahydrofuran- 3-yl-8-[[(3S)-tetrahydropyran-3-yl]amino]pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-1-yl ]ethanol (1R)-1- [2- [ [5- [ [4-(hydroxymethyl)-1-piperidyl]methyl]-2-pyridyl]amino]-8-(isopropylamino)pyrido [3,4-d] pyrimidin-6-yl]ethanol 1- [ [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-3 -pyridyl]methyl]piperidin-4-ol 1- [ [6- [ [8-(tert-butylamino)-6- [(1R)-1-hydroxyethyl]pyrido [3,4- d]pyrimidin-2-yl ]amino]-3-pyridyl]methyl]piperidin-4-ol (1R)-1- [8-(tert-butylamino)-2- [ [5- [ [4-(hydroxymethyl)-1-piperidyl]methyl] -2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [ [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isobutylamino)pyrido [3 ,4-d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperidin-4-ol (1R)-1- [2- [ [5- [ [4-(hydroxymethyl)-1-piperidyl] methyl]-2-pyridyl]amino]-8-(isobutylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [6- [ [6- [(1R)-1-hydroxypropyl]-8 -(isopropylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (1R)-1- [2- [ [5- [ [4-(2- hydroxyethyl)piperazin-1-yl]methyl]-6-methyl-2-pyridyl]amino]-8-(propylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol.

[0052] Aspect (25): a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (24) and a pharmaceutically acceptable carrier.

[0053] Aspect (26): A pharmaceutical composition having a CDK4/6 inhibitory activity, comprising the compound or pharmaceutically acceptable salt thereof according to any one of Aspects (1) to (24) as an active ingredient.

[0054] Aspect (27): A drug for the prevention or treatment of rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer, the drug comprising the compound or pharmaceutically acceptable salt thereof according to any of the Aspects ( 1) to (24) as an active ingredient.

ADVANTAGEOUS EFFECTS OF THE INVENTION

[0055] The compound of the present invention exhibits superior inhibitory activity against CDK4/6 and is useful as a drug for the prevention or treatment of rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Fig. 1 are graphs showing the results (scores) obtained upon administration of the compound of the present invention to mice.

DESCRIPTION OF MODALITIES

[0057] The structures (groups) of the compound of the present invention represented by Formula (I) will now be described. The description of “groups” in parentheses is as follows: for example, the term “(cycloalkyl)-alkyl” refers to a cycloalkyl group bonded to an alkyl group such that the alkyl group is bonded to a structure different from the cycloalkyl group. Similarly, the term "(heterocyclyl)-alkyl" refers to a heterocyclyl group attached to an alkyl group such that the alkyl group is attached to a structure different from the heterocyclyl group.

[0058] It should be noted that, as used herein, and in the attached claims, the singular form “a”, “an”, “the” or “a” may include the plural form unless the context clearly indicates on the contrary.

[0059] As used herein, “C3-6 cycloalkyl group substituted with zero to two -OH groups, zero to two C1-8 alkoxyl groups, and zero to six fluorine atoms” refers to the case in which the group C3-6-cycloalkyl is substituted with the following substituents: zero to two -OH groups, zero to two C1-8-alkoxyl groups, and zero to six fluorine atoms. Examples of substituted C3-6-cycloalkyl group include a C3-6-cycloalkyl group substituted with two -OH groups, one C1-8-alkoxyl group, and three fluorine atoms; a C3-6 cycloalkyl group substituted with two C1-8 alkoxy groups and four fluorine atoms; and a C3-6-cycloalkyl group substituted with an -OH group, and the like. The C3-6-cycloalkyl group is not substituted in the case in which the number of all substituents is zero.

[0060] As used herein, “C1-8” refers to a group having one to eight carbon atoms, and “C1-6” refers to a group having one to six carbon atoms. Similarly, “5- to 10-membered” refers to a structure having 5 to 10 carbon atoms, and “5- or 6-membered” refers to a structure having five or its carbon atoms.

[0061] Non-limiting examples of the groups described in this specification are the following:

[0062] The term “alkyl” as used herein refers to a monovalent group obtained by removing a hydrogen atom from an alkane on any carbon atom.

[0063] The term “alkylene” as used herein refers to a divalent group obtained by removing two hydrogen atoms from an alkane on any two different carbon atoms.

[0064] The term “alkane” as used herein refers to a saturated aliphatic hydrocarbon.

[0065] The term “C1-8-alkyl” as used herein refers to a linear or branched hydrocarbon group having one to eight carbon atoms. Examples of C1-8 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, 1,2-dimethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, isoheptyl, n-octyl, isooctyl, and the like.

[0066] “C1-8-alkylene” alkane as used herein refers to a linear or branched hydrocarbon having one to eight carbon atoms. Examples of the alkane include methane, ethane, propane, n-butane, 2-methylpropane, n-pentane, 2,2-dimethylpropane, n-hexane, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3- dimethylbutane, n-heptane, 2,2-dimethylhexane, 2,3-dimethylhexane, n-octane, 2-methylheptane, and the like.

[0067] The term “cycloalkyl” as used herein refers to a monovalent group obtained by removing a hydrogen atom from a cycloalkane on any carbon atom.

[0068] The term “cycloalkylene” as used herein refers to a divalent group obtained by removing two hydrogen atoms from a cycloalkane on any two different carbon atoms.

[0069] The term “cycloalkylidene” refers to a divalent group obtained by removing two hydrogen atoms from a cycloalkane on any carbon atom.

[0070] The term “cycloalkane” as used herein refers to an alicyclic hydrocarbon.

[0071] The “C3-12-cycloalkyl”, “C3-12-cycloalkylene”, or “C3-12-cycloalkylidene” cycloalkane as used herein refers to a 3- to 12-membered monocyclic or polycyclic aliphatic hydrocarbon ring . Specific examples of cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, spiro [3.3]heptane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, adamantane, and the like.

[0072] The term “heterocyclyl” as used herein refers to a monovalent group obtained by removing a hydrogen atom from a heterocycle on any carbon or nitrogen atom.

[0073] The term “heterocyclylene” as used herein refers to a divalent group obtained by removing two hydrogen atoms from a heterocycle on any two different carbon or nitrogen atoms.

[0074] The term “heterocyclylidene” as used herein refers to a divalent group obtained by removing two hydrogen atoms from a heterocycle on any one carbon atom.

[0075] The term “heterocycle” as used herein refers to a ring containing a heteroatom selected from the group of sulfur, nitrogen, and oxygen atoms.

[0076] The heterocycle of “4 to 12 membered heterocyclyl”, “4 to 12 membered heterocyclylene”, or “4 to 12 membered heterocyclylidene” as used herein refers to “4 to 12 membered heterocycloalkane”, “ 4 to 12 membered heterocycloalkane” having an unsaturated bond, a 4 to 12 membered ring composed of a heterocycloalkane and a heteroarene or arene bonded to a portion of the heterocycloalkane, a 4 to 12 membered ring composed of a cycloalkane and a heteroarene bonded to a portion of the cycloalkane, a 4- to 12-membered ring containing a heteroatom and having a spiro structure, or a 4 to 12-membered ring containing a heteroatom and having a cross-linked structure. The term “4- to 12-membered heterocycloalkane” refers to 4- to 12-membered cyclic heteroalkane; that is, a monocyclic or polycyclic aliphatic hydrocarbon ring containing one to four heteroatoms selected from sulfur, nitrogen, and oxygen atoms. Specific examples of the "4- to 12-membered heterocycloalkane" include aziridine, thiirane, azetidine, oxetane, thiethane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, piperidine, piperazine, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,4-diazepane, oxepane, and the like. A compound having a “spiro structure” is composed of two cyclic structures (cycloalkanes or heterocycloalkanes) that are bonded to a common carbon atom. Examples of the compound include 2-azaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 2,7-diazaspiro[3.5] nonane, 1,7-diazaspiro [4.5]decane, 2,8-diazaspiro [4.5]decane, 4,7-diazaspiro [2.5]octane, and the like. A compound having a “diazaspiro [2.5]octane structure, and the like. A compound having a “cross-linked structure” is composed of two cyclic structures (cycloalkanes and heterocycloalkanes) that are linked to two or more carbon, nitrogen, or oxygen atoms in common. Examples of the compound include 2,5-diazabicyclo[2.2.2]octane, 3,8-diazabicyclo[3.2.1]octane, 1,4-diazabicyclo[3.2.2]nonane, octahydropyrrole[3,4-b] pyrrole, and the like.

[0077] The term “aryl” as used herein refers to a monovalent group obtained by removing a hydrogen atom from an arene on any carbon atom.

[0078] The term “arylene” as used herein refers to a divalent group obtained by removing two hydrogen atoms from an arene on any two different carbon atoms.

[0079] The term “arene” as used herein refers to an aromatic hydrocarbon.

[0080] The “aryl-C6-10” or “arylene-C6-10” arene as used herein refers to an aromatic hydrocarbon ring having six to ten carbon atoms. Specific examples of arene include benzene, naphthalene, and the like.

[0081] The term “heteroaryl” as used herein refers to a monovalent group obtained by removing a hydrogen atom from a heteroarene on any carbon or nitrogen atom.

[0082] The term “heteroarylene” as used herein refers to a divalent group obtained by removing two hydrogen atoms from a heteroarene on any two different carbon or nitrogen atoms.

[0083] The term “heteroarene” as used herein refers to an aromatic heterocyclic ring containing a heteroatom selected from sulfur, nitrogen, and oxygen atoms.

[0084] “5-10 membered heteroaryl” or “5-10 membered heteroarylene” heteroarene as used herein refers to a 5- to 10-membered aromatic heterocyclic ring containing one to four heteroatoms selected from sulfur atoms , nitrogen, and oxygen. Specific examples of heteroarene include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinolone, isoquinolone, benzofuran, benzothiophene, indole, indazole , benzimidazole, and the like.

[0085] The term “(4- to 12-membered heterocyclyl)-C1-6-alkyl” as used herein refers to a 4- to 12-membered heterocyclyl group attached to a C1-6-alkyl group such that the C1-6 alkyl group is attached to a different structure than the 4- to 12-membered heterocyclyl group. Specific examples of the (4- to 12-membered heterocyclyl)-C1-6-alkyl group include groups prepared by attaching any of the 4- to 12-membered heterocyclyl groups exemplified above to any of the C1-6-alkyl groups exemplified above.

[0086] The term “(aryl-C6-10)-alkyl-C1-6” as used herein refers to an aryl-C6-10 group linked to a C1-6 alkyl group such that the alkyl group -C1-6 is attached to a different structure than the aryl group-C6-10. Specific examples of the (aryl-C6-10)-C1-6-alkyl group include groups prepared by attaching any of the aryl-C6-10 groups exemplified above to any of the C1-6-alkyl groups exemplified above.

[0087] The term “(5- to 10-membered heteroaryl)-C1-6-alkyl” as used herein refers to a 5- to 10-membered heteroaryl group attached to a C1-6-alkyl group such that the C1-6 alkyl group is attached to a different structure than the 5- to 10-membered heteroaryl group. Specific examples of the (5- to 10-membered heteroaryl)-C1-6-alkyl group include groups prepared by attaching any of the 5- to 10-membered heteroaryl groups exemplified above to any of the C1-6-alkyl groups exemplified above.

[0088] The term “C1-8-alkyl-sulfonyl” as used herein refers to a C1-8-alkyl group linked to a sulfonyl group (-S(=O)2-) such that the sulfonyl group it is linked to a structure different from the C1-8-alkyl group.

[0089] The term “C1-8 acyl” as used herein refers to a C1-7 alkyl group attached to a carbonyl group (-CO-) such that the carbonyl group is attached to a structure different from the C1-7-alkyl group.

[0090] The term “halogen” as used herein refers to an atom of fluorine, chlorine, bromine, or iodine.

[0091] The term “C1-8 alkoxy” as used herein refers to a linear, branched, or cyclic alkoxy group having one to eight carbon atoms. Specific examples of the C1-8-alkoxyl group include methoxy, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl, sec-butoxyl, tert-butoxyl, n-pentyloxy, neopentyloxy, tert-pentyloxy, 2-methylbutoxyl, n- hexyloxy, isohexyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, spiro [3.3]heptyloxy, bicyclo[2.2.2]octyloxy, and the like.

[0092] The term “alkenyl” as used herein refers to a monovalent group obtained by removing a hydrogen atom from an alkene on any carbon atom.

[0093] The term “alkenylene” as used herein refers to a divalent group obtained by removing two hydrogen atoms from an alkene on any two different carbon atoms.

[0094] The term “alkene” as used herein refers to an unsaturated aliphatic hydrocarbon having a double bond.

[0095] The term “achenyl-C2-8” as used herein refers to an aliphatic chain hydrocarbon having a double bond. Examples of C2-8-akenyl include ethenyl (or vinyl), propenyl (or allyl), butenyl, and the like.

[0096] The term “alkynyl” as used herein refers to a monovalent group obtained by removing a hydrogen atom from an alkyne on any carbon atom.

[0097] The term “alkynylene” as used herein refers to a divalent group obtained by removing two hydrogen atoms from an alkyne on any two different carbon atoms.

[0098] The term “alkyne” as used herein refers to an unsaturated aliphatic hydrocarbon having a triple bond.

[0099] The term “C2-4-alkynyl” as used herein refers to a hydrocarbon chain group having a triple bond. Examples of C2-4-alkynyl include ethynyl, propynyl, butynyl, and the like.

[00100] L is preferably -NR5-.

[00101] The “C1-6-alkyl” of R5 is preferably methyl or ethyl.

[00102] R5 is preferably a hydrogen atom or a methyl group.

[00103] The “C1-8-alkyl” of R1 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, 1,2- dimethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, isoheptyl, n-octyl, or isooctyl.

[00104] The “C3-12-cycloalkyl” of R1 is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro [3.3]heptyl, bicyclo [1.1.1]pentane, bicyclo [2.2.2]octyl, or adamantyl.

[00105] The “(C3-12-cycloalkyl)-C1-6-alkyl” of R1 is preferably cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, or cyclopentylethyl.

[00106] The “4- to 12-membered heterocyclyl” heterocycle in R1 is preferably azetidine, oxetane, thiethane, tetrahydrofuran, 1,4-dioxane, morpholine, thiomorpholine, tetrahydropyran, tetrahydrothiophene, or oxepane.

[00107] The “(4- to 12-membered heterocyclyl)-C1-6-alkyl” of R1 is preferably (tetrahydrofuranyl)methyl, (tetrahydropyranyl)methyl, (tetrahydrofuranyl)ethyl, or (tetrahydropyranyl) ethyl.

[00108] The “aryl-C6-10” of R1 is preferably phenyl.

[00109] The “(aryl-C6-10)-alkyl-C1-6” of R1 is preferably phenylmethyl or phenylethyl.

[00110] The “5- to 10-membered heteroaryl” of R1 is preferably furanyl, pyrazolyl, or thienyl.

[00111] The “halogen” in the R1 substituent is preferably a fluorine or chlorine atom.

[00112] The “-COOR6” in the R1 substituent is preferably -COO-H or -COOCH3.

[00113] The “R7” in the substituent of R1 is preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, isopentyl, 1,1-dimethyl-2- methoxyethyl, 1-methyl-2-methoxyethyl, 1-methyl-2-hydroxyethyl, 2,2,2-trifluoroethyl, hydroxymethyl, or 1-methyl-2,2,2-trifluoroethyl.

[00114] The “C3-6-cycloalkyl optionally substituted with a substituent selected from the group consisting of one or two -O-H groups, one or two C1-8-alkoxyl groups, and one to six fluorine atoms” in the R1 substituent is preferably cyclopentyl, cyclohexyl, 4-methoxycyclohexyl, or 4-isopropoxycyclohexyl.

[00115] The 3 to 10 membered heterocyclyl optionally substituted with a substituent selected from the group consisting of one or two -O-H groups, one or two C1-8 alkoxyl groups, and one to six fluorine atoms in the R1 substituent is preferably tetra -hydrofuranyl, tetrahydropyranyl, or 2,2-dimethyltetrahydropyranyl.

[00116] R1 preferably has any of the following structures: [Formula 2]

[00117] The “C1-8-alkyl” of R2 is preferably methyl, ethyl, or n-propyl, and the substituent is preferably a hydroxyl, methoxy, or ethoxy group or a fluorine atom. The “4- to 6-membered heterocyclyl” of R2 is preferably oxetane or tetrahydrofuranyl.

[00118] The “acyl-C1-8” of R2 is preferably acetyl.

[00119] The “-COOR8” of R2 is preferably -COO-H or -COOCH3.

[00120] The “-CONR9R10” of R2 is preferably -CON(CH3)2.

[00121] R9 and R10 of -CONR9R10 of R2 can be linked via a single bond or -O- to form a ring including the nitrogen atom linked to R9 and R10. Examples of such a ring include the following structures: [Formula 3]

[00122] R2 preferably has any of the following structures [Formula 4]

[00123] The “C1-8-alkyl” of R3 is preferably methyl.

[00124] The “halogen” of R3 is preferably a fluorine or chlorine atom.

[00125] R3 is preferably a hydrogen, fluorine, or chlorine atom or a methyl group.

[00126] X, Y, and Z preferably correspond to any of the following combinations: X, Y, and Z are each CH; X is a nitrogen atom and Y and Z are each CH; Y is a nitrogen atom and X and Z are each CH; and Z is a nitrogen atom and X and Y are each CH.

[00127] The “C1-8-alkylene” of A1 is preferably methylene, ethylene, or n-propylene.

[00128] The structure obtained by replacing one or two sp3 carbon atoms in any of the positions of A1 is preferably -O-, -OCH2-, -OCH2CH2-, -OCH2CH2CH2-, -CH2O-, -CH2OCH2-, -CH2OCH2CH2 -, -CH2CO-, -COCH2-, -CH2CH2CO-, -COCH2CH2-, -CH2COCH2-, - CH2COCH2CH2-, -NR14-, -NR14CH2-, -CH2NR14-, -NR14CH2CH2-, - CH2NR14CH2-, or -CH2CH2NR14- .

[00129] The “C1-7 alkylene” of A2 is preferably methylene, ethylene, or n-propylene.

[00130] The “C3-12-cycloalkylene” of A2 is preferably cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene.

[00131] The “4- to 12-membered heterocyclylene” heterocycle of A2 is preferably piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydropyran, 1,4-diazepane, oxepane, 2-azaspiro [3.3]heptane, 1 ,6-diazaspiro [3.3]heptane, 2,6-diazaspiro [3.3]heptane, 2,6-diazaspiro [3.4]octane, 2,5-diazabicyclo [2.2.2]octane, 3,8-diazabicyclo [3.2.1 ]octane, 2,7- diazaspiro [3.5]nonane, 1,7-diazaspiro [4.5]decane, 2,8- diazaspiro [4.5]decane, 4,7-diazaspiro [2.5]octane, 1,4- diazabicyclo [3.2 .2]nonane, or octahydropyrrolo [3,4-b]pyrrole.

[00132] The “4- to 12-membered heterocyclylidene” heterocycle of A2 is preferably oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, morpholine, or oxepane.

[00133] The “arylene-C6-10” of A2 is preferably phenylene.

[00134] The “5- to 10-membered heteroarylene” heteroarene of A2 is preferably furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine , quinolone, isoquinoline, benzofuran, benzothiophene, indole, indazole, or benzimidazole.

[00135] The “halogen” of A3 is preferably a fluorine or chlorine atom.

[00136] The “-R25” of A3 is a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl group. The -R25 substituted with a substituent is preferably a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-propyl, 2-hydroxy-1-propyl, 1-hydroxy-2-propyl, 1-hydroxy-2 -methyl-2-propyl, 2-hydroxy-2-methyl-1-propyl, trifluoromethyl, 2,2,2-trifluoroethyl, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxy-2-propyl, or cyanomethyl.

[00137] The “-OR26” of A3 is preferably -O-H, methoxy, ethoxy, or isopropoxy.

[00138] The “-NR27R28” of A3 is preferably amino, dimethylamino, methylamino, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl.

[00139] The “-C(=O)R29” of A3 is preferably acetyl. The -C(=O)R29 substituted with a substituent is preferably hydroxyacetyl.

[00140] The “-C(=O)-OR30” of A3 is preferably -COO-H, methoxycarbonyl, ethoxycarbonyl, or isopropoxycarbonyl.

[00141] The “-C(=O)-NR34R35” of A3 is preferably aminocarbonyl (or carbamoyl), (methylamino)carbonyl, (dimethylamino)carbonyl, (pyrrolidin-1-yl)carbonyl, (piperidin-1-yl)carbonyl , (morpholin-1-yl)carbonyl, or (piperazin-1-yl)carbonyl.

[00142] The “-S(=O)2-R40” of A3 is preferably methanesulfonyl or ethylsulfonyl.

[00143] R14 to R44 in A1, A2, and A3 can be connected to A1, A2, or A3 or between A1 and A2, between A1 and A3, or between A2 and A3 via a single bond, -O-, -NR50 -, or -S(=O)p- to form a ring. Examples of such a ring include the following structures: [Formula 5]

[00144] R11 or R13 can be linked to A1, A2, or A3 via a single bond, -O-, -NR51-, or -S(=O)p- to form a ring. Examples of such a ring include the following structures:

[00145] Preferred examples of the aforementioned entire structure are as follows:

[00146] A preferred compound represented by Formula (I) is composed of a combination of a group selected from those defined above and a preferred group, or a combination of preferred groups.

[00147] The compound of the present invention represented by Formula (I) can optionally be transformed into a pharmaceutically acceptable salt. Examples of the salt include salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, and the like; salts with organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, phthalic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid , methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like; salts such as amino acids, such as lysine, arginine, ornithine, glutamic acid, aspartic acid, and the like; salts with alkali metals, such as sodium, potassium, lithium, and the like; salts with alkaline earth metals, such as calcium, magnesium, and the like; salts with metals, such as aluminum, zinc, iron, and the like; salts with organic bases, such as methylamine, ethylamine, t-octylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, piperidine, piperazine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N-methylglucamine, tris( hydroxymethyl)aminomethane, N,N'-dibenzylethylenediamine, and the like; and ammonium salts and the like.

[00148] The present invention also covers compounds prepared by replacing one or more atoms of the compound represented by Formula (I) with stable isotopes or radioisotopes.

[00149] The present invention also covers stereoisomers, racemates, and all acceptable optical isomers of the compound represented by Formula (I).

[00150] Tautomers of the compound of the present invention can be generated depending on the combination of substituents. The present invention also encompasses such tautomers.

[00151] A typical process will now be described for synthesizing the compound of the present invention represented by Formula (I).

[00152] The compound of the present invention can be synthesized by the process described below. R1, R3, R4, and R7 shown in the following reaction schemes are as defined in Formula (I). The reagents or solvents and the like shown in the reaction schemes are for illustrative purposes only as described below. Each substituent may be optionally protected with an appropriate protecting group or deprotected in an appropriate step (reference: “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS”, 4TH EDITION, John Wiley & Sons, Inc.). The abbreviations for substituents, reagents, and solvents described below and in the tables are as follows: Me: methyl Et: ethyl Ph: phenyl Boc: tert-butoxycarbonyl Cbz: benzyloxycarbonyl THF: tetrahydrofuran DMF: N,N-dimethylformamide NMP: N-methylpyrrolidone TFA: trifluoroacetic acid TBS: tert-butyldimethylsilyl BINAP: 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl TBDPS: tert-butyldiphenylsilyl DIPEA: N,N-diisopropylethylamine LAH: aluminum hydride and lithium DMAP: 4-dimethylaminopyridine Ac: acetyl Ms: mesyl WSC: water-soluble carbodiimide (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) m-CPBA: m-chloroperoxybenzoic acid DAST: diethylaminosulfur tetrafluoride dba: dibenzylideneacetone DIBAL- H: diisobutylaluminum hydride 1) Synthesis of compound Ie [Formula 20]

[00153] Compound I-e, which is a known compound, can be synthesized by any process known to those skilled in the art; for example, the aforementioned process.

[00154] 2) Synthesis of compound If from compound Ie [Formula 21]

[00155] Compound I-e is reacted with a terminal alkyne derivative represented by the Formula R2-C=CH in an appropriate organic solvent (e.g., THF or DMF) in the presence of an appropriate palladium catalyst (e.g., tetrakis(triphenylphosphine) palladium), appropriate copper catalyst (e.g., copper (I) iodide) and appropriate base (e.g., triethylamine) at a temperature of 0°C to the reflux temperature of the solvent, to produce compound I-f.

[00156] 3) Synthesis of compound Ih from compound If [Formula 22]

[00157] Compound I-f is reacted with hydroxylamine or a salt thereof in an appropriate organic solvent (e.g., ethanol) in the presence or absence of an appropriate base (e.g., sodium acetate) at a temperature of 0°C to solvent reflux temperature. The resulting hydroxyimine compound is reacted with an appropriate acid or an appropriate base (e.g., silver triflate or potassium carbonate) to produce compound I-h.

[00158] 4) Synthesis of compound Ii from compound Ih [Formula 23]

[00159] Compound I-h is reacted with an appropriate halogenating agent (e.g., thionyl chloride) in an appropriate organic solvent (e.g., dichloromethane) or under solvent-free conditions at a temperature of 0°C to 140°C, to produce compound I-i.

[00160] 5) Synthesis of compound Ij from compound Ii [Formula 24]

[00161] Compound I-i is reacted with an amine derivative, alcohol, or thiol represented by Formula R1-L-H in an appropriate organic solvent (e.g., THF or 1,4-dioxane) or under solvent-free conditions in the presence or absence of a suitable base (e.g., triethylamine, potassium carbonate, or sodium hydride) at a temperature of 0°C to the reflux temperature of the solvent, to produce compound I-j.

[00162] At this stage, R2 can be modified by any process known to those skilled in the art considering the intended structure of the compound.

[00163] 6) Synthesis of compound Ik from compound Ij [Formula 25]

[00164] Compound I-j is reacted with an appropriate oxidant (e.g., Oxone® or m-chloroperbenzoic acid) in an appropriate organic solvent (e.g., dichloromethane or water) at a temperature of 0°C to the reflux temperature of the solvent , to produce compound I-k.

[00165] 7) Synthesis of compound Il from compound Ik [Formula 26]

[00166] Compound I-k is reacted with an appropriate halogenating agent (e.g., N-chlorosuccinimide) in an appropriate organic solvent (e.g., dichloromethane or 1,2-dichloroethane) at a temperature of 0°C to the reflux temperature of the solvent, to produce compound I-1.

[00167] At this stage, R3 can be modified by any process known to those skilled in the art considering the intended structure of the compound.

[00168] 8) Synthesis of compound Im from compound Il [Formula 27]

[00169] Compound I-l is reacted with an amine derivative represented by Formula R4-(nitrogen-containing heteroaryl with X, Y, or Z)-NH2 of the above scheme in an appropriate organic solvent (e.g., NMP, THF, or toluene) or under solvent-free conditions in the presence or absence of an appropriate base (e.g., sodium hydride, triethylamine, or N,N-diisopropyl-N-ethylamine) at a temperature of 0°C to the reflux temperature of the solvent , to produce compound I-m.

[00170] If L, R1, R2, or R4 of compound I-m is protected with an appropriate protecting group, deprotection can be carried out by any process known to those skilled in the art. For example, deprotection can be accomplished by reacting the compound with an appropriate deprotecting reagent (e.g., TFA or hydrogen chloride for a Boc protecting group, lithium hydroxide for a benzoyl protecting group, or hydrogen in the presence of Pd/C for a Cbz protecting group) in an appropriate organic solvent (e.g., dichloromethane, methanol, or THF) or under solvent-free conditions at a temperature from 0°C to the reflux temperature of the solvent (reference: “Green's Protective Groups in Organic Synthesis”, 4th edition, John Wiley & Sons Inc.).

[00171] If compound I-m is protected with two or more protecting groups, deprotection can be carried out in an appropriate order depending on the structure of compound I-m.

[00172] In each of reactions 9) to 13) described below, L, R1, R2, or R4 of compound I-m is appropriately protected depending on the corresponding reaction conditions. After completion of the reaction, deprotection can be carried out by an appropriate process.

[00173] 9) Synthesis of compound In from compound Im

[00174] Compound I-m in which R4 has a primary or secondary amine structure is reacted with an optionally substituted epoxide in an appropriate organic solvent (e.g., dichloromethane, NMP, or THF) in the presence or absence of an appropriate acid (e.g. , boron trifluoride-diethyl ether complex) or a suitable base (e.g., potassium carbonate or triethylamine) at a temperature of 0°C to the reflux temperature of the solvent, to produce the compound I-n.

[00175] 10) Synthesis of compound Io from compound Im [Formula 28]

[00176] Compound I-m in which R4 has a primary or secondary amine structure is reacted with a carboxylic acid chloride, a carboxylic anhydride, or a carboxylic acid and a condensation reagent in an appropriate organic solvent (e.g., NMP, THF , or pyridine) in the presence or absence of an appropriate base (e.g., triethylamine or N,N-diisopropyl-N-ethylamine) at a temperature of 0°C to the reflux temperature of the solvent, to produce compound I-o .

[00177] 11) Synthesis of compound Ip from compound Im [Formula 30]

[00178] Compound I-m in which R4 has a primary or secondary amine structure is reacted with sulfonic acid chloride in an appropriate organic solvent (e.g., NMP, THF, or pyridine) in the presence or absence of an appropriate base (e.g. , triethylamine or N,N-diisopropyl-N-ethylamine) at a temperature of 0°C to the reflux temperature of the solvent, to produce compound I-p.

[00179] 12) Synthesis of compound Iq from compound Im [Formula 31]

[00180] Compound I-m in which R4 has a primary or secondary amine structure is reacted with an optionally substituted ketone or an optionally substituted aldehyde and an appropriate reductant (e.g., sodium triacetoxyborohydride or sodium cyanoborohydride) in a appropriate organic solvent (e.g., NMP or methanol) in the presence of an appropriate acid (e.g., acetic acid) at a temperature from room temperature to the reflux temperature of the solvent, to produce compound I-q.

[00181] 13) Synthesis of compound Ir from compound Im [Formula 32]

[00182] Compound I-m in which R4 has a primary or secondary amine structure is reacted with a compound having a leaving group (e.g., a halogen atom or a sulfonyloxy group) in an appropriate organic solvent (e.g., NMP, THF, or pyridine) in the presence or absence of an appropriate base (e.g., triethylamine or N,N-diisopropyl-N-ethylamine) at a temperature of 0°C to the reflux temperature of the solvent, to produce the compound Go.

[00183] 14) Synthesis of compound Is from compound Im [Formula 33]

[00184] Compound I-m in which R4 has a primary or secondary amine structure is reacted with a compound having a Michael acceptor structure in an appropriate organic solvent (e.g., methanol, THF) at a temperature of 0°C to reflux temperature of the solvent to produce compound I-s.

[00185] The compound of the present invention exhibits inhibitory activity against CDK4/6 and, therefore, is useful for the prevention or treatment of a disease associated with CDK4/6. Specifically, the compound is useful for treating rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer and protecting the bone marrow. In particular, the compound is effective for treating rheumatoid arthritis or cancer and protecting the bone marrow.

[00186] The compound of the present invention preferably presents selectivity for inhibitory activity against CDK4/6 compared to inhibitory activity against other cyclin-dependent kinases, such as inhibitory activity against CDK2. Such compound selectivity is supposed to reduce the expression of genotoxicity because inhibition of CDK2 is also involved in DNA replication. Preferably, the compound of the present invention selectively inhibits CDK4 rather than CDK2.

[00187] The active ingredient of the present invention can be supplied in any form of preparation, such as solid, semisolid, or liquid form and the like. The active ingredient may be provided in any dosage form, such as an oral form or a parenteral form (e.g., an injection, a transdermal agent, an eye drop, a suppository, a nasal agent, or an inhalant, and the like).

[00188] A drug containing the active ingredient of the present invention is prepared with a common additive used for preparing the drug. Examples of the solid drug additive include excipients such as lactose, sucrose, glucose, corn starch, potato starch, crystalline cellulose, light silicic anhydride, synthetic aluminum silicate, magnesium aluminometasilicate, calcium hydrogen phosphate, and the like; binders such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, poly(vinylpyrrolidone), and the like; disintegrants such as starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and the like; lubricants such as talc, stearic acid, and the like; coating agents such as hydroxymethylpropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose, and the like; and colorants. Examples of the additive for semi-solid drugs include bases, such as white petrolatum, and the like. Examples of the liquid drug additive include solvents such as ethanol and the like; solubilizers, such as ethanol, and the like; preservatives, such as para-oxybenzoic acid esters, and the like; isotonic agents, such as glucose, and the like; buffers, such as citric acid, and the like; antioxidants, such as L-ascorbic acid, and the like; chelators, such as EDTA, and the like; suspending and emulsifying agents, such as polysorbate 80, and the like; and the like.

[00189] The dose of the active ingredient of the present invention is typically about 1 to 1,000 mg/day. The active ingredient is typically administered once to three times daily.

EXAMPLES

[00190] The present invention will now be described in detail by way of examples, which should not be interpreted as limiting the invention.

[00191] The structure of a new isolated compound was determined by 1H-NMR and/or mass spectrometry with a single quadrupole instrumentation equipped with an electron spray source, and other appropriate analytical methods. Chemical shifts (d: ppm) and coupling constants (J: Hz) are shown for the 1H-NMR spectra (400 MHz, DMSO-D6, CD3OD or CDCl3). The abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), brs (wide singlet), em (multiplet). For mass spectrometry results, measurements are represented by (M+H)+; that is, a value that corresponds to a proton (H+) bound to a molecular mass (M) of a compound. Reference Example 1 Synthesis of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid [Formula 34]

[00192] Mucobromic acid (300 g, 1.16 mol) was added to an aqueous solution (2.5 L) of 2-methyl-2-pseudothiourea sulfate (324 g, 1.16 mol) at room temperature. The resulting suspension was cooled to 0°C with stirring, and triethylamine (486 mL, 3.49 mol) was added dropwise over four hours. The resulting reaction mixture was stirred overnight, and the completeness of the reaction was confirmed by TLC (Thin Layer Chromatography) on silica gel. The reaction mixture was then acidified with concentrated hydrochloric acid (about 250 mL). The resulting yellow solid was collected by filtration and washed twice with water (500 ml) and then twice with diethyl ether (500 ml). The solid was dried under reduced pressure to yield the title compound (160 g, 55%). Reference Example 2 Synthesis of methyl 5-bromo-2-methylthiopyrimidine-4-carboxylate [Formula 35]

[00193] A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (110 g, 0.44 mol) in methanol (1.1 L) was cooled to 0°C with stirring, and sodium chloride thionyl (50 mL, 0.66 mol) was added dropwise. The resulting reaction mixture was slowly heated, and the reaction was allowed to proceed under reflux for four hours. The completeness of the reaction was confirmed by LC/MS (Liquid Chromatography/Mass Spectrometry) and TLC (Thin Layer Chromatography), and the reaction mixture was cooled to room temperature. The volatiles were removed by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate (1 L). The resulting solution was washed three times with 10% aqueous sodium carbonate solution (200 mL) and then twice with saturated brine (200 mL). The resulting organic phase was dried with anhydrous magnesium sulfate, and the solid was filtered off. The filtrate was then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to yield the title compound (88 g, 75%). Reference Example 3 Synthesis of a mixture of 5-bromo-2-methylthiopyrimidine-4-carbaldehyde and (5-bromo-2-methylthiopyrimidin-4-yl)methoxymethanol [Formula 36]

[00194] A solution (375 mL) of methyl 5-bromo-2-methylsulfanylpyrimidine-4-carboxylate (25 g, 95 mmol) in THF was cooled to -78 ° C and stirred under a nitrogen atmosphere. DIBAL-H (84 mL, 143 mmol, 1.7M toluene solution) was added dropwise to the THF solution, and the mixture was stirred at -78°C for four hours. The completeness of the reaction was confirmed by TLC, and the reaction was inactivated by dropwise addition of methanol at -78°C. The resulting reaction mixture was allowed to slowly warm to 0°C and was diluted with ethyl acetate, and the mixture was filtered through Celite® (diatomaceous earth). The filtrate was washed twice with saturated brine (200 ml), and the resulting organic phase was dried with anhydrous magnesium sulfate. The resulting solid was separated by filtration, and the filtrate was concentrated to give the title compound mixture (25 g, crude product). The crude product was used in the subsequent reaction without further purification. Reference Example 4 Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate [Formula 37]

[00195] A mixture of 5-Bromo-2-nitropyridine (203 g, 1.37 mol), piperazine (153 g, 1.77 mol), tetrabutylammonium iodide (25.2 g, 0.068 mol), and carbonate potassium (207 g, 1.50 mol) in dimethyl sulfoxide (2.6 L) was stirred at 80°C overnight. The resulting reaction mixture was cooled to room temperature, and the mixture was poured into water (7 L). The resulting solid was collected by filtration, and the solid was washed with dichloromethane (1 L x 2) and dried. The filtrate was extracted with chloroform (2 L x 7). The resulting organic phase was washed with water (2 L) and then saturated brine (2 L), and the organic phase was concentrated under reduced pressure to give a solid. The resulting solid products were combined together and used in the subsequent reaction without further purification.

[00196] The solid product (490 g) was dissolved in THF (2 L) and water (500 mL), and sodium hydrogen carbonate (119 g, 1.42 mol) was added to the solution. To the resulting suspension was added di-tert-butyl dicarboxylate (262 g, 1.2 mol), and the mixture was stirred at room temperature for three hours. A reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (1 L) and the solution was extracted with dichloromethane (1 L x 3). The resulting organic phases were combined together and then washed with water (1 L). The aqueous phase was extracted with dichloromethane (300 ml). The resulting organic phases were combined together and dried with anhydrous magnesium sulfate. The solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended in ethyl acetate (2 L) and the suspension was heated to 60°C, and the solid was filtered off at 60°C. The solid was dried under reduced pressure to yield the title compound (191 g, 62%)

[00197] IQPA-EM (Chemical Ionization at Atmospheric Pressure - Mass Spectrometry): (M+H)+ 309.1, C14H20N4O4=308.15

[00198] 1H-NMR (400 MHz, CDCl3)d: 8.16 (d, J=9 Hz, 1H), 8.11 (d, J=3 Hz, 1H), 7.19 (dd, J= 9.3 Hz, 1H), 3.64-3.61 (m, 4H), 3.45-3.42 (m, 4H), 1.47 (s, 9H). Reference Example 5 Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate [Formula 38]

[00199] The tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate synthesized in Reference Example 4 (83 g, 269 mmol) was dissolved in methanol (1.3 L) on a Parr Shaker and Raney nickel (15 g, 50% aqueous suspension) was added. The resulting reaction mixture was stirred under a hydrogen atmosphere (50 psi [345 kPa]) for five hours. The reaction mixture was filtered through a pad of Celite® to separate the solid, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended in diethyl ether (120 mL) and stirred for four hours. Heptane was added to the suspension which was cooled to 0°C for 45 minutes. The resulting solid was filtered off and dried under reduced pressure to yield the title compound (62.5 g, 83%).

[00200] IES-EM (Electrospray Ionization-Mass Spectrometry): (M+H)+ 279, C14H22N4O2=278.17

[00201] Intermediates A-1 to A-44 were each synthesized by the process of Reference Examples 4 and/or 5 with corresponding halopyridine derivatives and amine derivatives. Appropriate protection or deprotection was carried out if necessary. Reference Example 6Synthesis of 6-aminopyridine-3-carbaldehyde [Formula 41]

[00202] 6-Aminopyridine-3-carbonitrile (1.9 g, 16 mmol) was dissolved in THF (160 mL) and the solution was cooled to -78°C with stirring. Diisobutylaluminum hydride (106.5 mL, 1.5M toluene solution) was slowly added dropwise to the solution at -78°C and the mixture was allowed to warm to 20°C with stirring, followed by further stirring for two hours. . The reaction was quenched by adding ice-cold water (100 mL) to the resulting reaction mixture, and the mixture was extracted three times with dichloromethane (50 mL). The resulting organic phases were combined together and then washed once with brine (100 ml) and dried with anhydrous sodium sulfate. The solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was approximately purified by silica gel column chromatography to yield a crude product of the title compound (1.7 g). The crude product was used in the subsequent reaction without further purification. Reference Example 7 Synthesis of tert-butyl 4-[(6-aminopyridin-3-yl)methyl]piperazine-1-carboxylate [Formula 42]

[00203] The crude 6-aminopyridine-3-carbaldehyde synthesized in Reference Example 6 (1.7 g, 13.9 mmol) and tert-butyl piperazine-1-carboxylate (3.2 g, 17.2 mmol) were dissolved in dichloromethane (50 mL) and the solution was stirred at room temperature for eight hours. To the resulting mixture was added sodium triacetoxyborohydride (8.84 g, 40.9 mmol) and the mixture was stirred at room temperature for two hours. The reaction was monitored by LC/MS. After completion of the reaction, the reaction was inactivated by adding saturated aqueous sodium carbonate solution (50 mL), and the reaction mixture was extracted three times with ethyl acetate (50 mL). The resulting organic phases were combined together, and the mixture was washed once with brine (100 mL) and dried over anhydrous sodium sulfate. The resulting solid was separated by filtration, and then the filtrate was concentrated under reduced pressure. The residue was approximately purified by silica gel column chromatography to yield the title compound (3.3 g, 81%). Reference Example 8 Synthesis of di-tert-butyl (5-methylpyridin-2-yl)imidodicarbonate [Formula 43]

[00204] Referring to the process disclosed in WO2010/141406, 5-methylpyridine-2-amine (20 g, 185 mmol) and di-tert-butyl dicarbonate (101 g, 462 mmol) were dissolved in THF (160 mL ) and 4-N,N-dimethylaminopyridine (3.6 g, 29.7 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature for three days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and the solution was washed with water. The resulting organic phase was washed with saturated brine and dried with anhydrous sodium sulfate. The solid was separated by filtration, and the filtrate was concentrated. The resulting solid was dissolved in ethyl acetate (50 mL) and heptane (50 mL) was added to the solution. The solid was collected by filtration and dried under reduced pressure to yield the title compound (25.1 g, 44%). The filtrate was concentrated, and the residue was purified by silica gel column chromatography to yield the title compound (17.9 g, 31%). Reference Example 9 Synthesis of di-tert-butyl [5-(bromomethyl)pyridin-2-yl]imidodicarbonate [Formula 44]

[00205] Di-tert-butyl (5-methylpyridin-2-yl)imidodicarbonate synthesized in Reference Example 8 (17.2 g, 55.8 mmol), N-bromosuccinimide (12.17 g, 68.4 mmol), and benzoyl peroxide (1.5 g, 8.1 mmol) were dissolved in carbon tetrachloride (100 mL) and the reaction was stirred at 80 ° C for six hours. The reaction mixture was cooled to room temperature, and the resulting solid was separated by filtration. The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield a mixture of the title compound, di-tert-butyl 5-(dibromomethyl)pyridin-2-yl]imidodicarbonate, and di-tert-butyl (5-methylpyridin-2-yl)imidodicarbonate (14.5 g, 60.3 : 4.4 : 35.3, determined by 1H-NMR spectrum). The mixture was used in the subsequent reaction without further purification. Reference Example 10 [Formula 45]

[00206] Di-tert-butyl [5-(Bromomethyl)pyridin-2-yl]imidodicarbonate (1 equivalent) was dissolved in DMF and an appropriate amine derivative (1.5 equivalents) and N,N-diisopropyl -N-ethylamine (3 equivalents) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for several hours, and the mixture was then diluted with ethyl acetate and washed with saturated brine. The resulting organic phase was dried with anhydrous sodium sulfate, and the solid was filtered off. The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield a target amine derivative. Reference Example 11 [Formula 46]

[00207] To the compound synthesized in Reference Example 10, an excess amount of trifluoroacetic acid was added and the mixture was stirred at room temperature for several hours. The reaction mixture was concentrated under reduced pressure, and the resulting TFA salt of the target product was dissolved in methanol and applied to a strong cation exchange resin (SCX). The SCX column was washed with methanol and the target product was eluted with ammonia (2 mol/L, methanol solution). The eluate was concentrated under reduced pressure to yield a target 2-aminopyridine derivative. The resulting product was used in the subsequent reaction without further purification.

[00208] In the case of the presence of a primary or secondary amino group in the compound in addition to the aminopyridine structure, the crude product was dissolved in THF and reacted with di-tert-butyl dicarbonate at room temperature. After completion of the reaction, the solvent was removed by evaporation, and the residue was approximately purified by silica gel column chromatography to produce a 2-aminopyridine derivative having a primary or secondary amino group protected with a Boc group.

[00209] Intermediates B-1 to B-68 were each synthesized by any of the processes of Reference Examples 6 and/or 7 or Reference Examples 8 to 11 or a combination of the processes with the corresponding derivatives of aldehyde or alkyl halide and amine derivatives. Appropriate protection or deprotection was carried out if necessary. [Formula 47] Reference Example 12 [Formula 49]

[00210] An appropriate amide derivative (1 equivalent) was dissolved in DMF, and sodium hydride (1 equivalent) was gradually added to the solution at 0°C and the mixture was stirred at room temperature for several minutes. The resulting reaction mixture was cooled to 0 ° C and di-tert-butyl [5-(bromomethyl)pyridin-2-yl]imidodicarbonate (1.5 equivalents) was gradually added to the mixture. The reaction mixture was stirred at room temperature for several hours and then water was added to the mixture to stop the reaction. The mixture was extracted with ethyl acetate and washed with saturated brine. The resulting organic phase was dried with anhydrous sodium sulfate, and the solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield a target amide derivative.

[00211] The following intermediates C-1 to C-5 were synthesized by the process of Reference Examples 12 and 11 with the corresponding alkyl halide derivatives, amide derivatives, or urea derivatives. Appropriate protection or deprotection was carried out if necessary. [Formula 50] Reference Example 13 Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)-3-oxopiperazine-1-carboxylate [Formula 51]

[00212] Referring to the process disclosed in WO2012/031004, tert-butyl 2-nitro-5-bromopyridine (1.01 g, 5.0 mmol), tert-butyl 2-oxo-4-piperazinecarboxylate (1.00 g, 5.0 mmol, and cesium carbonate (3.26 g, 10.0 mmol) were suspended in 1,4-dioxane, and the suspension was bubbled with nitrogen gas for 30 minutes. To the suspension was added Xantphos (246 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium (229 mg, 0.25 mmol), and the mixture was stirred under reflux for two hours. The resulting reaction mixture was cooled to room temperature, and water and ethyl acetate were then added to the mixture, followed by filtration with Celite®. The organic phase was separated from the filtrate, and the aqueous phase was extracted with ethyl acetate. The resulting organic phases were combined and dried with anhydrous sodium sulfate, and the solid The resultant was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.08 g, 67%). 1H-NMR (CDCl3)d: 8.67 (1H, d, J=2.4 Hz), 8.32 (1H, d, J=8.8 Hz), 8.15 (1H, dd, J= 8.8, 2.4 Hz), 4.33 (2H, s), 3.93-3.83 (4H, m), 1.51 (9H, s). Reference Example 14 Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)-3-oxopiperazine-1-carboxylate [Formula 52]

[00213] The compound synthesized in Reference Example 13 (1.08 g, 3.34 mmol) was dissolved in ethanol (45 mL) and THF (22 mL). Palladium-carbon (108 mg) was added to the solution, and the mixture was stirred under a hydrogen atmosphere for 24 hours. The resulting reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.928 g, 95%).

[00214] 1H-NMR (CDCl3)d: 7.99 (1H, d, J=2.4 Hz), 7.38 (1H, dd, J=8.8, 2.4 Hz), 6.53 (1H, d, J=8.8 Hz), 4.50 (2H, brs), 4.24 (2H, s), 3.78 (2H, t, J=5.1 Hz), 3.67 (2H, t, J=5.4 Hz), 1.50 (9H, s).

[00215] Intermediates D-1 to D-41 were each synthesized by the process of Reference Example 13 and/or 14 with the corresponding halopyridine derivatives and amide derivatives. Appropriate protection or deprotection was carried out if necessary. [Formula 53-1] Reference Example 15 Synthesis of dimethyl-[2-(6-nitropyridin-3-yloxy)ethyl]amine [Formula 54]

[00216] 2-Dimethylaminoethanol (0.32 mL, 3.17 mmol) was dissolved in DMF (4 mL) and cesium carbonate (1.03 g, 3.17 mmol) was added to the suspension, and the resulting suspension was stirred at room temperature for 10 minutes. 5-Fluoro-2-nitropyridine (0.30 g, 2.11 mmol) was added to the suspension at room temperature, and the mixture was then stirred at 80°C for 16 hours. The reaction was monitored by LC/MS. After completion of the reaction, the reaction was inactivated by adding ice-cold water, and the reaction mixture was extracted with ethyl acetate. The resulting organic phase was dried with anhydrous sodium sulfate, and the solid was filtered off. The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.40 g, 90%). Reference Example 16 Synthesis of 5-(2-dimethylaminoethoxy)pyridin-2-ylamine [Formula 55]

[00217] Dimethyl-[2-(6-nitropyridin-3-yloxy)ethyl]amine synthesized in Reference Example 15 (0.40 g, 1.90 mmol) was dissolved in THF (5 mL) and ethanol (5 mL ), and palladium-carbon (80 mg) was added to the solution. The mixture was stirred under a hydrogen atmosphere overnight. The resulting reaction mixture was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The resulting crude product was washed with a solvent mixture of ethyl acetate and hexane (1:9) to give the title compound (0.28 g, 82%).

[00218] Intermediates E-1 to E-61 were each synthesized by the process of Reference Examples 15 and/or 16 with corresponding halopyridine derivatives, alcohol derivatives, or thiol derivatives. Appropriate protection or deprotection was carried out if necessary. [Formula 56] Reference Example 17 Synthesis of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate [Formula 58]

[00219] A solution of 3,6-dichloropyridazine (5.01 g, 33.6 mmol) and tert-butyl piperazine-1-carboxylate (6.88 g, 37.0 mmol) in DMF (50 mL) was added triethylamine (11.7 mL, 50.4 mmol) and the solution was stirred at 80°C overnight. The resulting reaction mixture was cooled to room temperature, and water was added to the mixture. The mixture was extracted three times with a solvent mixture of dichloromethane and methanol (95:5) (50 ml). The resulting organic phases were combined together and dried with anhydrous magnesium sulfate. The resulting solid was separated by filtration, and the filtrate was then concentrated under reduced pressure. The resulting crude product was washed with diethyl ether to give the title compound (7.0 g, 70%). Reference Example 18 Synthesis of tert-butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate [Formula 59]

[00220] tert-Butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate synthesized in Reference Example 17 (59.8 mg, 0.20 mmol, benzophenonaimine (43.5 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (9.2 mg, 0.010 mmol), BINAP (12.5 mg, 0.020 mmol), and cesium carbonate (130.3 mg, 0.40 mmol) were suspended in toluene (1 .0 mL), and the suspension was stirred at 100°C overnight. The resulting reaction mixture was cooled to room temperature and then filtered through Celite®, and the Celite® was washed with sodium acetate. ethyl. The filtrate was washed with saturated brine and dried with anhydrous magnesium sulfate, and the solid was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to yield the compound of the title (67 mg, 76%).Reference Example 19 Synthesis of tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate [Formula 60]

[00221] tert-Butyl 4-(6-((Diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate synthesized in Reference Example 18 (67 mg, 0.151 mmol) was dissolved in THF (0.76 mL). To the solution was added an aqueous solution of citric acid (0.378 mL, 0.755 mmol, 2 mol/L) and the mixture was stirred at room temperature overnight. The resulting reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution (5 mL), and the mixture was extracted twice with ethyl acetate (5 mL). The resulting organic phases were combined together and dried with anhydrous magnesium sulfate, and the resulting solid was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting crude product was washed with methyl tert-butyl ether (5 mL) to give the title compound (30 mg, 71%).

[00222] Intermediates F-1 to F-77 were each synthesized by any of the processes of Reference Examples 17 to 19 or a combination of the processes with corresponding haloheteroaryl derivatives and amine derivatives. Appropriate protection or deprotection was carried out if necessary. [Formula 61]

[00223] Intermediates G-1 to G-12 were each synthesized by any of the processes of Reference Examples 15, 18, and 19 or a combination of the processes with corresponding halopyridazine derivative, as necessary. Reference Example 20 Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperidin-3-ene-1-carboxylate [Formula 64]

[00224] 3-Bromo-6-nitropyridine was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H )-tert-butyl carboxylate under heating in the presence of a palladium catalyst using the process described in J. Med. Chem. 2010, 53, p.7938-7957, to produce the title compound. Reference Example 21 Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate [Formula 65]

[00225] Tert-butyl 4-(6-Nitropyridin-3-yl)piperidin-3-ene-1-carboxylate synthesized in Reference Example 20 was reduced under a hydrogen atmosphere in the presence of palladium-carbon by using the process described in J. Med. Chem. 2010, 53, p.7938-7957 to produce the title compound.

[00226] Intermediates H-1 to H-12 were each synthesized by the process of Reference Examples 20 and/or 21 with the corresponding haloheteroaryl derivative or boric acid derivative. Appropriate protection or deprotection was carried out if necessary. [Formula 66] Reference Example 22

[00227] Intermediate I-1 was synthesized by reacting tert-butyl chlorosulfonylcarbamate with tert-butyl N-[5-(aminoethyl)-2-pyridyl]-N-tert-butoxycarbonylcarbamate synthesized by any of the processes of Reference Examples 8 to 10 or a combination of the processes, and then removing the Boc groups under acidic conditions. [Formula 67] Reference Example 23

[00228] Intermediate J-1 was synthesized by reacting potassium isocyanate with tert-butyl N-tert-butoxycarbonyl-N-[5-(N-methylaminoethyl)-2-pyridyl]carbamate synthesized as in the Reference Examples 8 to 10, and the removal of Boc groups under acidic conditions. [Formula 68]

[00229] Intermediate J-2 was synthesized by hydrogen reduction of the nitro group of 5-amino-2-nitropyridine in the presence of palladium hydroxide/activated carbon by the process of Reference Example 23. [Formula 69] Reference Example 24

[00230] Intermediate K-1 was synthesized by reacting isocyanatoethane with tert-butyl N-[5-(aminoethyl)-2-pyridyl]-N-tert-butoxycarbonylcarbamate synthesized by any of the processes in Reference Examples 8 to 10 or a combination of the processes, and the removal of Boc groups under acidic conditions. [Formula 70] Reference Example 25

[00231] Intermediate L-1 was synthesized by reacting 2-methoxyethyl bromide with tert-butyl N-[5-(aminoethyl)-2-pyridyl]-N-tert-butoxycarbonylcarbamate synthesized by any of the processes of Reference Examples 8 to 10 or a combination of the processes, removing the Boc groups under acidic conditions, and selectively protecting the secondary amino moiety with a Boc group as in Reference Example 11. [Formula 71] Reference Example 26

[00232] Intermediate M-1 was synthesized by esterifying the carboxylic portion of 2-(6-chloropyridin-3-yl)acetic acid, dimethylating the carbonyl group in the a-position, reducing the ester portion with LAH, oxidizing the alcohol moiety, reductive amination with methylamine, moiety with a Boc group, amination of the 2-chloropyridine moiety in the presence of a Pd catalyst, and deprotection. [Formula 72] Reference Example 27

[00233] Intermediate N-1 was synthesized by reacting 5-bromo-2-nitropyridine with tert-butyl cyanoacetate under basic conditions, removing the tert-butyl group and decarboxylation under acidic conditions, and reducing the cyano group. [Formula 73] Reference Example 28

[00234] Intermediate O-1 was synthesized by reacting an alkyne derivative with an imide derivative, subsequent reaction with 5-bromo-2-nitropyridine under Sonogashira coupling reaction conditions, and reduction with hydrogen in the presence of hydroxide palladium/activated carbon, involving protection and deprotection. [Formula 74] Reference Example 29

[00235] Intermediate P-1 was synthesized by acylation of 2-(6-nitropyridin-3-yl)ethylamine and reduction with hydrogen in the presence of palladium hydroxide/activated carbon. [Formula 75]

[00236] Intermediates P-2 to P-17 were each synthesized by the process of Reference Example 29 with the corresponding amine derivative synthesized, for example, by any of the processes of Reference Examples 8 to 10 and the corresponding acylating agent, involving appropriate deprotection if necessary. Appropriate acylation conditions were selected depending on the structure to be introduced. For example, an acid chloride or a combination of a carboxylic acid and a condensing agent was used as the acylating agent in place of an acid anhydride. Reference Example 30

[00237] Intermediate Q-1 was synthesized by mesylation of 2-(6-nitropyridin-3-yl)ethylamine and reduction with hydrogen in the presence of palladium hydroxide/activated carbon. [Formula 77]

[00238] Intermediates Q-2 to Q-9 were each synthesized by the process of Reference Example 29 with the corresponding derivative synthesized, for example, by any of the processes of Reference Examples 8 to 10, involving deprotection appropriate if necessary. [Formula 78] Reference Example 31

[00239] Intermediate R-1 was synthesized by reacting 5-bromo-2-nitropyridine with an alkyne derivative under conditions of Sonogashira coupling reaction, protection and reduction with hydrogen in the presence of palladium hydroxide/activated carbon, involving protection and lack of protection. [Formula 79]

[00240] Intermediates R-2 to R-6 were each synthesized by the process of Reference Example 31; that is, by reactions 1) to 3) in Reference 31 with a halopyridine derivative and the corresponding terminal alkyne derivative.

[00241] Reference Example 32 Intermediate S-1 was synthesized through mesylation of intermediate R-1 synthesized in Reference Example 31, reaction with an amide derivative under basic conditions and subsequent deprotection. [Formula 81]

[00242] Intermediates S-2 and S-3 were each synthesized by the process of Reference Example 32 with the corresponding alcohol derivative, amide derivative, or sulfonamide derivative. [Formula 82] Reference Example 33

[00243] Intermediate T-1 was synthesized through basic hydrolysis of methyl 6-((tert-butoxycarbonyl)amino)nicotinate, condensation with morpholine, and deprotection. [Formula 83]

[00244] Intermediates T-2 to T-17 were each synthesized by the process of Reference Example 33 with the corresponding ester derivative synthesized, for example, by the process of Reference Example 31, or with the corresponding derivative of carboxylic acid and amine derivative. Appropriate protection and deprotection were carried out if necessary. [Formula 84] Reference Example 34

[00245] Intermediate U-1 was synthesized by the oxidation of 5-((3-((tert-butyldimethylsilyl)oxy)propyl)thio)-2-nitropyridine synthesized by the process of Reference Example 15 with m-chloroperbenzoic acid and reduction with hydrogen in the presence of palladium hydroxide/activated carbon. [Formula 85] Reference Example 35

[00246] Intermediate V-1 was synthesized by reacting 5-amino-2-nitropyridine with sodium azide and orthoformate and subsequent reduction with hydrogen in the presence of palladium hydroxide/activated carbon. [Formula 86] Reference Example 36

[00247] Intermediate W-1 was synthesized through the reaction of 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-tert-butyl carboxylate and with benzophenonaimine and tert-butyl sodium in the presence of a Pd catalyst and deprotection. [Formula 87]

[00248] Intermediates W-2 to W-4 were each synthesized by the process of Reference Example 36 with the corresponding halopyridine derivative. [Formula 88] Example 1 Synthesis of 3-(4-formyl-2-methylthiopyrimidin-5-yl)-2-propynyl benzoate [Formula 89]

[00249] A solution of Pd(PhCN)2Cl2 (2.4 g, 6.4 mmol), copper iodide (0.82 g, 4.3 mmol), and [(t-Bu)3P]HBF4 (4 g, 13.9 mmol) in 1,4-dioxane (55 mL) was degassed and purged with argon, and diisopropylamine (18.5 mL, 128.8 mmol) was added to the solution at room temperature. The resulting reaction mixture was stirred at room temperature for five minutes. A solution of a mixture (25 g, crude product) of 5-bromo-2-methylsulfanylpyrimidine-4-carbaldehyde and (5-bromo-2-methylsulfanylpyrimidin-4-yl)methoxymethanol described in Reference Example 3 and propargyl benzoate ( 20 g, 128.8 mmol) in 1,4-dioxane (55 mL) was slowly added dropwise to the reaction mixture, and the reaction mixture was then stirred at room temperature for five hours. The reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (1 L). The mixture was subjected to suction filtration through Celite®, and the Celite® was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting crude product was used directly in the subsequent reaction. Example 2 Synthesis of 6-((benzo)methyl)-2-(methylthio)pyrido [3,4-d]pyrimidine 7-oxide [Formula 90]

[00250] The crude product of 3-(4-formyl-2-methylthiopyrimidin-5-yl)-2-proponyl benzoate synthesized in Example 1 was dissolved in ethanol (500 mL), and hydroxylamine hydrochloride (8.3 g , 120 mmol) and sodium acetate (10 g, 120 mmol) were added to the solution at room temperature. The resulting reaction mixture was stirred at room temperature for six hours, and then diluted with ethanol (1 L). Potassium carbonate (27.8 g, 200 mmol) was added to the mixture, and the mixture was then stirred at 50°C for three hours. The reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was subjected to suction filtration through Celite®, and the Celite® was washed with ethyl acetate. The filtrate was dried with anhydrous sodium sulfate, and the solid was filtered off. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to yield the title compound (5.0 g, 16%). Example 3 Synthesis of 8-chloro-2-methylthiopyrido [3,4-d]pyrimidin-6-yl benzoate [Formula 91]

[00251] 6-((Benzoyloxy)methyl)-2-(methylthio)pyrido [3,4-d]pyrimidine 7-oxide synthesized in Example 2 (5.0 g, 15.3 mmol) was dissolved in dichloromethane (60 mL) and the solution was cooled to 0°C. Thionyl chloride (25 mL, 343 mmol) was added dropwise to the solution at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, followed by azeotropic distillation twice with toluene (20 mL) to remove thionyl chloride. The residue was approximately purified by neutral alumina column chromatography to yield the title compound (2.75 g, 52%). Example 4 Synthesis of (R)-1-(2-(methylthio)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido [3,4-d]pyrimidin benzoate -6-yl)ethyl [Formula 92]

[00252] A mixture of (R)-1-(8-chloro-2-(methylthio)pyrido [3,4-d]pyrimidin-6-yl)ethyl benzoate synthesized by the process described in Example 3 (360 mg, 1.0 mmol), (S)-tetrahydro-2H-pyran-3-amine hydrochloride (206 mg, 1.5 mmol), and potassium carbonate (415 mg, 3.0 mmol) in 1.4 -dioxane (4.0 mL) was stirred at 100°C overnight. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with water, and the mixture was extracted twice with ethyl acetate (10 mL). The resulting organic phase was washed with brine and dried with anhydrous magnesium sulfate. The solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to yield the title compound (232 mg, 55%). 1H-NMR (CDCl3)d: 8.97 (1H, s), 8.17-8.14 (2H, m), 7.62-7.57 (1H, m), 7.517.46 (2H, m ), 6.87 (1H, s), 6.65 (1H, d, J=7.8 Hz), 6.10 (1H, q, J=6.7 Hz), 4.39-4.31 (1H, m), 4.08-4.03 (1H, m), 3.82-3.76 (1H, m), 3.70-3.64 (1H, m), 3.56-3 .51 (1H, m), 2.65 (3H, s), 2.09-2.02 (1H, m), 1.89-1.78 (2H, m), 1.761.65 (4H, m )

[00253] CL/MS: (M+H)+=425.2, C22H24N4O3S=424.16 Example 5 Synthesis of 2-methylthio-8-(propan-2-yl)aminopyrido [3,4-d]pyrimidin- 6-ylmethanol [Formula 93]

[00254] 8-isopropylamino-2-methylthiopyrido [3,4-d]pyrimidine-6-yl benzoate synthesized by the process described in Example 4 (3.7 g, 10.0 mmol) was dissolved in methanol (20 mL ) and THF (20 mL), and an aqueous solution (10 mL) of lithium hydroxide (0.96 g, 40 mmol) was added dropwise to the solution at room temperature. The resulting reaction mixture was stirred at room temperature for one hour. The reaction was monitored by LC/MS. After completion of the reaction, hydrochloric acid (2 mol/L) was added dropwise to the reaction mixture to adjust the pH of the mixture to 7. The resulting solid was separated by filtration and dried under reduced pressure to yield the title compound. (2.55 g, 96%).

[00255] Example 6 Synthesis of 2-methylthio-8-(propan-2-yl)aminopyrido [3,4-d]pyrimidine-6-carbaldehyde [Formula 94]

[00256] 2-Methylthio-8-(propan-2-yl)aminopyrido [3,4-d]pyrimidin-6-ylmethanol synthesized in Example 5 (3.1 g, 11.7 mmol) was dissolved in dichloromethane ( 30 mL) and the solution was stirred at 0°C. Dess-Martin periodinane (15 g, 35.2 mmol) was gradually added to the solution at 0 ° C, and the reaction mixture was stirred at room temperature for three hours. The reaction was monitored by LC/MS. After completion of the reaction, the reaction was inactivated by adding an aqueous solution of sodium thiosulfate to reduce the excess reagent. The aqueous phase was extracted three times with dichloromethane (50 mL). The resulting organic phases were combined together and dried with anhydrous sodium sulfate. The solid was separated by filtration, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.9 g, 94%). Example 7 Synthesis of 6-difluoromethyl-2-methylthio-N-(propan-2-yl)pyrido [3,4-d]pyrimidine-8-amine [Formula 95]

[00257] The 2-methylthio-8-(propan-2-yl)aminopyrido [3,4-d]pyrimidine-6-carbaldehyde synthesized in Example 6 (2.9 g, 11.1 mmol) was dissolved in dichloromethane ( 30 mL) and the solution was stirred at 0°C. DAST (7.1 g, 44.2 mmol) was gradually added to the solution at 0 ° C, and the reaction mixture was stirred at room temperature for three hours. The reaction was monitored by LC/MS. After completion of the reaction, the reaction was inactivated by the addition of saturated aqueous sodium carbonate solution (20 mL). The aqueous phase was extracted three times with dichloromethane (50 mL). The resulting organic phases were combined together and dried with anhydrous sodium sulfate. The solid was separated by filtration, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.37 g, 75%).

[00258] The compounds Intermediate-1 (Int-1) to Intermediate-8 (Int-8) were synthesized by the process described in Example 4 or Examples 5 to 7 in an appropriate order depending on the substituents. [Table 1-1] Example 8 Synthesis of (R)-1-(2-(methylsulfonyl)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido [3,4-d]pyrimidin benzoate -6-yl)ethyl [Formula 96]

[00259] (R)-1-(2-(methylthio)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido [3,4-d]pyrimidin benzoate -6-yl)ethyl synthesized in Example 4 (232 mg, 0.55 mmol) and Oxone® (672 mg, 1.09 mmol) were added to THF (2.7 mL) and water (2.7 mL) and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC/MS. After completion of the reaction, saturated aqueous sodium hydrogen carbonate solution was slowly added to the reaction mixture, and the aqueous phase was extracted three times with ethyl acetate. The resulting organic phases were combined together and washed with saturated brine, and then dried with anhydrous magnesium sulfate. The solid was separated by filtration, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield the crude product of the title compound (245 mg, 98%). 1H-NMR (CDCl3)d: 9.30 (1H, s), 8.16 (2H, d, J=7.3 Hz), 7.65-7.60 (1H, m), 7.53- 7.48 (2H, m), 7.02 (1H, s), 6.87 (1H, d, J=7.8 Hz), 6.13 (1H, q, J=6.7 Hz), 4.45-4.36 (1H, m), 4.08-4.04 (1H, m), 3.85-3.80 (1H, m), 3.67-3.60 (1H, m ), 3.52-3.47 (1H, m), 3.41 (3H, s), 2.14-2.07 (1H, m), 1.90-1.74 (6H, m).

[00260] CL/MS: (M+H)+=457.2, C22H24N4O5S=456.15 Example 9 Synthesis of (R)-1-(8-(1-methoxy-2-methylpropan-2-ylamino)- (Methylsulfinyl)pyrido[3,4-d]pyrimidin-6-yl)ethyl 2-benzoate [Formula 97]

[00261] (R)-1-(8-(1-methoxy-2-methylpropan-2-ylamino)-2-(methylthio)pyrido [3,4-d]pyrimidin-6-yl)ethyl benzoate synthesized by process described in Example 7 (1.9 g, 4.46 mmol) was dissolved in dichloromethane (30 mL) and the solution was stirred at 0°C. m-CPBA (0.767 g, 4.46 mmol) was gradually added to the solution at 0 ° C, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC/MS. After completion of the reaction, the reaction was inactivated by adding an aqueous solution of sodium thiosulfate to reduce the excess reagent. The aqueous phase was extracted three times with dichloromethane (30 mL). The resulting organic phases were combined together and washed once with saturated aqueous sodium hydrogen carbonate solution (50 ml) and once with saturated brine (50 ml). The organic phase was dried with anhydrous sodium sulfate, and the solid was filtered off. The filtrate was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.9 g, 96%).

[00262] The compounds Intermediate-9 (Int-9) to Intermediate-16 (Int-16) were synthesized by the process described in Example 8 or 9. [Table 2] Example 10 Synthesis of (R)-1-(5-chloro-2-(methylsulfonyl)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido benzoate [3.4 -d]pyrimidin-6-yl)ethyl [Formula 98]

[00263] A mixture of (R)-1-(2-(methylsulfonyl)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido benzoate [3,4-d ]pyrimidin-6-yl)ethyl synthesized in Example 8 (268 mg, 0.587 mmol) and N-chlorosuccinimide (96 mg, 0.72 mmol) in 1,2-dichloroethane (2.9 mL) was stirred at 65°C overnight. The reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was directly purified by silica gel column chromatography to yield the title compound (255 mg, 89%). 1H-NMR (CDCl3)d: 9.70 (1H, s), 8.11-8.06 (2H, m), 7.60-7.53 (1H, m), 7.487.42 (2H, m ), 6.90 (1H, d, J=7.8 Hz), 6.46 (1H, q, J=6.7 Hz), 4.28-4.18 (1H, m), 3.82 (1H, dd, J=11.5, 3.2 Hz), 3.76-3.69 (1H, m), 3.65-3.56 (1H, m), 3.45-3.37 (4H, m), 2.09-2.00 (1H, m), 1.88-1.61 (6H, m).

[00264] Intermediate Compound-17 (Int-17) was synthesized by the process described in Example 10. [Table 3] Example 11 Synthesis of tert-butyl 4-[6-(6-difluoromethyl-8-isopropylaminopyrido [3,4-d]pyrimidin-2-ylamino)pyridin-3-yl]piperazine-1-carboxylate [Formula 99]

[00265] Tert-Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate synthesized in Reference Example 5 (88 mg, 0.316 mmol) was dissolved in THF (3.5 mL), and hydride Sodium (22.8 mg, 0.57 mmol, 60%) was added to the solution at 0°C and stirred for 10 minutes. To the suspension was added a solution of the (6-difluoromethyl-2-methanesulfonylpyrido[3,4-d]pyrimidin-8-yl)isopropylamine synthesized in Example 8 (Int-11, 100 mg, 0.316 mmol) in THF (3.5 mL) at room temperature and the reaction mixture was stirred at 35°C for one hour. The reaction was monitored by TLC and LC/MS. After completion of the reaction, the reaction was inactivated by the addition of ice-cold water (10 mL). The aqueous phase was extracted twice with ethyl acetate (25 mL). The resulting organic phases were combined together and washed with saturated brine, and the mixture was dried with anhydrous sodium sulfate. The solid was separated by filtration, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (56.7 mg, 35%). Example 12 Synthesis of 6-difluoromethyl-8-isopropyl-2-(5-piperazin-1-ylpyridin-2-yl)pyrido [3,4-d]pyrimidine-2,8-diamine (compound 3) [Formula 100]

[00266] Tert-butyl 4-[6-(6-difluoromethyl-8-isopropylaminopyrido [3,4-d]pyrimidin-2-ylamino)pyridin-3-yl]piperazine-1-carboxylate synthesized in Example 11 ( 195 mg, 0.378 mmol) was dissolved in dichloromethane (5 mL) and stirred at 0°C. Hydrogen chloride (0.4 mL, 4 mol/L, solution in 1,4-dioxane) was added dropwise to the solution and stirred at room temperature for 30 minutes. The reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by fractionation HPLC (acetonitrile/water/TFA) to yield a TFA salt of the title compound (114 mg, purity: 99% or greater). The TFA salts obtained by the multiple reactions were combined and used in the next step.

[00267] TFA salt (200 mg) was dissolved in methanol (0.625 mL) and dichloromethane (1.875 mL) and applied to a strong cation exchange resin (SCX) column. The SCX column was washed with a solvent mixture of methanol and dichloromethane (1:3). The target compound was subsequently eluted from the SCX column with a solvent mixture of methanol and dichloromethane (1:3) containing 2.5% ammonia (2 mol/L, solution in methanol). The eluate was concentrated under reduced pressure to yield the title compound (105 mg, purity: >99%). Example 13 Synthesis of (R)-4-(6-(6-(benzoyloxy)ethyl-8-(1-methoxy-2-methylpropan-2-ylamino)pyrido [3,4-d]pyrimidin-2-ylamino) tert-butyl pyridin-3-yl)piperazine-1-carboxylate [Formula 101]

[00268] (R)-1-(8-(1-methoxy-2-methylpropan-2-ylamino)-2-benzoate of (methylsulfinyl)pyrido [3,4-d]pyrimidin-6-yl)ethyl synthesized in Example 9 (1.9 g, 4.3 mmol) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate synthesized in Reference Example 5 (3.59 g, 12.0 mmol) 9 mmol) were suspended in toluene (30 mL) and the reaction mixture was stirred at 120°C overnight. The reaction was monitored by LC/MS. The resulting reaction mixture was cooled to room temperature, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (850 mg, 30%). Example 14 Synthesis of (R)-1-(8-(1-methoxy-2-methylpropan-2-ylamino)-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido [3.4 -d]pyrimidin-6-yl)ethanol (compound 195) [Formula 102]

[00269] O (R)-4-(6-(6-(benzoyloxy)ethyl-8-(1-methoxy-2-methylpropan-2-ylamino)pyrido [3,4-d]pyrimidin-2-ylamino) Tert-butyl pyridin-3-yl)piperazine-1-carboxylate synthesized in Example 13 (850 mg, 1.3 mmol) was dissolved in THF (15 mL) and methanol (15 mL), and lithium hydroxide (124 mg , 5.2 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature overnight, and the reaction was monitored by LC/MS. After completion of the reaction, hydrogen chloride (4 mol/L, solution in methanol) was added dropwise to the reaction mixture, to adjust the pH of the mixture to 7. The reaction mixture was concentrated under reduced pressure to yield the product gross. The crude product was used in the subsequent reaction without purification.

[00270] The crude product was dissolved in hydrogen chloride (20 mL, 4 mol/L, methanol solution) and stirred at room temperature for four hours. The reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (30 mL), and concentrated aqueous ammonia (25%) was added dropwise to the solution to adjust the pH of the solution to 10 or higher. Saturated brine (100 mL) was added to the solution, and the mixture was extracted three times with a solvent mixture of dichloromethane and methanol (9:1) (30 mL). The resulting organic phases were combined together and washed once with saturated brine (50 ml). The organic phase was dried with anhydrous sodium sulfate, and the solid was filtered off. The filtrate was concentrated under reduced pressure to yield the crude product of the title compound. The crude product was then washed with methanol to give the title compound (470 mg, 80%). Example 15 Synthesis of (S)-1-(4-(6-((6-((R)-1-hydroxyethyl)-8-(isopropylamino)pyrido [3,4-d]pyrimidin-2-yl)amino )pyridazin-3-yl)piperazin-1-yl)propan-2-ol (compound 676) [Formula 103]

[00271] (R)-1-(8-(isopropylamino)-2-((6-(piperazin-1-yl)pyridazin-3-yl)amino)pyrido [3,4-d]pyrimidin-6-yl )ethanol synthesized by the process described in Example 14 (compound 261, 25 mg, 0.061 mmol) was dissolved in methanol (0.31 mL), and (S)-propylene oxide (3.5 mg, 0.061 mmol) was added to the solution. The resulting reaction mixture was stirred at 55°C overnight, and the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting crude product was purified by fractionation HPLC (acetonitrile/water/TFA) and applied to a strong cation exchange resin (SCX) column. The SCX column was washed with methanol, and the target product was then eluted with ammonia (2 mol/L, methanol solution). The eluate was concentrated under reduced pressure to give the title compound (19 mg). Example 16 Synthesis of (R)-1-(8-(isopropylamino)-2-((6-(4-(oxetan-3-yl)piperazin-1-yl)pyridazin-3-yl)amino)pyrido [3 ,4-d]pyrimidin-6-yl)ethanol (compound 682) [Formula 104]

[00272] (R)-1-(8-(isopropylamino)-2-((6-(piperazin-1-yl)pyridazin-3-yl)amino)pyrido [3,4-d]pyrimidin-6-yl )ethanol synthesized by the process described in Example 14 (compound 261, 16.4 mg, 0.040 mmol) was dissolved in acetic acid (2.8 µL) and 1,2-dichloroethane (0.4 mL). To the mixture was added 3-oxetanone (2.8 µL, 0.048 mmol) and sodium triacetoxyborohydride (12.7 mg, 0.060 mmol). The resulting reaction mixture was stirred at 55°C for two hours, and the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction was inactivated by adding water. The reaction mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting crude product was then purified by amine modified column chromatography (ethyl acetate/methanol) to give the title compound (7.5 mg). Example 17 Synthesis of acid (R)-3-(4-(6-((8-(isopropylamino)-6-(1-methoxyethyl)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridazin- 3-yl)piperazin-1-yl)propanoic acid (compound 684) [Formula 105]

[00273] (R)-N8-isopropyl-6-(1-methoxyethyl)-N2-(6-(piperazin-1-yl)pyridazin-3-yl)pyrido [3,4-d]pyrimidine-2,8 -diamine synthesized by the process described in Example 14 (compound 217, 29.6 mg, 0.07 mmol) was dissolved in methanol (0.35 mL), and methyl acrylate (6.3 µL, 0.07 mmol) was added to the solution. The resulting reaction mixture was stirred at 55°C for two hours, and the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was approximately purified by silica gel column chromatography (ethyl acetate/heptane). The crude product was then dissolved in THF (0.56 mL) and methanol (0.56 mL), and 4M aqueous lithium hydroxide solution (0.028 mL, 0.112 mmol) was added to the solution. The resulting reaction mixture was stirred at room temperature overnight, and the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was acidulated with 2M aqueous hydrochloric acid solution and then adsorbed on a strong cation exchange resin (SCX) column. The SCX column was washed with water and dichloromethane, and the target product was then eluted with ammonia (2 mol/L, methanol solution). The eluate was concentrated under reduced pressure to give the title compound (27.5 mg).

[00274] Example 18 Synthesis of (R)-2-(4-(6-((8-(isopropylamino)-6-(1-methoxyethyl)pyrido [3,4-d]pyrimidin-2-yl)amino acid )pyridazin-3-yl)piperazin-1-yl)-2-methylpropanoic acid (compound 678) [Formula 106]

[00275] (R)-N8-isopropyl-6-(1-methoxyethyl)-N2-(6-(piperazin-1-yl)pyridazin-3-yl)pyrido [3,4-d]pyrimidine-2,8 -diamine synthesized by the process described in Example 14 (compound 217, 42.3 mg, 0.10 mmol) was dissolved in acetonitrile (0.2 mL). To the mixture were added tert-butyl 2-bromo-2-methylpropanoate (22.4 µL, 0.12 mmol) and potassium carbonate (16.6 mg). The resulting reaction mixture was stirred at 85°C overnight, and the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was cooled to room temperature, and the reaction was inactivated by adding water. The reaction mixture was extracted with ethyl acetate, and the resulting crude product was briefly purified by silica gel column chromatography (ethyl acetate/heptane). The crude product was then dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added to the solution. The resulting reaction mixture was stirred at room temperature for 24 hours, and the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was adsorbed on a strong cation exchange resin (SCX) column. The SCX column was washed with methanol, and the target product was then eluted with ammonia (2 mol/L, methanol solution). The eluate was concentrated under reduced pressure to give the title compound (8.5 mg). Example 19

[00276] Compounds 1 to 1239 were synthesized by the processes described in Examples 11 to 18. [Table 4-1]

[00277] *: SEPARATE COMPOUNDS AS OPTICALLY ACTIVE ISOMERS VIA HPLC purification with a chiral column (note: absolute configuration is not determined). Abbreviations: DEA: diethylamine, TEA = triethylamine, DCM: dichloromethane, AIP: isopropyl alcohol, TR = Retention Time (1) Compound 581: DAICEL CHIRALPAK AD 5µm, n-hexane/MeO-H/AIP, TR = 12.31 min.: optically active isomer with shorter retention time; (2) Compound 582: DAICEL CHIRALPAK AD 5µm, n-hexane/MeO-H/AIP, RT = 15.35 min.: optically active isomer with longer retention time; (3) Compound 671: CHIRALPAK IA-3µm, 100%EtO-H, RT= 4.388min.: optically active isomer with shorter retention time; (4) Compound 672: CHIRALPAK IA-3µm, 100%EtO-H, RT= 6,490 min.: optically active isomer with longer retention time; (5) Compound 689: DAICEL CHIRALPAK AD-H 5µm, n-hexane/EtO-H, TR = 17.61 min.: optically active isomer with shorter retention time; (6) Compound 690: DAICEL CHIRALPAK AD-H 5µm, n-hexane/EtO-H, RT = 20.71 min.: optically active isomer with longer retention time; (7) Compound 704: CHIRALPAK AD-3µm, Hexane (0.2%TEA)/EtO-H=50:50, TR = 6.446 min.: optically active isomer with longer retention time. (8) Compound 705: CHIRALPAK AD-3µm, Hexane (0.2%TEA)/EtO-H=50:50, TR = 4.679 min.: optically active isomer with shorter retention time; (9) Compound 713: CHIRALPAK IA-3µm, 100%MeO-H (0.1%DEA), TR = 3.628 min.: optically active isomer with longer retention time; (10) Compound 714: CHIRALPAK IA-3µm, 100%MeO-H (0.1%DEA), TR = 2.533 min.: optically active isomer with shorter retention time; (11) Compound 724: CHIRALPAK AD-3, Hexane (0.1%DEA)/EtO-H = 50:50, TR = 4.32 min.: optically active isomer with shorter retention time; (12) Compound 725: CHIRALPAK AD-3, Hexane (0.1%DEA)/EtO-H = 50:50, RT = 5.06 min.: optically active isomer with longer retention time; (13) Compound 729: CHIRALPAK IA-3, 0.46*5cm; 3µm, Hexane (0.1%AIP)/EtO-H = 50:50, TR = 4.01 min.: optically active isomer with longer retention time; (14) Compound 730: CHIRALPAK IA-3, 0.46*5cm; 3µm, Hexane (0.1%AIP)/EtO-H = 50:50, TR = 1.68 min.: optically active isomer with shorter retention time; (15) Compound 735: DAICEL CHIRALPAK AD-H 5µm, Hexane/AIP = 90/10, TR = 9.18 min.: optically active isomer with shorter retention time; (16) Compound 736: DAICEL CHIRALPAK AD-H 5µm, Hexane/AIP = 90/10, TR = 10.65 min.: optically active isomer with longer retention time; (17) Compound 773: DAICEL CHIRALPAK IA 5µm, MeO-H/AIP = 6/4, TR = 17.90 min.: optically active isomer with shorter retention time; (18) Compound774: DAICEL CHIRALPAK IA 5µm, MeO-H/AIP = 6/4, TR = 21.84 min.: optically active isomer with longer retention time. (19) Compound 775: DAICEL CHIRALPAK IA 5µm, Hexane/MeO-H/AIP = 6/1/1, TR = 10.25 min.: optically active isomer with shorter retention time; (20) Compound776: DAICEL CHIRALPAK IA 5µm, Hexane/MeO-H/AIP = 6/1/1, TR = 14.71 min.: optically active isomer with longer retention time; (21) Compound 809: DAICEL CHIRALPAK AD-H 5µm, 4.6*250mm, n-Hexane/EtO-H/MeO-H = 70/15/15, TR = 21.62 min.: optically active isomer with time shorter retention period; (22) Compound 810: DAICEL CHIRALPAK AD-H 5µm, 4.6*250mm, n-Hexane/EtO-H/MeO-H = 70/15/15, TR = 25.87 min.: optically active isomer with time longer retention; (23) Compound 865: CHIRALPAK IA-3; 0.46*5cm; 3µm; Hexane (0.1%DEA)/EtO-H = 70:30, TR = 4.81 min.: optically active isomer with shorter retention time; (24) Compound 866: CHIRALPAK IA-3; 0.46*5cm; 3µm; Hexane (0.1%DEA)/EtO-H = 70:30, TR = 5.48 min.: optically active isomer with longer retention time; (25) Compound 869: CHIRALPAK IA-3; 0.46*5cm; 3µm; Hexane (0.1%DEA)/EtO-H = 60:40, RT = 2.27 min.: optically active isomer with shorter retention time; (26) Compound 870: CHIRALPAK IA-3; 0.46*5cm; 3µm; Hexane (0.1%DEA)/EtO-H = 60:40, TR = 2.93 min.: optically active isomer with longer retention time; (27) Compound 875: DAICEL CHIRALPAK AD-H 5µm, Hexane/MeO-H/EtO-H = 80/10/10, TR = 22.30 min.: optically active isomer with shorter retention time; (28) Compound 876: DAICEL CHIRALPAK AD-H 5µm, Hexane/MeO-H/EtO-H = 80/10/10, TR = 29.24 min.: optically active isomer with longer retention time; (29) Compound 938: DAICEL CHIRALPAK AD-H 5µm, (100%EtO-H+0.1%DEA), TR = 33.58 min.: optically active isomer with shorter retention time; (30) Compound939: DAICEL CHIRALPAK AD-H 5µm, (100%EtO-H+0.1%DEA), TR = 42.68 min.: optically active isomer with longer retention time; (31) Compound 940: DAICEL CHIRALPAK AD-H 5µm, (Hexane/MeO-H/EtO-H +0.1%DEA = 6/2/2), TR = 20.23 min.: optically active isomer with time shorter retention period; (32) Compound 941: DAICEL CHIRALPAK AD-H 5µm, (Hexane/MeO-H/EtO-H +0.1%DEA = 6/2/2), TR = 22.07 min.: optically active isomer with time longer retention; (33) Compound 942: DAICEL CHIRALPAK AD-H 5µm, (Hexane/MeO-H/EtO-H +0.1%DEA = 6/2/2), TR = 13.99 min.: optically active isomer with time shorter retention period; (34) Compound 943: DAICEL CHIRALPAK AD-H 5µm, (Hexane/MeO-H/EtO-H +0.1%DEA = 6/2/2), TR = 15.66 min.: optically active isomer with time longer retention; (35) Compound 989: CHIRALPAK IA, n-Hexane/EtO-H = 70/30, TR = 13.32 min.: optically active isomer with shorter retention time; (36) Compound 990: CHIRALPAK IA, n-Hexane/EtO-H = 70/30, TR = 16.69 min.: optically active isomer with longer retention time; (37) Compound 992: CHIRALPAK IA-3: 0.46*5cm; 3µm, Hexane (0.1%DEA)/EtO-H = 50:50, 1.5ml/min, RT = 1.87 min.: optically active isomer with shorter retention time; (38) Compound 993: CHIRALPAK IA-3: 0.46*5cm; 3µm, Hexane (0.1%DEA)/EtO-H = 50:50, 1.5ml/min, TR = 3.56 min.: optically active isomer with longer retention time; (39) Compound 1025: CHIRALPAK IA, 0.46*25cm; 5µm, MeO-H (0.1%DEA)/DCM = 75:25, 1.0mL/min., TR = 6.597 min.: optically active isomer with shorter retention time; (40) Compound 1026: CHIRALPAK IA, 0.46*25cm; 5µm, MeO-H (0.1%DEA)/DCM = 75:25, 1.0mL/min., TR = 8.199 min.: optically active isomer with longer retention time; (41) Compound 1034: CHIRALPAK AS-3, 0.46*10cm; 3µm, Hexane (0.1%DEA)/(MeO-H/EtO-H = 1:1) = 70:30, 1.0mL/min., TR = 6.23 min.: optically active isomer with shorter retention; (42) Compound 1035: CHIRALPAK AS-3, 0.46*10cm; 3µm, Hexane (0.1%DEA)/(MeO-H/EtO-H = 1:1) = 70:30, 1.0mL/min., TR = 9.94 min.: optically active isomer with longer retention; (43) Compound 1036: CHIRALPAK IC-3, 0.46*10cm; 3µm, DCM (0.1%DEA)/MeO-H = 20:80, 1.0mL/min., TR = 5.10 min.: optically active isomer with shorter retention time; (44) Compound 1037: CHIRALPAK IC-3, 0.46*10cm; 3µm, DCM (0.1%DEA)/MeO-H = 20:80, 1.0mL/min., TR = 5.95 min.: optically active isomer with longer retention time; (45) Compound 1066: CHIRALPAK IC-3, 0.46*10cm; 3µm, MeO-H (0.1%DEA)/DCM = 95:5, 1.0ml/min., TR = 5.421 min.: optically active isomer with shorter retention time; (46) Compound 1067: CHIRALPAK IC-3, 0.46*10cm; 3µm, MeO-H (0.1%DEA)/DCM = 95:5, 1.0ml/min., TR = 6.00 min.: optically active isomer with longer retention time; (47) Compound 1068: CHIRALPAK IC, 0.46*25cm; 5µm, MeO-H (0.1%DEA)/DCM = 90:10, 1.0ml/min., TR = 17.429 min.: optically active isomer with shorter retention time; (48) Compound 1069: CHIRALPAK IC, 0.46*25cm; 5µm, MeO-H (0.1%DEA)/DCM = 90:10, 1.0ml/min., TR = 20.57 min.: optically active isomer with longer retention time; (49) Compound 1088: CHIRALPAK IA, n-Hexane/EtO-H/MeO-H = 50/25/25, 1.0 mL/min., TR = 15.21 min.: optically active isomer with retention time shorter; (50) Compound 1089: CHIRALPAK IA, n-Hexane/EtO-H/MeO-H = 50/25/25, 1.0 mL/min., TR = 18.59 min.: optically active isomer with retention time longer.

[00278] *: Compound separated as diastereoisomers via reversed-phase HPLC purification (note: absolute configuration is not determined); (1) Compound 831: C-18: RT = 1.67 min.: diastereoisomer with shorter retention time; (1) Compound 832: C-18: TR = 1.71 min.: diastereoisomer with longer retention time.

[00279] *: Compound represented its relative configurations of two substituents; Compound-No.: 577, 607, 608, 609, 610, 618, 619, 621, 622, 645, 646, 647, 673, 708, 739, 742, 799, 801, and 864. [Table 5-1

Example 20 Inhibitory activity against human CDK4/cyclin D3

[00280] Each compound was analyzed for inhibitory activity against CDK4/cyclin D3 with an assay kit (“QS S Assist CDK4/Cyclin D3_FP Kit”, available from Carna Biosciences, Inc.). This assay kit determines kinase activity based on IMAP® (“Immobilized Metal Affinity Phosphorylation”) Technology from Molecular Devices. Specifically, kinase activity is determined by quantifying a change in fluorescent polarization caused by the binding of a kinase-phosphorylated fluorescent substance to an IMAP-binding reagent.

[00281] Each solution was prepared with the 10x assay buffer included in the kit or a separately prepared assay buffer having the same composition as the assay buffer included in the kit. An assay buffer was prepared by 10-fold dilution of the 10x assay buffer with distilled water. The assay buffer contains 20mM HEPES (pH 7.4), 0.01% Tween20, and 2mM dithiothreitol. A test compound solution was prepared by diluting the test compound with dimethyl sulfoxide (DMSO) to a concentration 100 times greater than the final concentration and then diluting 25 times with assay buffer to a concentration four times greater than the final concentration. final concentration. An ATP/substrate/Metal solution was prepared by fivefold dilution of the 5x ATP/substrate/Metal solution included in the kit with the assay buffer. An enzyme solution was prepared by diluting the CDK4/cyclin D3 included in the kit with the assay buffer to a concentration twice the final concentration (final CDK4/cyclin D3 concentration: 12.5 to 25 ng/well). A detection reagent was prepared by diluting each of 5x IMAP-binding buffer A and 5x IMAP-binding buffer B with distilled water, mixing IMAP-binding buffer A with 5x IMAP-binding buffer B. IMAP in a ratio of 85:15, and 400-fold dilution of the IMAP-binding reagent with the mixed buffer.

[00282] The test compound solution (5 µL/well) and the ATP/substrate/Metal solution (5 µL/well) were added to a 384-well plate, and the enzyme solution or assay buffer ( 10 µL/well) was added to the plate (total amount of reaction mixture: 20 µL/well) to initiate the enzymatic reaction. The reaction mixture had a composition of 20 mM HEPES (pH 7.4), 0.01% Tween 20, 2mM dithiothreitol, 100nM FITC-labeled peptide substrate (peptide substrate sequence is not disclosed by Carna Biosciences, Inc .), ATP 100µM, magnesium chloride 1mM, DMSO 1%, and CDK4/cyclin D3 12.5 to 25 ng/well. The reaction was carried out at room temperature for 45 minutes, and the detection reagent (60 µL/well) was then added to the plate, followed by additional reaction for 30 minutes at room temperature under conditions protected from light. Subsequently, fluorescent polarization was determined with a microplate reader at an excitation wavelength of 485 nm and at an emission wavelength of 535 nm.

[00283] The percentage inhibition of enzyme activity was calculated for each test compound (note: enzyme activity = 100% in the case of adding the enzyme solution and adding DMSO in place of the test compound solution, while that enzyme activity = 0% in the case of adding assay buffer in place of the enzyme solution, and adding DMSO in place of the test compound solution). Percent inhibition of enzyme activity was fitted to a dose-response curve to determine the 50% inhibitory concentration (IC) against CDK4/cyclin D3.

[00284] The inhibitory activity of each compound against CDK4/cyclin D3 is shown in the tables described below.

[00285] In each table, “+++” corresponds to IC50 < 10 nM, “++” 10 nM <IC50 < 100 nM, and “+” 100 nM <IC50.

Example 21 Inhibitory activity against human CDK2/cyclin A2

[00286] Each compound was analyzed for inhibitory activity against CDK2/cyclin A2 with an assay kit (“QS S Assist CDK2/Cyclin A2_FP Kit”, available from Carna Biosciences, Inc.). This assay kit determines kinase activity based on IMAP® (“Immobilized Metal Affinity Phosphorylation”) Technology from Molecular Devices. Specifically, kinase activity is determined by quantifying a change in fluorescent polarization caused by the binding of a kinase-phosphorylated fluorescent substance to an IMAP-binding reagent.

[00287] An assay buffer was prepared by diluting 10-fold the 10x assay buffer included in the kit with distilled water, and each solution was prepared with the assay buffer. The assay buffer contained 20 mM HEPES (pH 7.4), 0.01% Tween 20, and 2 mM dithiothreitol. A test compound solution was prepared by diluting the test compound with dimethyl sulfoxide (DMSO) to a concentration 100 times greater than the final concentration and then diluting 25 times with assay buffer to a concentration four times greater than the final concentration. final concentration. An ATP/substrate/Metal solution was prepared by fivefold dilution of the 5x ATP/substrate/Metal solution included in the kit with the assay buffer. An enzyme solution was prepared by diluting the CDK2/cyclin A2 included in the kit with the assay buffer to a concentration twice the final concentration (final CDK2/cyclin A2 concentration: 2.5 ng/well). A detection reagent was prepared by five-fold dilution of 5x IMAP-binding buffer A with distilled water and 400-fold dilution of the IMAP-binding reagent with the diluted buffer.

[00288] The test compound solution (5 µL/well) and the ATP/substrate/Metal solution (5 µL/well) were added to a 384-well plate, and the enzyme solution or assay buffer ( 10 µL/well) was added to the plate (total amount of reaction mixture: 20 µL/well) to initiate the enzymatic reaction. The reaction mixture had a composition of 20 mM HEPES (pH 7.4), 0.01% Tween 20, 2mM dithiothreitol, 100nM FITC-labeled peptide substrate (peptide substrate sequence is not disclosed by Carna Biosciences, Inc .), ATP 30µM, magnesium chloride 5mM, DMSO 1%, and CDK2/cyclin A2 2.5 ng/well. The reaction was carried out at room temperature for 60 minutes, and the detection reagent (60 µL/well) was then added to the plate, followed by additional reaction for 30 minutes at room temperature under conditions protected from light. Subsequently, fluorescent polarization was determined with a microplate reader at an excitation wavelength of 485 nm and at an emission wavelength of 535 nm.

[00289] Percent inhibition of enzyme activity was calculated for each test compound (note: enzyme activity = 100% in the case of adding the enzyme solution and adding DMSO in place of the test compound solution, while that enzyme activity = 0% in the case of adding assay buffer in place of the enzyme solution and adding DMSO in place of the test compound solution). Percent inhibition of enzyme activity was fitted to a dose-response curve to determine the 50% inhibitory concentration against CDK2/cyclin A2.

[00290] The inhibitory activity of each compound against CDK2/cyclin A2 is shown in the tables described below.

[00291] In each table, “+++” corresponds to IC50 < 10 nM, “++” 10 nM <IC50 < 100 nM, and “+” 100 nM <IC50. [Table 6-1]

Example 22 Inhibitory activity against human CDK6/cyclin D3

[00292] The inhibitory activity against CDK6/cyclin D3 was determined by the “Off-Chip Mobility Shift Assay” (MSA). MSA separates proteins from each other based on a difference in electrophoretic mobility depending on the molecular weight or electrical charge of the proteins. Kinase activity is determined by quantifying the degree of phosphorylation through electrophoretic analysis of a change from positive to negative in the electrical charge of the substrate phosphorylated by the kinase.

[00293] Each solution was prepared with an assay buffer containing 20 mM HEPES (pH 7.5), 0.01% Triton X-100, and 2mM dithiothreitol. A test compound solution was prepared by diluting the test compound with dimethyl sulfoxide (DMSO) to a concentration 100 times greater than the final concentration and then diluting 25 times with assay buffer to a concentration four times greater than the final concentration. final concentration. An ATP/substrate/Metal solution was prepared to have a concentration four times greater than the final concentration. An enzyme solution was prepared to have a concentration twice the final concentration. The final enzyme concentration was adjusted to an appropriate level based on the enzyme activity signal and the inhibitory activity of a positive control compound.

[00294] The test compound solution (5 µL/well) and the ATP/substrate/Metal solution (5 µL/well) were added to a 384-well plate, and the enzyme solution or assay buffer ( 10 µL/well) was added to the plate (total amount of reaction mixture: 20 µL/well) to initiate the enzymatic reaction. The reaction mixture had a composition of 20 mM HEPES (pH 7.5), 0.01% Triton 1%, and a predetermined concentration of CDK6/cyclin D3. The reaction was carried out at room temperature for five hours, and a termination buffer (“QuickScout Screening Assist MSA”, manufactured by Carna Biosciences, Inc.) (60 µL/well) was then added to the plate to terminate the reaction. Subsequently, the peptide substrate and the phosphorylated peptide in the reaction mixture were separated from each other and quantified with “LabChip 3000” (manufactured by Caliper Lifesciences). The kinase reaction was evaluated by the product ratio (P/(P+S)) calculated from the peak height (S) of the peptide substrate and the peak height (P) of the phosphorylated peptide.

[00295] The percentage inhibition of enzyme activity was calculated for each test compound (note: enzyme activity = 100% in the case of adding the enzyme solution and adding DMSO in place of the test compound solution, while that enzyme activity = 0% in the case of adding assay buffer in place of the enzyme solution and adding DMSO in place of the test compound solution). Percent inhibition of enzyme activity was fitted to a dose-response curve to determine the 50% inhibitory concentration against CDK6/cyclin D3.

[00296] The inhibitory activity of each compound against CDK6/cyclin D3 is shown in the table described below. In the table, “+++” corresponds to IC50 < 10 nM, “++” 10 nM <IC50 < 100 nM, and “+” 100 nM <IC50. [Table 7]

Example 23

[00297] A monoclonal antibody cocktail against type II collagen (“Arthritogenic MoAb Cocktail” (Chondrex no. 53100), 4.8 mg/mL) was administered intraperitoneally (250 µL/head) to a group of mice with induced arthritis by anti-collagen antibody (CAIA, “Collagen Antibody-Induced Arthritis”) (drug administration group, vehicle/+) (1st day). LPS (Lipopolysaccharide) solution (“LPS Solution (E. coli 0111:B4)” (Chondrex no. 9028), 0.5 mg/mL) was administered intraperitoneally (100 µL/head) on the 4th day, to induce illness. The drug was evaluated based on the pathological score until the 9th day. The drug was administered orally consecutively from the 4th day to the 8th day once a day.

[00298] In mice from a group without induced disease (vehicle/- group), PBS (“Phosphate Buffered Saline”) (pH 7.2, Gibco no. 20012-027) was administered intraperitoneally (250 µL/head) on the 1st day, and LPS solution was administered intraperitoneally on the 4th day.

[00299] The drug was evaluated based on the pathological score (score 0 to score 4 for each extremity, evaluated by the total score). The score determination criteria are as follows: score 0: no change; score 1: swelling of only one limb; score 2: swelling of the wrist and ankle or swelling of two or more limbs; score 3: swelling of the wrist and ankle and swelling of two or more limbs; and score 4: swelling of the wrist and ankle and swelling of all limbs.

[00300] Figure 1 shows the results (scores) on the 9th day (final day).

Claims (27)

1. Compound, characterized by the fact that it is represented by Formula (I) or a pharmaceutically acceptable salt thereof: [Formula] where L represents -NR5-, -O-, or -S-; R5 represents a hydrogen atom or a C16 alkyl group substituted with zero to two -OH groups, zero to two C1-8 alkoxy groups, and zero to six fluorine atoms; R1 represents a C1-8 alkyl, C3-12 cycloalkyl, (C3-12 cycloalkyl)-C1-6 alkyl, 4- to 12-membered heterocyclyl, (4- to 12-membered heterocyclyl)-C1-6 alkyl, C6-10 aryl , (C6-10 aryl)-C1-6 alkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)- C1-6 alkyl, C1-8 alkylsulfonyl, or C1-8 acyl group; each of the heteroatom-containing groups represented by R1 contains from one to four heteroatoms selected from oxygen, sulfur and nitrogen atoms; R1 is optionally substituted with one to six substituents selected from the group consisting of a halogen atom, =O, -OH, -CN, -COOH, -COOR6, -R7, a C3-6 cycloalkyl group substituted with zero to two groups -OH, zero to two C1-8 alkoxy groups, and zero to six fluorine atoms, a 3- to 10-membered heterocyclyl group substituted with zero to two -OH groups, zero to two C1-8 alkoxy groups, and zero to six fluorine atoms, a C1-8 acyl group substituted with zero to two -OH groups, zero to two C1-8 alkoxy groups, and zero to six fluorine atoms, and a C1-8 alkoxy group substituted with zero to two - groups OH, zero to two C1-8 alkoxy groups, and zero to six fluorine atoms; R6 and R7 each independently represent a C1-6 alkyl group substituted with zero to two -OH groups, zero to two C1-8 alkoxy groups, and zero to six fluorine atoms; R2 represents a C1-8 alkyl, C3-8 cycloalkyl, 4- to 6-membered heterocyclyl, C1-8 acyl group, -COOR8, or -CONR9R10; each of the C1-8 alkyl and C3-8 cycloalkyl groups represented by R2 is substituted with zero or one -OH group, zero to two C1-8 alkoxy groups substituted with zero or one -OH group, zero or one C1-4 alkoxy group , and zero to three fluorine atoms, and zero to five fluorine atoms; R2 is not an unsubstituted C1-8 alkyl, unsubstituted C3-8 cycloalkyl, or trifluoromethyl group; R8, R9, and R10 each independently represent a hydrogen atom or a C1-8 alkyl group; the 4 to 6 membered heterocyclyl group represented by R2 is optionally substituted with one to four substituents selected from the group consisting of a fluorine atom, -OH groups, C1-4 alkyl and C1-4 alkoxy; each of the C1-8, -COOR8, and -CONR9R10 acyl groups represented by R2 is optionally substituted with one to four substituents selected from the group consisting of a fluorine atom, -OH, and a C1-4 alkoxy group; R9 and R10 of -CONR9R10 represented by R2 are optionally linked via a single bond or -O- to form a ring including the nitrogen atom attached to R9 and R10; the heterocyclyl group represented by R2 having a 4- to 5-membered ring contains an oxygen heteroatom, and the heterocyclyl group having a 6-membered ring contains one or two oxygen heteroatoms; R3 represents a hydrogen atom, a C1-8 alkyl group, or a halogen atom; X represents CR11 or a nitrogen atom; Y represents CR12 or a nitrogen atom; Z represents CR13 or a nitrogen atom; R11 to R13 each independently represents a hydrogen fluorine, or chlorine atom or a C1-6 alkyl or C1-6 alkoxy group; R4 represents -A1-A2-A3; A1 represents a single bond or a C1-8 alkylene, C2-8 alkenylene, or C2-8 alkynylene group; one or two sp3 carbon atoms at any positions of A1 are optionally substituted with one or two structures selected from the group consisting of -O-, -NR14-, -C(=O)-, -C(=O)-O- , -OC(=O)-, -O- C(=O)-O-, -C(=O)-NR15-, -OC(=O)-NR16-, -NR17-C(=O)- , -NR18-C(=O)-O-, -NR19-C(=O)-NR20-, -S(=O)p-, -S(=O)2-NR21-, -NR22-S( =O)2-, and -NR23- S(=O)2-NR24-, and a structure of -OO-, -O-NR14-, -NR14-O-, -O-CH2-O-, - O -CH2-NR14-, or -NR14-CH2-O- is not formed in the case of replacement of two sp3 carbon atoms; A2 represents a single bond or a group C1-7 alkylene, C3-12 cycloalkylene, C3-12 cycloalkylidene, 4- to 12-membered heterocyclylene, 4- to 12-membered heterocyclylidene, C6-10 arylene, or 5- to 10-membered heteroarylene; A3 represents a halogen atom, -CN, -NO2, -R25, -OR26, 27 28 29 30 31 32 33 -NR R , -C(=O)R , -C(=O)-OR , -OC( =O)R , -OC(=O)-NR R , - C(=O)-NR34R35, -NR36-C(=O)R37, -NR38-C(=O)-OR39, -S(=O )2-R40, -S(=O)2- NR41R42, or -NR43-S(=O)2R44; A3 represents -R25, if the A1 end on the A2 side has a structure selected from the group consisting of -O-, -NR14-, -C(=O)-, -C(=O)- O-, -OC( =O)-, -OC(=O)-O-, -C(=O)-NR15-, -OC(=O)-NR16-, -NR17-C(=O)- , -NR18-C( =O)-O-, -NR19-C(=O)-NR20-, -S(=O)p-, -S(=O)2-NR21-, -NR22- S(=O)2-, and -NR23-S(=O)2-NR24- and A2 is a single bond; R 14 32 34 36 38 41 43 , R , R , R , R , R , and R each independently represents a hydrogen atom or a C1-8 alkyl, C1-8 acyl, C1-8 alkylsulfonyl, heterocyclyl with 4 to 12 members, C3-12 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, (4-12 membered heterocyclyl)-C1-3 alkyl, (C3-12 cycloalkyl)-C1-3 alkyl, (C6-10 aryl )- C1-3 alkyl, or (heteroaryl with 5 to 10 members)-C1-3 alkyl group; 15 31 33 35 37 39 40 42 44 R to R, R, R, R, R, R, R, and R each independently represents a hydrogen atom or a C1-8 alkyl, 4- to 12-membered heterocyclyl, C3 cycloalkyl -12, C6-10 aryl, 5-10 membered heteroaryl, (4-12 membered heterocyclyl)-C1-3 alkyl, (C3-12 cycloalkyl)-C1-3 alkyl, (C6-10 aryl)-C1 alkyl -3, or (heteroaryl with 5 to 10 members)-C1-3 alkyl group; A1, A2, A3, and R14 to R44 in A1 and A3 are each optionally substituted with one to four substituents selected from the group consisting of -OH, =O, -COOH, -SO3H, -PO3H2, -CN, -NO2, a halogen atom, one C1-8 alkyl group substituted with zero to two -OH groups, zero to two -OR45 groups, and zero to six fluorine atoms, one C3-12 cycloalkyl group substituted with zero to two -OH groups, zero to two -OR46 groups, and zero to six fluorine atoms, a C1-8 alkoxy group substituted with zero to two -OH groups, zero to two -OR47 groups, and zero to six fluorine atoms, and a heterocyclyl group with 4 to 12 members with zero to two -OH groups, zero to two -OR49 groups, and zero to six fluorine atoms; R14 to R44 are optionally connected at A1 or A3 or between A1 and A2, between A1 and A3, or between A2 and A3 via a single bond, -O-, -NR50-, or -S(=O)p- for form a ring; R11 or R13 is optionally linked to A1, A2, or A3 via a single bond, -O-, -NR51-, or -S(=O)p- to form a ring; R45 to R47 and R49 to R51 each represent one hydrogen atom or one zero-substituted C1-4 alkyl group or one -OH group and zero to six fluorine atoms; p represents an integer from 0 to 2; and each of the heteroatom-containing groups represented by A1, A2, and A3 contains one to four heteroatoms selected from oxygen, sulfur, and nitrogen atoms]. 2. Compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that L represents -NH-. 3. Compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that R1 represents a C1-8 alkyl, C3-12 cycloalkyl, (C3-12 cycloalkyl)-C1-6 alkyl, heterocyclyl with 4 to 12 members, or (heterocyclyl with 4 to 12 members)- C1-6 alkyl group. 4. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that R2 is a C1-8 alkyl group substituted with one to four fluorine atoms. 5. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that R2 is a C1-8 alkyl group substituted with zero or one -OH group and zero to two C1-8 alkoxy groups substituted with zero or one -OH group, zero or one C1-4 alkoxy group, and zero to three fluorine atoms. 6. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that R2 is a 4 to 6 membered heterocyclyl group optionally substituted with one to four substituents selected from the group consisting of an atom of fluorine, -OH, and C1-4 alkyl and C1-4 alkoxy groups. 7. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized by the fact that R2 is -COOR8, -CONR9R10, or a C1-8 acyl group, optionally each group being substituted with one to four substituents selected from the group consisting of a fluorine atom, -OH, and a C1-4 alkoxy group. 8. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized by the fact that X represents CR11, Y represents CR12, and Z represents CR13. 9. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized by the fact that X represents a nitrogen atom, Y represents CR12, and Z represents CR13. 10. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized by the fact that X represents CR11, Y represents a nitrogen atom, and Z represents CR13. 11. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized by the fact that X represents CR11, Y represents CR12, and Z represents a nitrogen atom. 12. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized by the fact that A1 is a single bond. 13. A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized by the fact that A1 represents a C1-8 alkylene group, and the sp3 carbon atom in A1 is substituted with another structure. 14. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized by the fact that A1 represents a C1-8 alkylene group, and an sp3 carbon atom in any position of A1 is substituted with -O- . 15. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized by the fact that A1 represents a C1-8 alkylene group, and an sp3 carbon atom in any position of A1 is substituted with -NR14- . 16. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, characterized by the fact that A1 represents a C1-8 alkylene group, an sp3 carbon atom in any position of A1 is substituted with -NR14-, and an sp3 carbon atom at any other position of A1 is optionally substituted with -O-. 17. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, characterized by the fact that A2 represents a 4 to 12 membered heterocyclylene group; and A2 is optionally substituted with one to four substituents selected from the group consisting of -OH, -COOH, -SO3H, -PO3H2, -CN, -NO2, a halogen atom, a zero to two substituted C1-8 alkyl group -OH groups, zero to two -OR45 groups, and zero to six fluorine atoms, a C3-12 cycloalkyl group substituted with zero to two -OH groups, zero to two -OR46= groups, and zero to six fluorine atoms, a C1-8 alkoxy group substituted with zero to two -OH groups, zero to two -OR47 groups, and zero to six fluorine atoms, and a 4 to 12-membered heterocyclyl group with zero to two -OH groups, zero to two -OR49 groups, and zero to six fluorine atoms. 18. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, characterized by the fact that A2 represents a 4 to 12 membered heterocyclylene group substituted with =O; and A2 is optionally substituted with one to four substituents selected from the group consisting of -OH, =O, -COOH, -SO3H, -PO3H2, -CN, -NO2, a halogen atom, a C1-8 alkyl group substituted with zero to two -OH groups, zero to two -OR45 groups, and zero to six fluorine atoms, one C3-12 cycloalkyl group substituted with zero to two -OH groups, zero to two -OR46 groups, and zero to six fluorine, a C1-8 alkoxy group substituted with zero to two -OH groups, zero to two -OR47 groups, and zero to six fluorine atoms, and a 4 to 12 membered heterocyclyl group substituted with zero to two -OH groups, zero to two -OR49 groups, and zero to six fluorine atoms. 19. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, characterized by the fact that X represents CR11, Y represents CR12, Z represents CR13, and R11 or R13 is linked to A1, A2, or A3 by through a single bond, -O-, -NR51-, or -S(=O)p- to form a ring. 20. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, characterized by the fact that A3 is a hydrogen atom. 21. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, characterized by the fact that A3 is a halogen atom, -CN, -R25, -OR26, -NR27R28, - C(=O)R29 , or -C(=O)-OR30, and R25 to R30 each independently represent a hydrogen atom, an optionally substituted C1-8 alkyl group, an optionally substituted 4- to 12-membered heterocyclyl group, an optionally substituted C3-12 cycloalkyl group substituted, an optionally substituted C1-3-alkyl group (4 to 12 membered heterocyclyl), or an optionally substituted C1-3-alkyl group (C3-12 cycloalkyl). 22. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, characterized by the fact that R3 is a hydrogen atom. 23. Compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, characterized by the fact that R3 represents a C1-4 alkyl group, a fluorine atom, or a chlorine atom. 24. Compound or pharmaceutically acceptable salt thereof, characterized by the fact that it is selected from: 6-(difluoromethyl)-N8-isopropyl-N2-(5-piperazin-1-yl-2-pyridyl)pyrido [3,4-d] pyrimidine-2,8-diamine (1R)-1-[8-(isopropylamino-2-[(5-piperazin-1-yl-2-pyridyl)amino]pyrido[3,4-d]pyrimidin-6-yl ]ethanol 1- [2- [(5-piperazin-1-yl-2-pyridyl)amino]-8-(tetrahydrofuran-3-ylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [2- [(5-piperazin-1-yl-2-pyridyl)amino]-8-(tetrahydropyran-3-ylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol N8- isopropyl-6-[(1R)-1-methoxyethyl]-N2-(6-piperazin-1-ylpyridazin-3-yl)pyrido [3,4-d]pyrimidine-2,8-diamine N8-isopropyl-6- [(1R)-1-methoxyethyl]-N2- [5-(piperazin-1-ylmethyl)-2-pyridyl]pyrido [3,4-d]pyrimidine-2,8-diamine 1- [6- [ [6 - [(1R)-1-hydroxyethyl]-8-(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one 1- [6- [ [5-chloro -6- [(1R)-1-hydroxyethyl]-8- (isopropylaminopyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (1R)-1- [2 - [(6-piperazin-1-ylpyridazin-3-yl)amino]-8-(tetrahydropyran-4-ylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [(6-piperazin-1-ylpyridazin-3-yl)amino]-8- [ [(3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6- yl]ethanol (1R)-1- [2- [(6-piperazin-1-ylpyridazin-3-yl)amino]-8- [ [(3R)-tetrahydropyran-3-yl]amino]pyrido [3 ,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[5-(piperazin-1-ylmethyl)-2-pyridyl]amino]-8-(tetrahydropyran-4-ylamino )pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [ [5-(piperazin-1-ylmethyl)-2-pyridyl]amino]-8- [ [(3S )- tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [[5-(piperazin-1-ylmethyl)-2- pyridyl]amino]-8- [ [(3R)- tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [6- [ [6- [(1R )-1-hydroxyethyl]-8-(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]pyridazin-3-yl]piperidin-4-ol (1R)-1-[8-(isopropylamino-2 - [(6-piperazin-1-ylpyridazin-3-yl)amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [ [6- [ [6- [(1R)-1-hydroxyethyl ]-8-(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-2-one 6- [(1R)-1-methoxyethyl]-N2- [5- (piperazin-1-ylmethyl)-2-pyridyl]- N8- [(3S)-tetrahydropyran-3-yl]pyrido [3,4-d]pyrimidine-2,8-diamine 6- [(1R)- 1-methoxyethyl]-N2-(6-piperazin-1-ylpyridazin-3-yl)-N8-[(3S)-tetrahydropyran-3-yl]pyrido [3,4-d]pyrimidine-2,8- diamine 6- [(1R)-1-methoxyethyl]-N2- [5-(piperazin-1-ylmethyl)-2-pyridyl]- N8-(tetrahydropyran-4-ylmethyl)pyrido [3,4-d] pyrimidine-2,8-diamine N8-isopropyl-6-[(1R)-1-methoxyethyl]-N2-(5-piperazin-1-ylpyrazin-2-yl)pyrido[3,4-d]pyrimidine-2, 8-diamine N8-isopropyl-6-[(1R)-1-methoxyethyl]-N2-[6-[(2S)-2-methylpiperazin-1-yl]pyridazin-3-yl]pyrido[3,4-d ]pyrimidine-2,8-diamine N8-isopropyl-6- [(1R)-1-methoxyethyl]-N2- [6- [(2R)-2-methylpiperazin-1-yl]pyridazin-3-yl]pyrido [ 3,4-d]pyrimidine-2,8-diamine (1R)-1- [2- [ [6-(4,7-diazaspiro [2,5]octan-7-yl)pyridazin-3-yl]amino ]-8-(isopropylaminopyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [ [5-(4,7-diazaspiro [2,5]octan-7-ylmethyl) -2- pyridyl]amino]-8-(isopropylaminopyrido [3,4-d]pyrimidin-6-yl]ethanol 2- [1- [ [6- [ [6- [(1R)-1-hydroxyethyl]-8 -(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]-4-piperidyl]propan-2-ol (1R)-1- [2- [ [5- [ [ 4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino]-8-(isopropylaminopyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [ [5- [2-(dimethylamino)ethoxy]-2-pyridyl]amino]-8- [ [(3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6- yl]ethanol (1R)-1- [2- [ [6-(4-methylpiperazin-1-yl)pyridazin-3-yl]amino]-8- [ [(3S)-tetrahydropyran-3-yl] amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 2-hydroxy-1- [4- [6- [ [6- [(1R)-1-hydroxyethyl]-8- (isopropylaminopyrido [3, 4-d]pyrimidin-2-yl]amino]pyridazin-3-yl]piperazin-1-yl]ethanone 1-[6-[[8-(isopropylamino-6-[(2S)-tetrahydrofuran-2- yl]pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (1R)-1-[8-(isopropylamino-2-(5,6,7,8 -tetrahydro-1,6-naphthyridin-2-ylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol 2- [4- [ [6- [ [6- [(1R)-1- hydroxyethyl]-8-(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-1-yl]-2-methylpropan-1-ol 4- [6- [ [ 6- [(1R)-1-hydroxyethyl]-8-(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]-1- [(2S)-2-hydroxypropyl]-1 ,4-diazepan-5-one 4- [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl ]-1- [(2R)-2-hydroxypropyl]-1,4-diazepan-5-one N8-isopropyl-N2- [5-(piperazin-1-ylmethyl)-2-pyridyl]-6- [(2S )-tetrahydrofuran-2-yl]pyrido [3,4-d]pyrimidine-2,8-diamine 1-[6-[[6-[(1R)-1-hydroxyethyl]-8-(isopropylaminopyrido [3 ,4-d]pyrimidin-2-yl]amino]-2-methyl3-pyridyl]piperazin-2-one 1-[6-[[8-(isopropylamino-6-[(3S)-tetrahydrofuran-3- yl]pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (1R)-1-[2-(5,6,7,8-tetrahydro- 1,6-naphthyridin-2-ylamino)-8- [ [(3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [6- [ [8-(isopropylamino-6-(3-methyloxetan-3-yl)pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (1R)-1- [ 2- [ [5- [4-(dimethylamino)cyclohexoxy]-2-pyridyl]amino]- 8- [ [(3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d] pyrimidin-6-yl]ethanol 6- [(1R)-1-methoxyethyl]-N2- [5-(piperazin-1-ylmethyl)-2-pyridyl]- N8-propyl-pyrido [3,4-d]pyrimidine -2,8-diamine 6-[(1R)-1-methoxyethyl]-N2-(6-piperazin-1-ylpyridazin-3-yl)-N8-propyl-pyrido [3,4-d]pyrimidine-2, 8-diamine 1- [ [6- [ [6-(difluoromethyl)-8- [(4-methylcyclohexyl)amino]pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl] methyl]piperidine-4-carboxylic acid (1R)-1-[8-(ethylamino)-2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino ]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [ [5- [ [4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl ]amino]-8-(propylaminopyrido [3,4-d]pyrimidin-6-yl]ethanol N8-isopropyl-6-(3-methyloxetan-3-yl)-N2-(6-piperazin-1-ylpyridazin-3 -yl)pyrido [3,4-d]pyrimidine-2,8-diamine N8-isopropyl-6-(3-methyloxetan-3-yl)-N2-[5-(piperazin-1-ylmethyl)-2-pyridyl ]pyrido [3,4-d]pyrimidine-2,8-diamine 6-(3-methyloxetan-3-yl)-N2- [5-(piperazin-1-ylmethyl)-2-pyridyl]- N8- [( 3S)-tetrahydropyran-3-yl]pyrido[3,4-d]pyrimidine-2,8-diamine 4-[6-[[6-[(1R)-1-hydroxyethyl]-8-[isopropyl( methyl)amino]pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]-1,4-diazepan-5-one (1R)-1- [8-(isopropylamino-2- [ (6-methyl5-piperazin-1-yl-2-pyridyl)amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [2- [ [6-(2-hydroxyethyl) -7,8-dihydro-5H-1,6-naphthyridin-2-yl]amino]-8-(isopropylaminopyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [8 -(isopropylamino-2-[[6-[2-(methylamino)ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-yl]amino]pyrido[3,4-d]pyrimidin -6-yl]ethanol N2-(6-piperazin-1-ylpyridazin-3-yl)-6-[(3S)-tetrahydrofuran-3-yl]-N8-[(3S)-tetrahydropyran-3 -yl]pyrido [3,4-d]pyrimidine-2,8-diamine N2- [5-(piperazin-1-ylmethyl)-2-pyridyl]-6- [(3R)-tetrahydrofuran-3-yl ]-N8- [(3S)-tetrahydropyran-3-yl]pyrido [3,4-d]pyrimidine-2,8-diamine (1R)-1- [2- [ [6- [2-(dimethylamino )ethyl]-7,8-dihydro-5H-1,6-naphthyridin-2-yl]amino]-8-(isopropylaminopyrido [3,4-d]pyrimidin-6-yl]ethanol (2S)-1 - [4- [ [6- [ [8-(ethylamino)-6- [(1R)-1-hydroxyethyl]pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]methyl] piperazin-1-yl]propan-2-ol (2R)-1- [4- [ [6- [ [8-(ethylamino)-6- [(1R)-1-hydroxyethyl]pyrido [3,4- d ]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-1-yl]propan-2-ol (1R)-1- [8-(isopropylamino-2- [ [5- [(2R)- 2-methylpiperazin-1-yl]- 2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [8-(isopropylamino-2- [ [5- [( 2S)-2-methylpiperazin-1-yl]- 2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol N8-isopropyl-N2-(5-piperazin-1-yl-2- pyridyl)-6- [(2S)-tetrahydrofuran-2-yl]pyrido [3,4-d]pyrimidine-2,8-diamine (1R)-1- [8-(cyclobutylamino)-2- [ [ 5- [ [4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol (1R)-1- [8- (cyclopropylmethylamino)-2- [ [5- [ [4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 6 -(3-methyloxetan-3-yl)-N2-(5-piperazin-1-yl-2-pyridyl)-N8-propyl-pyrido [3,4-d]pyrimidine-2,8-diamine 6-(3 -methyloxetan-3-yl)-N2-[5-(piperazin-1-ylmethyl)-2-pyridyl]-N8-propyl-pyrido[3,4-d]pyrimidine-2,8-diamine N2-(5- piperazin-1-yl-2-pyridyl)-N8-propyl-6-tetrahydrofuran-3-yl-pyrido[3,4-d]pyrimidine-2,8-diamine N2-[5-(piperazin-1- ylmethyl)-2-pyridyl]-N8-propyl-6-tetrahydrofuran-3-yl-pyrido[3,4-d]pyrimidine-2,8-diamine N8-isopropyl-6-(3-methyloxetan-3- yl)-N2-(5-piperazin-1-yl-2-pyridyl)pyrido [3,4-d]pyrimidine-2,8-diamine N8-isopropyl-N2-(5-piperazin-1-yl-2- pyridyl)-6-tetrahydrofuran-3-yl-pyrido [3,4-d]pyrimidine-2,8-diamine 2- [4- [ [6- [ [8-(isopropylamino-6-tetrahydrofuran- 3-yl-pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-1-yl]ethanol 2-[4-[[6-[[6-tetrahydrofuran -3-yl-8- [[(3S)-tetrahydropyran-3-yl]amino]pyrido [3,4-d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperazin-1- yl]ethanol (1R)-1- [2- [ [5- [ [4-(hydroxymethyl)-1-piperidyl]methyl]-2-pyridyl]amino]-8-(isopropylaminopyrido [3,4-d]pyrimidin -6-yl]ethanol 1- [ [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl] methyl]piperidin-4-ol 1- [ [6- [ [8-(tert-butylamino)-6- [(1R)-1-hydroxyethyl]pyrido [3,4- d]pyrimidin-2-yl]amino] -3-pyridyl]methyl]piperidin-4-ol (1R)-1- [8-(tert-butylamino)-2- [ [5- [ [4-(hydroxymethyl)-1- piperidyl]methyl]-2- pyridyl]amino]pyrido [3,4-d]pyrimidin-6-yl]ethanol 1- [ [6- [ [6- [(1R)-1-hydroxyethyl]-8-(isobutylamino)pyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]methyl]piperidin-4-ol (1R)-1- [2- [ [5- [ [4-(hydroxymethyl)-1-piperidyl]methyl]- 2-pyridyl]amino]-8-(isobutylamino)pyrido [3,4-d]pyrimidin-6-yl]ethanol 1-[6-[[6-[(1R)-1-hydroxypropyl]-8-(isopropylaminopyrido [3,4- d]pyrimidin-2-yl]amino]-3-pyridyl]piperazin-2-one (1R)-1- [2- [ [5- [ [4-(2-hydroxyethyl)piperazin-1 -yl]methyl]-6-methyl2-pyridyl]amino]-8-(propylaminopyrido [3,4-d]pyrimidin-6-yl]ethanol. 25. Pharmaceutical composition, characterized by the fact that it comprises the compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 24 and a pharmaceutically acceptable carrier. 26. Pharmaceutical composition exhibiting CDK4/6 inhibition activity, characterized by the fact that it comprises the compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 24 as an active ingredient. 27. Use of a compound characterized by the fact that it is for the manufacture of a medicament to prevent or treat a disease, wherein the disease is rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer, wherein the compound comprises the compound or pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 24 as an active ingredient.