HK1249502B - Pyrido(3,4-d) pyrimidine derivative and pharmaceutically acceptable salt thereof - Google Patents

Description

Pyrido[3,4-d]pyrimidine derivatives and pharmaceutically acceptable salts thereof

Technical Field

The present invention relates to pyrido[3,4-d]pyrimidine derivatives and pharmaceutically acceptable salts thereof, and particularly to compounds having inhibitory activity against cyclin-dependent kinase 4 and/or cyclin-dependent kinase 6 (hereinafter also referred to as "CDK4/6") and useful for preventing or treating rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer.

Background Art

Cell proliferation is a process in which cells increase and divide in response to various stimuli.

Diseases caused by excessive cell proliferation, such as cancer, are characterized by uncontrolled cell cycle progression, resulting from, for example, abnormalities in genes or proteins that directly or indirectly regulate the cell cycle. Therefore, substances that regulate excessive cell proliferation by controlling the cell cycle can be used to treat a variety of diseases characterized by uncontrolled or undesirable cell proliferation.

The progression of the cell cycle is a complex process in which the transitions between phases of each cycle are highly controlled and involve multiple checkpoints.

Cyclin-dependent kinases and related serine/threonine protein kinases are important intracellular enzymes that play essential roles in regulating cell division and proliferation. The catalytic units of cyclin-dependent kinases are known to be activated by regulatory subunits known as cyclins, and a large number of cyclins have been identified in mammals (Non-Patent Document 1).

Retinoblastoma protein (Rb) is a checkpoint protein involved in the transition from G1 to S phase of the cell cycle. Rb is associated with the E2F family of transcription factors and inhibits their activity in the absence of appropriate growth stimuli (Non-Patent Documents 2 and 3). Upon stimulation by mitogenic substances, cells begin to enter the S phase through the new synthesis of cyclin D, which acts as an activator of CDK4/6. CDK4/6, temporarily bound to cyclin D, inactivates the Rb protein through phosphorylation. Phosphorylation of Rb releases E2F, which directs the transcription of genes essential for S phase. Complete inactivation of Rb requires phosphorylation by both cyclin D-CDK4/6 and cyclin E-CDK2. Phosphorylation of Rb by CDK4/6 at specific sites on the cell cycle has been shown to be essential for phosphorylation of cyclin E-CDK2 (Non-Patent Document 4). Therefore, cyclin D-CDK4/6 is a key enzyme complex controlling the transition from G1 to S phase.

CDK2 is known to form a complex with cyclin A in addition to cyclin E, and is also known to function in processes after the S phase and is involved in DNA replication. There are also reports of hypothesized genotoxicity when CDK2 is inhibited (Non-Patent Document 5).

It is known that cyclin D is a molecular mechanism that positively controls the activity of CDK4/6. In contrast, p16 encoded by the INK4a gene selectively negatively controls the activity of CDK4/6 (Non-Patent Document 6).

CDK inhibitors can be used to treat various diseases caused by abnormal cell proliferation, including cancer, cardiovascular disorders, kidney disease, specific infections, and autoimmune diseases. There is no limitation to this, and it is expected that they will be effective in treating, for example, rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, and cancer. In such cases, based on the insights of the following technologies, it is expected that inhibition of cell cycle and cell proliferation via CDK inhibition will be effective.

In rheumatoid arthritis, pannus formation, which is caused by the hyperproliferation of synovial cells, has been reported to be ameliorated by introducing p16 into the affected area of model animals and administering CDK4/6 inhibitors (Non-Patent Documents 7-9). Furthermore, it has been reported that MMP3 production is also suppressed in synovial cells from rheumatoid arthritis patients by the CDK4-cyclin D complex, negatively controlling CDK4/6 activity and thereby inhibiting not only proliferation but also MMP3 production (Non-Patent Document 10).

Based on the above, it is expected that CDK4/6 inhibitors will have a chondroprotective effect in addition to an inhibitory effect on synoviocyte proliferation in rheumatoid arthritis.

Cell proliferation regulatory pathways involving genes involved in the G1 and S phase checkpoints of the cell cycle are associated with plaque progression, stenosis, and restenosis following angiogenesis. Overexpression of the CDK inhibitory protein p21 has been shown to suppress vascular smooth muscle proliferation and intimal hyperplasia following angiogenesis (Non-Patent Literatures 11-12).

Abnormal cell cycle control is also associated with polycystic kidney disease, which is characterized by the growth of fluid-filled cysts in the urinary tract. Treatment with small molecule CDK inhibitors is effective (Non-Patent Document 13).

In a mouse model of pulmonary fibrosis, it has been reported that induction of expression of the cell cycle inhibitory protein p21 using an adenoviral vector is effective (Non-Patent Document 14).

In a rat cerebral infarction model, it has been reported that the increase in cyclin D1/CDK4 levels associated with neuronal cell death caused by local anemia is suppressed, and that neuronal cell death can be suppressed by administering flavopiridol, a non-selective CDK inhibitor (Non-Patent Document 15).

The cyclin D-CDK4/6-INK4a-Rb pathway is frequently detected in human cancers, which are caused by abnormalities in factors that contribute to cancer cell proliferation, such as loss of functional p16INK4a, overexpression of cyclin D1, overexpression of CDK4, and loss of functional Rb (Non-Patent Documents 16-18). These abnormalities promote progression from the G1 phase to the S phase, clearly indicating that this pathway plays a key role in cancerous development and abnormal cancer cell growth.

CDK4/6 inhibitors may be particularly effective against tumors harboring genetic abnormalities that activate CDK4/6 kinase activity, such as cancers with translocation of cyclin D, cancers with amplification of cyclin D, cancers with amplification or overexpression of CDK4 or CDK6, and cancers with inactivation of p16. Furthermore, this deficiency may be useful in treating cancers harboring genetic abnormalities in upstream regulators of cyclin D that increase the amount of cyclin D present, and therapeutic efficacy may also be expected.

In fact, attempts have been made to synthesize compounds that inhibit CDK4/6 activity, and many compounds have been disclosed in the art. Clinical trials have been conducted on various cancers, including breast cancer (Non-Patent Document 19).

Most acute and severe toxicities from radiation therapy and chemotherapy are caused by effects on stem cells and progenitor cells. Hematopoietic stem cells and progenitor cells rendered dormant by CDK4/6 inhibitors can protect against cytotoxicity caused by radiation therapy and chemotherapy. After cessation of inhibitor treatment, hematopoietic stem cells and progenitor cells (HSPCs) recover from this temporary dormancy and subsequently resume normal function. Therefore, chemotherapy resistance using CDK4/6 inhibitors is expected to provide significant bone marrow protection (Non-Patent Document 20).

From the above, it is expected that CDK4/6 inhibitors will be useful for the treatment of rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, cancer, and bone marrow protection, and will be particularly effective for rheumatoid arthritis, cancer treatment, and bone marrow protection.

Patent Document 1 and Non-Patent Document 21 are known as CDK4 inhibitors; Patent Documents 2 and 3 and Non-Patent Documents 22 to 24 are known as CDK4/6 inhibitors; and Non-Patent Document 25 is known as a CDK4/FLT3 inhibitor.

Furthermore, pyrido[3,4-d]pyrimidine derivatives are known to have an inhibitory effect on Mps1 (a kinase known as TTK) (Patent Document 4), which is an action completely different from the CDK4/6 inhibition of the present invention.

In addition, Non-Patent Documents 26 and 27 also disclose pyrido[3,4-d]pyrimidine derivatives and report that CDK2 inhibitory activity was observed in a variety of compounds. This is a group of compounds with completely different directions from the excellent CDK4/6 inhibition of the present invention.

Prior art literature

Patent Literature

[Patent Document 1] WO2003/062236

[Patent Document 2] WO2010/020675

[Patent Document 3] WO2010/075074

[Patent Document 4] WO2014/037750

Non-patent literature

[Non-patent document 1] Johnson D. G. and Walker C. L., Annual Review of Pharmacology and Toxicology 1999;39:p.295-312

[Non-patent document 2] Ortega et al., Biochimica et Biophysica Acta-Reviews on Cancer 2002; 1602 (1): p.73-87

[Non-patent document 3] Shapiro, Journal of Clinical Oncology 2006; 24 (11): p.1770-1783

[Non-patent document 4] Lundberg et al., Molecular and Cellular Biology 1998;18(2):p.753-761

[Non-patent document 5] Andrew J. Olaharski, PLoS Computational Biology 2009, 5(7): e1000446.

[Non-patent document 6] Kamb et al., Science 1994; 264 (5157): p.436-440

[Non-patent document 7] Taniguchi, K et al., Nature Medicine, Vol. 5, pp. 760-767 (1999)

[Non-patent document 8] Sekine, C et al., Journal of immunology 2008, 180: p.1954-1961

[Non-patent document 9] Hosoya, T et al., Annnl Rheumatic Diseases. 2014 Aug 27 Epub ahead of print

[Non-patent document 10] Nonomura Y et al., Arthritis & Rheumatology 2006 Jul;54(7):p.2074-83.

[Non-patent document 11] Chang M.W. et al., Journal of Clinical Investigation, 1995, 96: p.2260

[Non-patent document 12] Yang Z-Y. et al., Proceedings of the National Academy of Sciences (USA), 1996, 93: p.9905

[Non-patent document 13] Bukanov N.O. et al., Nature, 2006, 4444: p.949-952

[Non-patent document 14] American Journal Physiology: Lung Cellular and Molecular Physiology, 2004, Vol. 286, pp. L727-L733

[Non-patent document 15] Proceedings of the National Academy of Sciences of the United States of America, 2000, Volume 97, p.10254-10259

[Non-patent document 16] Science (Science), Volume 254, Pages 1138-1146, (1991)

[Non-patent document 17] Cancer Research, 1993, Volume 53, p.5535-5541

[Non-patent document 18] Current Opinion in Cell Biology, Vol. 8, 1996, p. 805-814

[Non-patent document 19] Guha M, Nature Biotechnology 2013 Mar;31(3):p.187

[Non-patent document 20] Journal of Clinical Investigation 2010;120(7):p.2528-2536 Soren M. Johnson

[Non-patent document 21] Journal of Medicinal Chemistry, 2005, 48, pp. 2371-2387

[Non-patent document 22] Journal of Medicinal Chemistry, 2000, 43, pp. 4606-4616

[Non-patent document 23] Journal of Medicinal Chemistry, 2005, 48, pp. 2388-2406

[Non-patent document 24] Journal of Medicinal Chemistry, 2010, 53, pp.7938-7957

[Non-patent document 25] Journal of Medicinal Chemistry, 2014, 57, pp.3430-3449

[Non-patent document 26] Organic & Biomolecular Chemistry, 2015, 13, pp.893-904

[Non-patent document 27] Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitorsof Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based HybridizationApproach, 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

Problems to be solved by the invention

An object of the present invention is to provide a compound having excellent CDK4/6 inhibitory activity.

Solutions to the Problem

The present inventors have conducted intensive studies to solve the above-mentioned problems and, as a result, have discovered novel pyrido[3,4-d]pyrimidine derivatives represented by formula (I) having CDK4/6 inhibitory activity, thereby completing the present invention.

The present invention is as follows.

(1) A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

Where,

L represents -NR ⁵ -, -O-, or -S-;

^R5 represents a hydrogen atom, or a _C1-6 alkyl group substituted with [0 to 2 -OH groups, 0 to 2 _C1-8 alkoxy groups, and 0 to 6 fluorine atoms];

^R1 represents a _C1-8 alkyl group, a _C3-12 cycloalkyl group, a ( _C3-12 cycloalkyl) _C1-6 alkyl group, a 4- to 12-membered heterocyclic group, a (4- to 12-membered heterocyclic group) _C1-6 alkyl group, a _C6-10 aryl group, a ( _C6-10 aryl) _C1-6 alkyl group, a 5- to 10-membered heteroaryl group, a (5- to 10-membered heteroaryl) _C1-6 alkyl group, a _C1-8 alkylsulfonyl group, or a _C1-8 acyl group; the heteroatoms in ^R1 are, in each group, independently selected from 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms;

R ¹ is optionally substituted by 1 to 6 substituents selected from halogen, ＝O, -OH, -CN, -COOH, -COOR ⁶ , -R ⁷ , C _3-6 cycloalkyl substituted with [0 to 2 -OH, 0 to 2 C _1-8 alkoxy groups, and 0 to 6 fluorine atoms], 3-10 membered heterocyclyl substituted with [0 to 2 -OH, 0 to 2 C _1-8 alkoxy groups, and 0 to 6 fluorine atoms], C _1-8 acyl substituted with [0 to 2 -OH, 0 to 2 C _1-8 alkoxy groups, and 0 to 6 fluorine atoms], and C _1-8 alkoxy substituted with [0 to 2 -OH, 0 to 2 C _1-8 alkoxy groups, and 0 to 6 fluorine atoms];

^R6 and ^R7 each independently represent a _C1-6 alkyl group substituted with [0 to 2 -OH groups, 0 to 2 _C1-8 alkoxy groups, and 0 to 6 fluorine atoms];

R ² represents a C _1-8 alkyl group, a C _3-8 cycloalkyl group, a 4- to 6-membered heterocyclic group, a C _1-8 acyl group, -COOR ⁸ , or -CONR ⁹ R ¹⁰ ;

The C _1-8 alkyl group and C _3-8 cycloalkyl group of R ² are each independently substituted by 0 to 1 -OH, 0 to 2 C _1-8 alkoxy groups substituted with [0 to 1 -OH, 0 to 1 C _1-4 alkoxy, and 0 to 3 fluorine atoms], and 0 to 5 fluorine atoms;

wherein R ² is not unsubstituted C _1-8 alkyl, unsubstituted C _3-8 cycloalkyl, or trifluoromethyl;

R ⁸ , R ⁹ , and R ¹⁰ each independently represent a hydrogen atom or a C _1-8 alkyl group;

The 4- to 6-membered heterocyclic group of R ² is optionally substituted by 1 to 4 substituents selected from fluorine atoms, -OH, C _1-4 alkyl groups, and C _1-4 alkoxy groups;

The C _1-8 acyl group, -COOR ⁸ , and -CONR ⁹ R ¹⁰ of R ² are optionally substituted with 1 to 4 substituents selected from a fluorine atom, -OH, and a C _1-4 alkoxy group;

R ⁹ and R ¹⁰ in -CONR ⁹ R ¹⁰ of R ² are optionally bonded via a single bond or -O- to form a ring including the nitrogen atom to which they are bonded;

The heteroatom in the heterocyclic group of R ² is 1 oxygen atom in a 4-5 membered ring and 1 to 2 oxygen atoms in a 6 membered ring;

R ³ represents a hydrogen atom, a C _1-8 alkyl group, or a halogen atom;

X represents CR ¹¹ or a nitrogen atom;

Y represents CR ¹² or a nitrogen atom;

Z represents CR ¹³ or a nitrogen atom;

R ¹¹ to R ¹³ each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group;

R ⁴ is represented by -A ¹ -A ² -A ³ ;

^A1 represents a single bond, _C1-8 alkylene, _C2-8 alkenylene, or _C2-8 alkynylene;

1 to 2 ^sp3 carbon atoms at any position of ^A1 are optionally substituted by 1 to 2 structures selected from [-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- ],

When two sp ³ carbon atoms are substituted, structures such as -OO-, -O-NR ¹⁴ -, -NR ¹⁴ -O-, -O-CH ₂ -O-, -O-CH ₂ -NR ¹⁴ -, and -NR ¹⁴ -CH ₂ -O- are not formed;

^A2 represents a single bond, a _C1-7 alkylene group, a _C3-12 cycloalkylene group, a _C3-12 cycloalkylidene group, a 4- to 12-membered heterocyclylene group, a 4- to 12-membered heterocycloalkylidene group, a _C6-10 arylene group, or a 5- to 10-membered heteroarylene group;

A ³ represents halogen, -CN, -NO ₂ , -R ²⁵ , -OR ²⁶ , -NR ²⁷ R ²⁸ , -C(=O)R ²⁹ , -C(=O)-OR ³⁰ , -OC(=O)R ³¹ , -OC(=O)-NR ³² R ³³ , -C(=O)-NR ³⁴ R ³⁵ , -NR ³⁶ -C (＝O) R ³⁷ , -NR ³⁸ -C (＝O) -OR ³⁹ , -S (＝O) ₂ -R ⁴⁰ , -S (＝O) ₂ -NR ⁴¹ R ⁴² , or -NR ⁴³ -S (＝O) ₂ R ⁴⁴ ;

wherein the terminal of ^A1 on the ^A2 side is a structure selected from [-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 when ^A2 is a single bond, ^A3 represents ^-R25 ;

R ¹⁴ , R ³² , R ³⁴ , R ³⁶ , R ³⁸ , R ⁴¹ , and R ⁴³ each independently represent a hydrogen atom, a C _1-8 alkyl group, a C _1-8 acyl group, a C _1-8 alkylsulfonyl group, a 4- to 12-membered heterocyclic group, a C _3-12 cycloalkyl group, a C _6-10 aryl group, a 5- to 10-membered heteroaryl group, a (4- to 12-membered heterocyclic group)C _1-3 alkyl group, a (C _3-12 cycloalkyl group)C _1-3 alkyl group, a (C _6-10 aryl group)C _1-3 alkyl group, or a (5- to 10-membered heteroaryl group)C _1-3 alkyl group;

R ¹⁵ to R ³¹ , R ³³ , R ³⁵ , R ³⁷ , R ³⁹ , R ⁴⁰ , R ⁴² , and R ⁴⁴ each independently represent a hydrogen atom, a C _1-8 alkyl group, a 4- to 12-membered heterocyclic group, a C _3-12 cycloalkyl group, a C _6-10 aryl group, a 5- to 10-membered heteroaryl group, a (4- to 12-membered heterocyclic group)C _1-3 alkyl group, a (C _3-12 cycloalkyl group)C _1-3 alkyl group, a (C _6-10 aryl group)C _1-3 alkyl group, or a (5- to 10-membered heteroaryl group)C _1-3 alkyl group;

A ¹ , A ² , A ³ , and R ¹⁴ to R ⁴⁴ in A ¹ , A ² , and A ³ are each independently optionally substituted with 1 to 4 substituents selected from —OH, ═O, —COOH ^, —SO ₃ H, —PO ₃ H, —CN, —NO ₂ , halogen, C _1-8 alkyl substituted with [0 to 2 —OH, 0 to 2 —OR ⁴⁵ , and 0 to 6 fluorine atoms], C _3-12 cycloalkyl substituted with [0 to 2 —OH, 0 to 2 —OR ⁴⁶ , and 0 to 6 fluorine atoms], C _1-8 alkoxy substituted with [0 to 2 —OH, 0 to 2 —OR 47 , and 0 to 6 fluorine atoms], and 4-12 membered heterocyclic group substituted with [0 to 2 —OH, 0 to 2 —OR ⁴⁹ , and 0 to 6 fluorine atoms];

R ¹⁴ to R ⁴⁴ are optionally bonded within A ¹ , within A ² , within A ³ , between A ¹ and A ² , between A ¹ and A ³² , or between A ² and A ³² , through a single bond, -O-, -NR ⁵⁰ -, or -S(=O) _p - to form a ring;

R ¹¹ or R ¹³ may be bonded to [A ¹ , A ² , or A ³ ] via [single bond, -O-, -NR ⁵¹ -, or -S(=O) _p -] to form a ring;

R ⁴⁵ to R ⁵¹ represent a hydrogen atom, or a C _1-4 alkyl group substituted with [0 to 1 -OH and 0 to 6 fluorine atoms];

P represents an integer from 0 to 2;

The heteroatoms in A ¹ , A ² , and A ³ are 1 to 4 heteroatoms independently selected from oxygen atoms, sulfur atoms, and nitrogen atoms in each group.

(2) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein L represents -NH-.

(3) The compound according to (1) or (2), or a pharmaceutically acceptable salt thereof, wherein ^R1 represents a _C1-8 alkyl group, a _C3-12 cycloalkyl group, a ( _C3-12 cycloalkyl) _C1-6 alkyl group, a 4- to 12-membered heterocyclic group, or a (4- to 12-membered heterocyclic group) _C1-6 alkyl group.

(4) The compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof, wherein R ² is a C _1-8 alkyl group substituted with 1 to 4 fluorine atoms.

(5) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein ^R2 is a _C1-8 alkyl group substituted by 0 to 1 -OH groups and 0 to 2 _C1-8 alkoxy groups substituted by [0 to 1 -OH groups, 0 to 1 C1-4 alkoxy groups, and 0 to ₃ fluorine atoms].

(6) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein ^R2 is a 4- to 6-membered heterocyclic group optionally substituted with 1 to 4 substituents selected from a fluorine atom, -OH, a _C1-4 alkyl group, and a _C1-4 alkoxy group.

(7) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein R ² is a C _1-8 acyl group optionally substituted with 1 to 4 substituents selected from a fluorine atom, -OH, and a C _1-8 alkoxy group, -COOR ⁸ , or -CONR ⁹ R ¹⁰ .

(8) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein X represents CR ¹¹ , Y represents CR ¹² , and Z represents CR ¹³ .

(9) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein X represents a nitrogen atom, Y represents CR ¹² , and Z represents CR ¹³ .

(10) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein X represents CR ¹¹ , Y represents a nitrogen atom, and Z represents CR ¹³ .

(11) The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (7), wherein X represents CR ¹¹ , Y represents CR ¹² , and Z represents a nitrogen atom.

(12) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (11), wherein ^A1 is a single bond.

(13) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (11), wherein ^A1 represents a _C1-8 alkylene group, and all ^sp3 carbon atoms of ^A1 are not substituted by other structures.

(14) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (11), wherein ^A1 represents a _C1-8 alkylene group, and one ^sp3 carbon atom at any position of ^A1 is substituted by -O-.

(15) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (11), wherein A ¹ represents a C _1-8 alkylene group, and one sp ³ carbon atom at any position of A ¹ is substituted by -NR ¹⁴ -.

(16) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (11), wherein ^A1 represents a _C1-8 alkylene group, one sp3 carbon atom at any position of ^A1 is substituted by ^-NR14- , and one ^{sp3 carbon} atom at any position of ^A1 is optionally substituted by -O-.

(17) The compound according to any one of (1) to (16) or a pharmaceutically acceptable salt thereof, wherein ^A2 represents a 4- to 12-membered heterocyclylene group; ^A2 is optionally substituted by 1 to 4 substituents selected from -OH, -COOH, _-SO3H , _-PO3H , -CN, _-NO2 , halogen, _C1-8 alkyl optionally substituted by [0 to 2 -OH, 0 to 2 ^-OR45 , and 0 to 6 fluorine atoms], _C3-12 cycloalkyl optionally substituted by [0 to 2 -OH, 0 to 2 ^-OR46 , and 0 to 6 fluorine atoms], _C1-8 alkoxy optionally substituted by [0 to 2 -OH, 0 to 2 ^-OR47 , and 0 to 6 fluorine atoms], and a 4- to 12-membered heterocyclyl group substituted by [0 to 2 -OH, 0 to 2 ^-OR49 , and 0 to 6 fluorine atoms].

(18) The compound according to any one of (1) to (16) or a pharmaceutically acceptable salt thereof, wherein A ² represents a 4- to 12-membered heterocyclylene substituted with ＝O; A ² is optionally selected from -OH, ＝O, -COOH, -SO ₃ H, -PO ₃ H, -CN, -NO ₂ , halogen, C _1-8 alkyl substituted with [0 to 2 -OH, 0 to 2 -OR ⁴⁵ , and 0 to 6 fluorine atoms], C _3-12 cycloalkyl substituted with [0 to 2 -OH, 0 to 2 -OR ⁴⁶ , and 0 to 6 fluorine atoms], C 1-8 alkoxy substituted with [0 to 2 -OH, 0 to 2 -OR ⁴⁷ , and 0 to 6 fluorine atoms], and C _1-8 alkoxy substituted with [0 to 2 -OH, 0 to 2 -OR ⁴⁹ , and 0 to 6 fluorine atoms] substituted by 1 to 4 substituents in a 4- to 12-membered heterocyclic group.

(19) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (18), wherein X represents CR ¹¹ , Y represents CR ¹² , and Z represents CR ¹³ , and R ¹¹ or R ¹³ is bonded to [A ¹ , A ² , or A ³ ] via [a single bond, -O-, -NR ⁵¹ -, or -S(=O) _p -] to form a ring.

(20) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (19), wherein A ³ is a hydrogen atom.

(21) The compound according to any one of (1) to (19) or a pharmaceutically acceptable salt thereof, wherein A ³ is halogen, -CN, -R ²⁵ , -OR ²⁶ , -NR ²⁷ R ²⁸ , -C(═O)R ²⁹ , or -C(═O)-OR ³⁰ , and R ²⁵ to R ³⁰ each independently represent a hydrogen atom, an optionally substituted C _1-8 alkyl group, an optionally substituted 4- to 12-membered heterocyclic group, an optionally substituted C _3-12 cycloalkyl group, an optionally substituted (4- to 12-membered heterocyclic group)C _1-3 alkyl group, or an optionally substituted (C _3-12 cycloalkyl)C _1-3 alkyl group.

(22) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (21), wherein R ³ is a hydrogen atom.

(23) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (21), wherein R ³ represents a C _1-4 alkyl group, a fluorine atom, or a chlorine atom.

(24) A compound selected from the following compounds or pharmaceutically acceptable salts thereof.

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-pyridinyl)amino]-8-(tetrahydrofuran-3-ylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol

1-[2-[(5-piperazin-1-yl-2-pyridinyl)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-pyridinyl]amino]-8-(tetrahydropyran-4-ylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol

(1R)-1-[2-[[5-(Piperazin-1-ylmethyl)-2-pyridinyl]amino]-8-[[(3S)-tetrahydropyran-3-yl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol

(1R)-1-[2-[[5-(Piperazin-1-ylmethyl)-2-pyridinyl]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-pyridine]-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-pyridine]-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-(isopropylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol

(1R)-1-[2-[[5-(4,7-diazaspiro[2.5]octan-7-ylmethyl)-2-pyridinyl]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-piperidinyl]propan-2-ol

(1R)-1-[2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridinyl]amino]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol

(1R)-1-[2-[[5-[2-(Dimethylamino)ethoxy]-2-pyridinyl]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-pyridinyl]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-pyridinyl]-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-pyridine]-1-[(2R)-2-hydroxypropyl]-1,4-diazepan-5-one

N8-isopropyl-N2-[5-(piperazin-1-ylmethyl)-2-pyridine]-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)cyclohexyloxy]-2-pyridinyl]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-pyridine]-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-pyridinyl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol

(1R)-1-[2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridinyl]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-pyridine]-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-pyridine]-1,4-diazepan-5-one

(1R)-1-[8-(Isopropylamino)-2-[(6-methyl-5-piperazin-1-yl-2-pyridinyl)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-pyridine]-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-pyridinyl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol

(1R)-1-[8-(Isopropylamino)-2-[[5-[(2S)-2-methylpiperazin-1-yl]-2-pyridinyl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol

N8-Isopropyl-N2-(5-piperazin-1-yl-2-pyridine)-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-pyridinyl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol

(1R)-1-[8-(Cyclopropylmethylamino)-2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridinyl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol

6-(3-Methyloxetane-3-yl)-N2-(5-piperazin-1-yl-2-pyridine)-N8-propyl-pyrido[3,4-d]pyrimidine-2,8-diamine

6-(3-Methyloxetan-3-yl)-N2-[5-(piperazin-1-ylmethyl)-2-pyridine]-N8-propyl-pyrido[3,4-d]pyrimidine-2,8-diamine

N2-(5-Piperazin-1-yl-2-pyridine)-N8-propyl-6-tetrahydrofuran-3-yl-pyrido[3,4-d]pyrimidine-2,8-diamine

N2-[5-(Piperazin-1-ylmethyl)-2-pyridine]-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-pyridine)pyrido[3,4-d]pyrimidine-2,8-diamine

N8-Isopropyl-N2-(5-piperazin-1-yl-2-pyridine)-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-piperidinyl]methyl]-2-pyridinyl]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-piperidinyl]methyl]-2-pyridinyl]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-piperidinyl]methyl]-2-pyridinyl]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-pyridinyl]amino]-8-(propylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol

(25) A pharmaceutical composition comprising the compound according to any one of (1) to (24) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(26) A pharmaceutical composition having CDK4/6 inhibitory activity, comprising the compound described in any one of (1) to (24) or a pharmaceutically acceptable salt thereof as an active ingredient.

(27) A preventive or therapeutic drug for rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer, comprising the compound described in any one of (1) to (24) or a pharmaceutically acceptable salt thereof as an active ingredient.

Effects of the Invention

The compound of the present invention has excellent CDK4/6 inhibitory activity and is useful as a preventive or therapeutic agent for rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[ Fig. 1 ] is a graph showing the scoring results of administering the compound of the present invention to mice.

DETAILED DESCRIPTION

The various structures (groups) of the compound represented by general formula (I) of the present invention are described below. Regarding the term "group," for example, "(cycloalkyl)alkyl" refers to a group bonded to an alkyl group via a cycloalkyl group, with the alkyl side being the side bonded to the other structure. Similarly, "(heterocyclyl)alkyl" refers to a group bonded to an alkyl group via a heterocyclyl group, with the alkyl side being the side bonded to the other structure.

Please note that in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms thereof, except where the content clearly indicates otherwise.

In the present invention, for example, "a _C3-6 cycloalkyl group substituted with [0 to 2 -OH groups, 0 to 2 _C1-8 alkoxy groups, and 0 to 6 fluorine atoms]" means a group substituted with 0 to 2 -OH groups, 0 to 2 C1-8 alkoxy groups, and 0 to 6 fluorine atoms. For example, a C3-6 cycloalkyl group substituted with 2 -OH groups, 1 C1-8 alkoxy group, and 3 fluorine atoms, a _C3-6 cycloalkyl group substituted with 2 _C1-8 alkoxy groups and 4 fluorine atoms, and a _C3-6 cycloalkyl group substituted with 1 -OH group, etc., where all the numbers are 0, means a completely unsubstituted _C3-6 cycloalkyl group.

"C _1-8 " means having 1 to 8 carbon atoms, while "C _1-6 " refers to a structure having 1 to 6 carbon atoms in the context of "C _1-8 ". Similarly, "5- to 10-membered" refers to a structure consisting of 5 to 10 carbon atoms, and "5- to 6-membered" refers to "5- to 6-membered" in the context of "5- to 10-membered".

The meaning of each group in this specification is described below, but the groups are not limited to the groups listed as examples.

The alkyl group in the present invention refers to a monovalent group obtained by removing one hydrogen atom from any carbon atom of an alkane.

The alkylene group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from any carbon atom of an alkane.

The alkane in the present invention refers to a saturated aliphatic hydrocarbon.

The "C _1-8 alkyl group" in the present invention refers to a linear or branched carbon chain having 1 to 8 carbon atoms, and examples thereof 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, and isooctyl.

In the present invention, the term "C _1-8 alkylene" refers to an alkane having a linear or branched carbon chain of 1 to 8 carbon atoms, and examples thereof 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, and 2-methylheptane.

The cycloalkyl group in the present invention refers to a monovalent group obtained by removing one hydrogen atom from any carbon atom of a cycloalkane.

The cycloalkylene group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from any two different carbon atoms of a cycloalkane.

The cycloalkylidene group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from one carbon atom of a cycloalkane.

The cycloalkane in the present invention refers to an alicyclic hydrocarbon.

The cycloalkane of the "C _3-12 cycloalkyl group" in the present invention, the "C _3-12 cycloalkylene group" in the present invention, and the "C _3-12 cycloalkylidene group" in the present invention refers to a monocyclic or polycyclic 3- to 12-membered aliphatic hydrocarbon ring, and specific examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, spiro[3.3]heptane, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane, and adamantane.

The heterocyclic group in the present invention refers to a monovalent group obtained by removing one hydrogen atom from any carbon atom or nitrogen atom in a heterocyclic ring.

The heterocyclic group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from any two different carbon atoms or nitrogen atoms in a heterocycle.

The heterocycloalkylidene group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from one carbon atom of a heterocycle.

The heterocyclic ring in the present invention refers to a ring containing a heteroatom selected from a sulfur atom, a nitrogen atom, and an oxygen atom.

The heterocycles in the "4- to 12-membered heterocyclic group," the "4- to 12-membered heterocyclylene group," and the "4- to 12-membered heterocycloalkylidene group" herein refer to "4- to 12-membered heterocycloalkane," a ring having an unsaturated bond in a "4- to 12-membered heterocycloalkane," a ring having 4- to 12-membered members in which a heterocycloalkane is partially bonded to a heteroaromatic hydrocarbon or aromatic hydrocarbon, a ring having 4- to 12-membered members in which a cycloalkane is partially bonded to a heteroaromatic hydrocarbon, a ring having 4- to 12-membered members in which a heteroatom is contained, a ring having a spiro structure containing 4- to 12-membered heteroatoms, and a ring having a cross-linked structure containing 4- to 12-membered heteroatoms. "4- to 12-membered heterocycloalkane" refers to a monocyclic or polycyclic aliphatic hydrocarbon ring, a 4- to 12-membered cyclic heteroalkane containing 1 to 4 heteroatoms selected from sulfur atoms, nitrogen atoms, and oxygen atoms. Specific examples of the “4- to 12-membered heterocycloalkane” include aziridine, thiirane, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, piperidine, piperazine, pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydrothiophene, 1,4-diazepane, and oxepane. "Spirocyclic structure" refers to a compound in which two ring structures (cycloalkanes or heterocycloalkanes) share one carbon atom, and examples thereof 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, and 4,7-diazaspiro[2.5]octane. "Cross-linked structure" refers to a compound in which two ring structures (cycloalkanes or heterocycloalkanes) share two or more carbon atoms, nitrogen atoms, or oxygen atoms, and examples thereof include 2,5-diazabicyclo[2.2.2]octane, 3,8-diazabicyclo[3.2.1]octane, 1,4-diazabicyclo[3.2.2]nonane, and octahydropyrrolo[3,4-b]pyrrole.

The aryl group in the present invention refers to a monovalent group obtained by removing one hydrogen atom from any carbon atom of an aromatic hydrocarbon.

The arylene group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from any carbon atom of an aromatic hydrocarbon.

The aromatic hydrocarbons in the present invention refer to aromatic hydrocarbons.

The "C _6-10 aryl group" and the aromatic hydrocarbon of the "C _6-10 arylene group" in the present invention refer to an aromatic hydrocarbon ring having 6 to 10 carbon atoms, and specific examples thereof include benzene and naphthalene.

The heteroaryl group in the present invention refers to a monovalent group obtained by removing one hydrogen atom from any carbon atom or nitrogen atom of a heteroarene.

The heteroarylene group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from any carbon atom or nitrogen atom of heteroarene.

The heteroaromatic hydrocarbon in the present invention refers to an aromatic heterocycle containing a heteroatom selected from a sulfur atom, a nitrogen atom, and an oxygen atom.

The "5- to 10-membered heteroaryl group" and the heteroarene group of the "5- to 10-membered heteroarylene group" in the present invention refer to a 5- to 10-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from sulfur atoms, nitrogen atoms, and oxygen atoms. Specific examples thereof include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, and benzimidazole.

In the present invention, "(4- to 12-membered heterocyclic group) C _1-6 alkyl" refers to a group in which a 4- to 12-membered heterocyclic group is bonded to a C _{1-6 alkyl} group, which is in turn bonded to another structure. Specifically, groups bonded to the specific examples of the above-mentioned 4- to 12-membered heterocyclic group and the specific examples of the above-mentioned C _1-6 alkyl group are included.

In the present invention, "(C _6-10 aryl)C _1-6 alkyl" refers to a group in which a C _6-10 aryl group is bonded to a C _{1-6 alkyl} group, which is in turn bonded to another structure. Specifically, the group includes the groups bonded to the specific examples of the C _6-10 aryl group and the specific examples of the C _1-6 alkyl group described above.

In the present invention, "(5- to 10-membered heteroaryl)C _1-6 alkyl" refers to a group in which a 5- to 10-membered heteroaryl group is bonded to a C _{1-6 alkyl} group, which is in turn bonded to another structure. Specifically, groups bonded to the specific examples of the above-mentioned 5- to 10-membered heteroaryl group and the specific examples of the C _1-6 alkyl group are included.

The "C _1-8 alkylsulfonyl group" in the present invention refers to a group in which a C _1-8 alkyl group is bonded to a sulfonyl group (-S(=O) ₂ -), and the sulfonyl group is bonded to another structure.

The "C _1-8 acyl group" in the present invention refers to a group in which a C _1-7 alkyl group is bonded to a carbonyl group (-CO-), and the carbonyl group is bonded to another structure.

The "halogen" in the present invention refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The "C _1-8 alkoxy group" in the present invention refers to a linear, branched, or cyclic alkoxy group having 1 to 8 carbon atoms. Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, neopentyloxy, tert-pentyloxy, 2-methylbutoxy, n-hexyloxy, isohexyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, spiro[3.3]heptyloxy, and bicyclo[2.2.2]octyloxy.

The alkenyl group in the present invention refers to a monovalent group obtained by removing one hydrogen atom from any carbon atom of an alkene.

The alkenylene group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from any carbon atom of an alkene.

In the present invention, olefins refer to unsaturated aliphatic hydrocarbons with one double bond. " _C2-8 alkenyl" in the present invention refers to chain aliphatic hydrocarbons with one double bond, and examples include vinyl (also known as ethenyl), propenyl (also known as allyl), and butenyl.

The alkynyl group in the present invention refers to a monovalent group obtained by removing one hydrogen atom from any carbon atom of alkyne.

The alkynylene group in the present invention refers to a divalent group obtained by removing two hydrogen atoms from any carbon atom of alkyne.

In the present invention, alkyne refers to an unsaturated aliphatic hydrocarbon having a triple bond.

The "C _2-4 alkynyl group" in the present invention is a chain hydrocarbon group having a triple bond, and examples thereof include ethynyl, propynyl, and butynyl.

L is preferably -NR ⁵ -.

The "C _1-6 alkyl" in R ⁵ is preferably methyl or ethyl.

As all R ⁵ , a hydrogen atom or a methyl group is preferred.

The “C _1-8 alkyl” in R ¹ 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.

The "C _3-12 cycloalkyl group" in R ¹ is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptyl, bicyclo[1.1.1]pentane, bicyclo[2.2.2]octyl, or adamantyl.

The "(C _3-12 cycloalkyl)C _1-6 alkyl" in R ¹ is preferably cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, or cyclopentylethyl.

The heterocycle in the "4- to 12-membered heterocyclic group" in R ¹ is preferably azetidine, oxetane, thietane, tetrahydrofuran, 1,4-dioxane, morpholine, thiomorpholine, tetrahydropyran, tetrahydrothiophene, or oxepane.

The "(4- to 12-membered heterocyclic group) C _1-6 alkyl group" in R ¹ is preferably (tetrahydrofuranyl)methyl, (tetrahydropyranyl)methyl, (tetrahydrofuranyl)ethyl, or (tetrahydropyranyl)ethyl.

The "C _6-10 aryl group" in R ¹ is preferably a phenyl group.

The "(C _6-10 aryl)C _1-6 alkyl" in R ¹ is preferably phenylmethyl or phenylethyl.

The "5- to 10-membered heteroaryl group" in R ¹ is preferably furyl, pyrazolyl or thienyl.

The "halogen" in the substituent of R ¹ is preferably a fluorine atom or a chlorine atom.

"-COOR ⁶ " in the substituent of R ¹ is preferably -COOH or -COOCH ₃ .

"R ⁷ " in the substituent of R ¹ 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.

The "C _3-6 cycloalkyl group optionally substituted with a substituent selected from [1 to 2 -OH groups, 1 to 2 C _1-8 alkoxy groups, and 1 to 6 fluorine atoms]" in the substituent of R ¹ is preferably a cyclopentyl group, a cyclohexyl group, a 4-methoxycyclohexyl group, or a 4-isopropoxycyclohexyl group.

The 3- to 10-membered heterocyclic group optionally substituted with a substituent selected from [1 to 2 -OH groups, 1 to 2 C _1-8 alkoxy groups, and 1 to 6 fluorine atoms] among the substituents of R ¹ is preferably tetrahydrofuranyl, tetrahydropyranyl, or 2,2-dimethyltetrahydropyranyl.

As all R ¹ , the following structures are preferred.

The "C _1-8 alkyl" in R ² is preferably a methyl group, an ethyl group, or an n-propyl group, and the substituent is preferably a hydroxyl group, a methoxy group, an ethoxy group, or a fluorine atom. The "4- to 6-membered heterocyclic group" in ^{R 2} is preferably an oxetane group or a tetrahydrofuranyl group.

The "C _1-8 acyl group" in R ² is preferably an acetyl group.

"-COOR ⁸ " in R ² is preferably -COOH or -COOCH ₃ .

"-CONR ⁹ R ¹⁰ " in R ² is preferably -CON(CH ₃ ) ₂ .

In -CONR ⁹ R ¹⁰ of R ² , R ⁹ and R ¹⁰ may be bonded via a single bond or —O— to form a ring including the nitrogen atom bonded thereto. For example, the following structures may be mentioned.

As a ^whole , the following structures are preferred.

The "C _1-8 alkyl" in R ³ is preferably methyl.

The "halogen" in R ³ is preferably a fluorine atom or a chlorine atom.

As all R ³ , a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group is preferable.

X, Y, and Z are preferably a combination of X, Y, and Z being CH; X being a nitrogen atom and Y and Z being CH; Y being a nitrogen atom and X and Z being CH; and Z being a nitrogen atom and X and Y being CH.

The "C _1-8 alkylene group" in A ¹ is preferably a methylene group, an ethylene group, or an n-propylene group.

_{Preferred structures in} ^{which A1} is substituted with ₁ or ₂ ^sp3 carbon atoms _at any position _include -O- _, -OCH2-, _{-OCH2CH2- ,} -OCH2CH2CH2- _, -CH2O- _, -CH2OCH2- _, -CH2OCH2CH2- ^, -CH2CO- _, -COCH2- _{, -CH2CH2CO-} ^, _{-COCH2CH2- , -CH2COCH2-} ^, _{-CH2COCH2CH2- , -NR14- ,} ^-NR14CH2- _{, -CH2NR14- , -NR14CH2CH2- , -CH2NR14CH2-} ^, _{-CH2CH2NR14- .}

The "C _1-7 alkylene group" in A ² is preferably a methylene group, an ethylene group, or a n-propylene group.

The "C _3-12 cycloalkylene group" in A ² is preferably a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, or a cyclohexylene group.

The heterocycle in the "4- to 12-membered heterocyclylene" in ^A2 is preferably piperidine, piperazine, pyrrolidine, morpholine, tetrahydrofuran, tetrahydropyran, 1,4-diazacycloheptane, 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-diazaspiro[3.5]octane, Bicyclo[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.

The heterocycle in the "4- to 12-membered heterocycloalkylidene group" in ^A2 is preferably oxetane, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, morpholine, or oxepane.

The "C _6-10 arylene group" in A ² is preferably a phenylene group.

The heteroarene in the "5- to 10-membered heteroarylene" in ^A2 is preferably furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, or benzimidazole.

The "halogen" in ^A3 is preferably a fluorine atom or a chlorine atom.

"-R ²⁵ " in A ³ is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group. When -R ²⁵ is substituted with a substituent, it is preferably a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2-hydroxy-2-propyl group, a 2-hydroxy-1-propyl group, a 1-hydroxy-2-propyl group, a 1-hydroxy-2-methyl-2-propyl group, a 2-hydroxy-2-methyl-1-propyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a carboxymethyl group, a 1-carboxyethyl group, a 2-carboxyethyl group, a 2-carboxy-2-propyl group, or a cyanomethyl group.

"-OR ²⁶ " in A ³ is preferably -OH, methoxy, ethoxy, or isopropoxy.

"-NR ²⁷ R ²⁸ " in A ³ is preferably amino, dimethylamino, methylamino, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl.

"-C(=O)R ²⁹ " in A ³ is preferably an acetyl group. When -C(=O)R ²⁹ is substituted with a substituent, it is preferably a hydroxyacetyl group.

"-C(=O)-OR ³⁰ " in A ³ is preferably -COOH, methoxycarbonyl, ethoxycarbonyl, or isopropoxycarbonyl.

"-C(=O)-NR ³⁴ R ³⁵ " in A ³ is preferably aminocarbonyl (also known as carbamoyl), (methylamino)carbonyl, (dimethylamino)carbonyl, (pyrrolidin-1-yl)carbonyl, (piperidin-1-yl)carbonyl, (morpholin-1-yl)carbonyl, or (piperazin-1-yl)carbonyl.

"-S(=O) ₂ -R ⁴⁰ " in A ³ is preferably a methylsulfonyl group or an ethylsulfonyl group.

R ¹⁴ to R ⁴⁴ in A ¹ , A ² , and A ³ may be bonded via a ^single bond, -O-, -NR ⁵⁰ -, or -S(=O) _{p -} to form a ring within A ¹ , within A ² , within A ³ , between A 1 and A ² , between A ^{1 and} A ³ , or between A ² and A 3. Examples of the structures include the following.

R ¹¹ or R ¹³ may be bonded to [A ¹ , A ² , or A ³ ] via [single bond, -O-, -NR ⁵¹ -, or -S(=O) _p -] to form a ring. Examples of the rings include the following structures.

As a whole of the above-mentioned structures, the following structures are preferable.

Among the compounds represented by formula (I), compounds having the above-mentioned definitions and preferred groups of the respective groups, or combinations of the preferred groups, are preferred compounds.

The compound represented by formula (I) of the present invention can be converted into a medically acceptable salt as needed. Examples of such salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; 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, benzenesulfonic acid, and p-toluenesulfonic acid; and salts with amino acids such as lysine, arginine, ornithine, glutamic acid, and aspartic acid. salts with alkali metals such as sodium, potassium and lithium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as aluminum, zinc and iron; salts with organic bases such as methylamine, ethylamine, tert-octylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, piperidine, piperazine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N-methylglucamine, tris(hydroxymethyl)aminomethane and N,N'-dibenzylethylenediamine; ammonium salts, etc.

The present invention also includes compounds represented by formula (I) in which one or more atoms are substituted by stable isotopes or radioactive isotopes.

The present invention also includes stereoisomers, racemates, and all possible optically active forms of the compound represented by formula (I). Furthermore, the compounds of the invention may sometimes form tautomers depending on the combination of substituents; such tautomers also belong to the compounds of the present invention.

A representative synthesis method of the compound of the present invention represented by general formula (I) is described below.

The compounds of the present invention can be synthesized by the following methods. In each formula, R ¹ , R ³ , R ⁴ , and R ⁷ are as defined in formula (I). The reagents and solvents listed as conditions in the chemical formulas are as described herein and are provided for illustrative purposes only. Each substituent may be protected with an appropriate protecting group as needed, and deprotection may be performed at an appropriate stage (reference: Protective Groups in Organic Synthesis, 4th Edition, John Wiley & Sons, Inc.). The abbreviations for substituents, reagents, and solvents used herein and in the tables are shown below.

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-butyldimethylsilane

BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

TBDPS: tert-butyldiphenylsilane

DIPEA: N,N-diisopropylethylamine

LAH: lithium aluminum hydroxide

DMAP: 4-dimethylaminopyridine

Ac：Acetyl

Ms：Methylsulfonyl

WSC: Water-soluble carbodiimide (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)

m-CPBA: meta-chloroperbenzoic acid

DAST: Diethylaminosulfur trifluoride

dba: dibenzylideneacetone

DIBAL-H: diisobutylaluminum hydride.

1) Synthesis of compound I-e

The compound represented by compound I-e is a known compound and can be synthesized by methods known to those skilled in the art. For example, it can be synthesized using the above-described steps.

2) Synthesis of Compound I-e to Compound I-f

Compound Ie is reacted with a terminal alkyne derivative represented by R 2 -C≡CH in the presence of a suitable palladium catalyst (e.g., tetrakistriphenylphosphine palladium), a suitable copper catalyst (e.g., copper(I) iodide), a suitable base (e.g., triethylamine), and a suitable organic solvent (e.g., THF, DMF) at a temperature ranging from ⁰ °C to reflux to obtain compound If.

3) Synthesis of Compound I-f to Compound I-h

Compound I-f is reacted with hydroxylamine or a salt thereof in a suitable organic solvent (e.g., ethanol) in the presence or absence of a suitable base (e.g., sodium acetate) at a temperature from 0°C to reflux, followed by hydroxyimidation, and then reacted with a suitable acid or base (e.g., silver trifluoromethanesulfonate, potassium carbonate) to obtain compound I-h.

4) Synthesis of Compound I-i from Compound I-h

Compound I-h is reacted with a suitable halogenating agent (eg, thionyl chloride) in a suitable organic solvent (eg, dichloromethane) or without a solvent at a temperature ranging from 0°C to 140°C to obtain compound I-i.

5) Synthesis of Compound I-i to Compound I-j

Compound Ij is obtained by reacting compound Ii with an amine derivative, alcohol derivative, or thiol derivative represented by R 1 -LH in the presence or absence of a suitable base (e.g., triethylamine, potassium carbonate, sodium hydride) in a suitable organic solvent (e.g., THF, ^1,4 -dioxane) or without a solvent at a temperature ranging from 0°C to reflux of the solvent.

Furthermore, at this stage, R ² can be varied according to the target structure using methods known to those skilled in the art.

6) Synthesis of Compound I-k from Compound I-j

Compound I-j is reacted with a suitable oxidizing agent (e.g., potassium persulfate (Oxone) (R), m-chloroperbenzoic acid) in a suitable organic solvent (e.g., dichloromethane, water) at a temperature ranging from 0°C to reflux of the solvent to obtain compound I-k.

7) Synthesis of Compound I-1 from Compound I-k

Compound I-k is reacted with a suitable halogenating agent (eg, N-chlorosuccinimide) in a suitable organic solvent (eg, dichloromethane, 1,2-dichloroethane) at a temperature ranging from 0°C to reflux to obtain compound I-1.

Furthermore, at this stage, R ³ can be modified according to the target structure using methods known to those skilled in the art.

8) Synthesis of Compound I-1 to Compound I-m

Compound Il is reacted with an amine derivative represented by the above formula R 4 -(nitrogen-containing heteroaryl containing X, Y and Z)-NH ² in a suitable organic solvent (e.g., NMP, THF, toluene) or in the absence of a suitable base (e.g., sodium hydride, triethylamine, N,N-diisopropyl-N-ethylamine) at a temperature ranging from 0° _C to reflux of the solvent to obtain compound Im.

When L, ^R1 , ^R2 , and ^R4 in Compound Im are protected with appropriate protecting groups, they can be deprotected using methods known to those skilled in the art. For example, deprotection can be achieved by reacting with an appropriate deprotecting agent (e.g., TFA or hydrogen chloride for a Boc protecting group; lithium hydroxide for a benzoyl protecting group; hydrogen in the presence of Pd/C for a Cbz protecting group) in an appropriate organic solvent (e.g., dichloromethane, methanol, THF) or in the absence of a solvent at a temperature between 0°C and reflux. (Reference: Green's Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons Inc.)

When compound I-m is protected by multiple protecting groups, deprotection can be carried out in an appropriate order according to the structure of compound I-m.

In the reactions shown in 9) to 13) below, L, R ¹ , R ² , and R ⁴ in compound Im are appropriately protected according to the respective reaction conditions. After each reaction, deprotection can be performed by an appropriate method.

9) Synthesis of Compound I-n from Compound I-m

In a suitable organic solvent (e.g., dichloromethane, NMP, THF), in the presence or absence of a suitable acid (boron trifluoride diethyl ether complex) or a suitable base (e.g., potassium carbonate, triethylamine), at a temperature range of 0°C to reflux of the solvent, a compound Im having a primary or secondary amine structure in ^R4 is reacted with an optionally substituted epoxide to obtain a compound In.

10) Synthesis of Compound I-o from Compound I-m

Compound Im having a primary or secondary amine structure in R4 is reacted with a carboxylic acid chloride, a carboxylic anhydride, or a carboxylic acid and a condensing agent in a suitable organic solvent (e.g., NMP, THF, pyridine) or in the presence or absence of a suitable base (e.g., triethylamine, N,N-diisopropyl-N-ethylamine) at a temperature range of 0° ^C to reflux of the solvent to obtain compound Io.

11) Synthesis of Compound I-p from Compound I-m

Compound Im having a primary or secondary amine structure in R4 is reacted with a sulfonic acid chloride in a suitable organic solvent (e.g., NMP, THF, pyridine) in the presence or absence of a suitable base (e.g., triethylamine, N,N-diisopropyl-N-ethylamine) at a temperature range of 0° ^C to reflux of the solvent to obtain compound Ip.

12) Synthesis of Compound I-q from Compound I-m

Compound Im having a primary or secondary amine structure in ^R4 is reacted with an optionally substituted ketone or an optionally substituted aldehyde and a suitable reducing agent (e.g., sodium triacetylborohydride, sodium cyanoborohydride) in a suitable organic solvent (e.g., NMP, methanol) in the presence of a suitable acid (e.g., acetic acid) at a temperature ranging from room temperature to reflux of the solvent to obtain compound Iq.

13) Synthesis of Compound I-r from Compound I-m

Compound Im having a primary or secondary amine structure in R4 is reacted with a compound bonded to a leaving group such as a halogen atom or a sulfonyloxy group in a suitable organic solvent (e.g., NMP, THF, pyridine) or in the absence of a suitable base (e.g., triethylamine, N,N-diisopropyl-N-ethylamine) at a temperature range of 0° ^C to reflux of the solvent to obtain compound Ir.

14) Synthesis of Compound I-s from Compound I-m

Compound Im having a primary or secondary amine structure in R ⁴ is reacted with a compound having a Michael acceptor structure in a suitable organic solvent (eg, methanol, THF) at a temperature ranging from 0°C to reflux to obtain compound Is.

Since the compounds of the present invention have CDK4/6 inhibitory activity, they are useful for the prevention or treatment of diseases mediated by CDK4/6. Specifically, they are useful for the treatment of rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, cancer, and bone marrow protection, and are particularly effective for the treatment of rheumatoid arthritis and cancer, and bone marrow protection.

Furthermore, the compounds of the present invention preferably exhibit selective inhibitory activity against CDK4/6 over other kinases. For example, they preferably exhibit selective inhibition against CDK2. Since CDK2 inhibition is also associated with DNA replication, selective inhibition can be expected to reduce concerns about genotoxicity. Among the compounds of the present invention, selective inhibition of CDK4 over CDK2 is preferred.

The active ingredient of the present invention can be used as any suitable preparation in any dosage form such as solid preparation, semisolid preparation, and liquid preparation, and any suitable preparation such as oral preparation and parenteral preparation (injection, transdermal preparation, eye drop, suppository, nasal drop, inhalation, etc.).

The preparation containing the active ingredient of the present invention is prepared using additives commonly used in pharmaceutical preparations. Examples of these additives include, for solid preparations, excipients such as lactose, white sugar, glucose, corn starch, potato starch, crystalline cellulose, light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminosilicate, and calcium hydrogen phosphate; binders such as crystalline cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone; disintegrants such as starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, and sodium carboxymethyl starch; and talc. , and lubricants such as stearic acid; coating agents such as hydroxymethylpropyl cellulose, hydroxypropyl methylcellulose phthalate, and ethyl cellulose; colorants; in the case of semi-solid preparations, bases such as white petrolatum can be listed; in the case of liquid preparations, solvents such as ethanol, dissolution aids such as ethanol, preservatives such as paraoxybenzoic acid esters, tonic agents such as glucose, buffers such as citric acid, antioxidants such as L-ascorbic acid, chelating agents such as EDTA, and suspending agents and emulsifiers such as polysorbate 80 can be listed.

The dosage of the active ingredient of the present invention is usually about 1 to 1000 mg/day, and the frequency of administration is usually 1 to 3 times/day.

Example

The present invention will be described below based on specific examples, but the present invention is not limited to these examples.

The structure of the isolated novel compound is confirmed by ¹ H-NMR and/or mass spectrometry using a single quadrupole instrumentation equipped with an electrospray source, or other appropriate analytical methods.

^1H -NMR spectra (400 MHz, DMSO- _d6 , _CD3OD , or _CDCl3 ) show chemical shifts (δ: ppm) and coupling constants (J: Hz). The following symbols represent the following: s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet. Mass spectrometry results are shown as (M+H) ⁺ , i.e., values obtained by adding protons (H ⁺ ) to the molecular mass (M) of the compound.

[Reference Example 1]

Synthesis of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid

To a 2.5 L aqueous solution of 2-methyl-2-isothiourea sulfate (324 g, 1.16 mol) was added mucobromic acid (300 g, 1.16 mol) at room temperature. The suspension was stirred and cooled to 0°C, and triethylamine (486 mL, 3.49 mol) was added dropwise over 4 hours. The reaction solution was stirred overnight. After confirming the completion of the reaction by silica gel TLC, the reaction solution was acidified with concentrated hydrochloric acid (approximately 250 mL). The resulting yellow solid was collected by filtration, washed twice with water (500 mL), and then twice with diethyl ether (500 mL). The resulting solid was dried under reduced pressure to yield the title compound (160 g, 55%).

[Reference Example 2]

Synthesis of 5-bromo-2-methylthiopyrimidine-4-carboxylic acid methyl ester

A methanol solution (1.1 L) of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (110 g, 0.44 mol) was stirred and cooled to 0°C, followed by the dropwise addition of thionyl chloride (50 mL, 0.66 mol). The reaction solution was slowly heated and allowed to react under reflux for 4 hours. Completion of the reaction was confirmed by LC/MS and TLC, and the reaction solution was cooled to room temperature. The volatile components were removed under reduced pressure, and the residue was dissolved in ethyl acetate (1 L), washed three times with 10% aqueous sodium carbonate (200 mL) and twice with saturated brine (200 mL). The resulting organic phase was dried over 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 (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

Under a nitrogen atmosphere, a THF solution (375 mL) of methyl 5-bromo-2-methylsulfanylpyrimidine-4-carboxylate (25 g, 95 mmol) was cooled to -78°C and stirred. DIBAL-H (84 mL, 143 mmol, 1.7 M in toluene) was added dropwise to the solution and stirred at -78°C for 4 hours. After confirming the completion of the reaction by TLC, methanol was added dropwise at -78°C to terminate the reaction. The reaction solution was then slowly warmed to 0°C. The reaction solution was diluted with ethyl acetate and filtered through Celite with suction. The filtrate was washed twice with saturated brine (200 mL). The resulting organic phase was dried over anhydrous magnesium sulfate and the solid was isolated by filtration. The filtrate was concentrated to obtain a mixture of the title compounds (25 g, crude). This crude product was used in the next reaction without further purification.

[Reference Example 4]

Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate

5-Bromo-2-nitropyridine (203 g, 1.37 mol), piperazine (153 g, 1.77 mol), tetrabutylammonium iodide (25.2 g, 0.068 mol), and potassium carbonate (207 g, 1.50 mol) were stirred in dimethyl sulfoxide (2.6 L) at 80°C overnight. After cooling the reaction solution to room temperature, it was poured into water (7 L) and the resulting solid was collected by filtration. The resulting 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 with saturated brine (2 L) and concentrated under reduced pressure to obtain a solid. The resulting solids were combined and used in the next reaction without further purification.

The solid (490 g) was dissolved in THF (2 L) and water (500 mL), and sodium bicarbonate (119 g, 1.42 mol) was added. Di-tert-butyl diformate (262 g, 1.2 mol) was added to the suspension, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (1 L) and extracted with dichloromethane (1 L x 3). The resulting organic phases were combined and washed with water (1 L). The aqueous phase was extracted with dichloromethane (300 mL). The combined organic phases were dried over anhydrous magnesium sulfate.

The solid was separated by filtration and concentrated under reduced pressure. The resulting solid was suspended in ethyl acetate (2 L), heated to 60°C, and separated by filtration at 60°C. The resulting solid was dried under reduced pressure to obtain the title compound (191 g, 62%).

APCI-MS (M+H) ⁺ 309.1, C ₁₄ H ₂₀ N ₄ O ₄ = 308.15

¹ H-NMR δ (400MHz, CDCl ₃ ): 8.16 (d, J=9Hz, 1H), 8.11 (d, J=3Hz, 1H), 7.19 (dd, J=9.3Hz, 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

tert-Butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (83 g, 269 mmol) obtained in Reference Example 4 was dissolved in methanol (1.3 L) in a Parr Shaker, and Raney nickel (15 g, 50% aqueous suspension) was added. The reaction solution was stirred under a hydrogen atmosphere (50 psi) for 5 hours. The reaction solution was filtered through a Celite pad 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 4 hours. Heptane was added, and the mixture was cooled at 0°C for 45 minutes. The solid was separated by filtration and dried under reduced pressure to obtain the title compound (62.5 g, 83%).

ESI-MS (M+H) ⁺ 279, C ₁₄ H ₂₂ N ₄ O ₂ = 278.17.

The following intermediates A-1 to A-44 were synthesized by using the corresponding halogenated pyridine derivatives and amine derivatives according to the method of Reference Example 4 and/or 5 and carrying out appropriate protection and deprotection reactions as needed.

[Reference Example 6]

Synthesis of 6-aminopyridine-3-carboxaldehyde

6-Aminopyridine-3-carbonitrile (1.9 g, 16 mmol) was dissolved in THF (160 mL) and stirred while cooling to -78°C. Diisobutylaluminum hydride (106.5 mL, a 1.5 M solution in toluene) was slowly added dropwise to the solution at -78°C. The temperature was raised to 20°C with stirring and continued stirring for 2 hours. Ice water (100 mL) was added to the reaction solution to stop the reaction, and the mixture was extracted three times with dichloromethane (50 mL). The resulting organic phases were combined, washed once with brine (100 mL), and dried over anhydrous sodium sulfate. After filtering to separate the solid, the filtrate was concentrated under reduced pressure, and the residue was crudely purified by silica gel column chromatography to obtain a crude product of the title compound (1.7 g). This crude product was used in the next reaction without further purification.

[Reference Example 7]

Synthesis of tert-butyl 4-[(6-aminopyridin-3-yl)methyl]piperazine-1-carboxylate

The crude product of 6-aminopyridine-3-carboxaldehyde 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 stirred at room temperature for 8 hours. Sodium triacetoxyborohydride (8.84 g, 40.9 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by LC/MS. After completion, saturated aqueous sodium carbonate solution (50 mL) was added to stop the reaction, and the mixture was extracted three times with ethyl acetate (50 mL). The resulting organic phases were combined, washed once with brine (100 mL), and dried over anhydrous sodium sulfate. After filtering and separating the solid, the filtrate was concentrated under reduced pressure, and the residue was crudely purified by silica gel column chromatography to obtain the title compound (3.3 g, 81%).

[Reference Example 8]

Synthesis of di-tert-butyl (5-methylpyridin-2-yl)imidodicarboxylate

Referring to the method of WO2010/141406, 5-methylpyridin-2-amine (20 g, 185 mmol) and di-tert-butyl dicarboxylate (101 g, 462 mmol) were dissolved in THF (160 mL), and 4-N,N-dimethylaminopyridine (3.6 g, 29.7 mmol) was added. The reaction solution was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with water. The organic phase was washed with saturated brine and dried over 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. The resulting solid was filtered and dried under reduced pressure to obtain the title compound (25.1 g, 44%). The filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (17.9 g, 31%).

[Reference Example 9]

Synthesis of di-tert-butyl [5-(bromomethyl)pyridin-2-yl]imidodicarboxylate

Di-tert-butyl (5-methylpyridin-2-yl)imidodicarboxylate (17.2 g, 55.8 mmol), N-bromosuccinimide (12.17 g, 68.4 mmol), and benzoyl peroxide (1.5 g, 8.1 mmol) synthesized in Reference Example 8 were dissolved in carbon tetrachloride (100 mL) and stirred at 80°C for 6 hours. The reaction solution was cooled to room temperature, the resulting solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain a mixture of the title compound, di-tert-butyl [5-(dibromomethyl)pyridin-2-yl]imidodicarboxylate, and di-tert-butyl (5-methylpyridin-2-yl)imidodicarboxylate (14.5 g, 60.3:4.4:35.3, as determined by ^1H -NMR spectroscopy). The resulting mixture was used in the next reaction without further purification.

[Reference Example 10]

Di-tert-butyl [5-(bromomethyl)pyridin-2-yl]imidodicarboxylate (1 equivalent) was dissolved in DMF, and the appropriate amine derivative (1.5 equivalents) and N,N-diisopropyl-N-ethylamine (3 equivalents) were mixed at room temperature. The reaction solution was stirred at room temperature for several hours, then diluted with ethyl acetate and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired amine derivative.

[Reference Example 11]

Trifluoroacetic acid was added in excess to the compound obtained in Reference Example 10, and the mixture was stirred at room temperature for several hours. The reaction solution was concentrated under reduced pressure, and the resulting trifluoroacetate salt of the target compound was dissolved in methanol and adsorbed onto a strongly acidic cation exchange resin (SCX). The SCX column was washed with methanol, and aqueous ammonia (2 mol/L in methanol) was passed through the column to elute the target compound. The resulting eluate was concentrated under reduced pressure to obtain the target 2-aminopyridine derivative. The resulting product was used in the next reaction without further purification.

When the compound contains a primary or secondary amino group in addition to the aminopyridine structure, the resulting crude product is dissolved in THF and reacted with di-tert-butyl dicarbonate at room temperature. After completion of the reaction, the solvent is distilled off and the resulting residue is crudely purified by silica gel column chromatography to obtain a 2-aminopyridine derivative in which the primary or secondary amino group is protected by a Boc group.

According to any one of the methods or a combination of methods in Reference Examples 6 and/or 7, or Reference Examples 8 to 11, the corresponding aldehyde derivatives, or the corresponding alkyl halide derivatives, and the corresponding amine derivatives are used to carry out appropriate protection and deprotection reactions as needed to synthesize the following intermediates B-1 to B-68.

[Reference Example 12]

The appropriate amide derivative (1 equivalent) was dissolved in DMF. Sodium hydride (1 equivalent) was added in small amounts at 0°C, and the mixture was stirred at room temperature for several minutes. The reaction solution was cooled to 0°C, and di-tert-butyl [5-(bromomethyl)pyridin-2-yl]imidodicarboxylate (1.5 equivalents) was added in small amounts. After stirring the reaction solution at room temperature for several hours, water was added to quench the reaction, followed by extraction with ethyl acetate and washing with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the desired amide derivative.

According to the methods of Reference Examples 12 and 11, the corresponding alkyl halide derivatives, the corresponding amide derivatives, or the corresponding urea derivatives were used, and appropriate protection and deprotection reactions were carried out as needed to synthesize the following intermediates C-1 to C-5.

[Reference Example 13]

Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)-3-oxopiperazine-1-carboxylate

Referring to the method described in WO2012/031004, 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 bubbled with nitrogen for 30 minutes. Xantphos (246 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium (229 mg, 0.25 mmol) were added to the suspension, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, water and ethyl acetate were added, and the mixture was filtered through Celite. The organic phase of the filtrate was separated, and the aqueous phase was extracted with ethyl acetate. The resulting organic phases were combined, dried over anhydrous sodium sulfate, filtered to isolate the solid, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (1.08 g, 67%).

¹ H-NMR (CDCl ₃ ) δ: 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

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

¹ H-NMR (CDCl ₃ ) δ: 7.99 (1H, d, J = 2.4Hz), 7.38 (1H, dd, J = 8.8, 2.4Hz), 6.53 (1H, d, J = 8.8Hz), 4.50 (2H , brs), 4.24 (2H, s), 3.78 (2H, t, J = 5.1Hz), 3.67 (2H, t, J = 5.4Hz), 1.50 (9H, s).

According to the method of Reference Example 13 and/or 14, the corresponding halogenated pyridine derivatives and the corresponding amide derivatives were used, and appropriate protection and deprotection reactions were carried out as needed to synthesize the following intermediates D-1 to D-41.

[Reference Example 15]

Synthesis of Dimethyl-[2-(6-nitropyridin-3-yloxy)ethyl]amine

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. The mixture 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 stirred at 80°C for 16 hours. The reaction was monitored by LC/MS. After completion, ice water was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.40 g, 90%).

[Reference Example 16]

Synthesis of 5-(2-dimethylaminoethoxy)pyridin-2-ylamine

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

According to the method of Reference Example 15 and/or 16, the corresponding halogenated pyridine derivatives and the corresponding alcohol derivatives or the corresponding thiol derivatives were used, and appropriate protection and deprotection reactions were carried out as needed to synthesize the following intermediates E-1 to E-61.

[Reference Example 17]

Synthesis of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate

3,6-Dichloropyridazine (5.01 g, 33.6 mmol) and tert-butyl piperazine-1-carboxylate (6.88 g, 37.0 mmol) were dissolved in DMF (50 mL). Triethylamine (11.7 mL, 50.4 mmol) was added and stirred at 80°C overnight. The reaction solution was cooled to room temperature, water was added, and then extracted three times with a 95:5 mixture of dichloromethane and methanol (50 mL). The combined organic phases were dried over anhydrous magnesium sulfate, the solids were separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was washed with diethyl ether to obtain the title compound (7.0 g, 70%).

[Reference Example 18]

Synthesis of tert-Butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate

Tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate (59.8 mg, 0.20 mmol) obtained in Reference Example 17, benzophenone imine (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 stirred at 100°C overnight. After cooling to room temperature, the reaction solution was filtered through celite and the celite was washed with ethyl acetate. The filtrate was washed with saturated brine and dried over anhydrous magnesium sulfate. The solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (67 mg, 76%).

[Reference Example 19]

Synthesis of tert-butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate

Tert-butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate (67 mg, 0.151 mmol) obtained in Reference Example 18 was dissolved in THF (0.76 mL), and aqueous citric acid (0.378 mL, 0.755 mmol, 2 mol/L) was added. The mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate (5 mL) was added to the reaction solution for neutralization, and the mixture was extracted twice with ethyl acetate (5 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude product was washed with tert-butyl methyl ether (5 mL) to obtain the title compound (30 mg, 71%).

According to any one of the methods described in Reference Examples 17 to 19 or a combination thereof, the corresponding halogenated heteroaryl derivatives and the corresponding amine derivatives were used, and appropriate protection and deprotection reactions were carried out as needed to synthesize the following intermediates F-1 to F-77.

According to any one of the methods in Reference Examples 15, 18, and 19, or a combination thereof, the corresponding halogenated pyridazine derivatives and the corresponding alcohol derivatives or the corresponding thiol derivatives were used, and appropriate protection and deprotection reactions were carried out as needed to synthesize the following intermediates G-1 to G-12.

[Reference Example 20]

Synthesis of tert-butyl 4-(6-nitropyridin-3-yl)piperidin-3-ene-1-carboxylate

Referring to the method described in J. Med. Chem. 2010, 53, pp. 7938-7957, 3-bromo-6-nitropyridine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate were reacted by heating in the presence of a palladium catalyst to obtain the title compound.

[Reference Example 21]

Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperidine-1-carboxylate

Referring to the method described in J. Med. Chem. 2010, 53, pp. 7938-7957, tert-butyl 4-(6-nitropyridin-3-yl)piperidin-3-ene-1-carboxylate obtained in Reference Example 20 was reduced in the presence of palladium on carbon under a hydrogen atmosphere to give the title compound.

According to the method of Reference Example 20 and/or 21, the corresponding halogenated heteroaryl derivatives and the corresponding boronic acid derivatives were used, and appropriate protection and deprotection reactions were carried out as needed to synthesize the following intermediates H-1 to H-12.

[Reference Example 22]

Intermediate I-1 was synthesized by reacting tert-butyl N-[5-(aminoethyl)-2-pyridine]-N-tert-butoxycarbonylcarbamate synthesized by any one of the methods in Reference Examples 8 to 10, or a combination of the methods, with tert-butyl chlorosulfonylcarbamate to remove the Boc group under acidic conditions.

[Reference Example 23]

Intermediate J-1 was synthesized by reacting tert-butyl N-tert-butoxycarbonyl-N-[5-(N-methylaminoethyl)-2-pyridine]carbamate synthesized according to Reference Examples 8 to 10 with potassium isocyanate to remove the Boc group under acidic conditions.

According to the method of Reference Example 23, 5-amino-2-nitropyridine was used to reduce the nitro group with hydrogen in the presence of palladium hydroxide/activated carbon to synthesize the following intermediate J-2.

[Reference Example 24]

Intermediate K-1 was synthesized by reacting tert-butyl N-[5-(aminoethyl)-2-pyridine]-N-tert-butoxycarbonylcarbamate synthesized according to any one of the methods of Reference Examples 8 to 10 or a combination of the methods with ethyl isocyanate to remove the Boc group under acidic conditions.

[Reference Example 25]

N-[5-(Aminoethyl)-2-pyridine]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester synthesized by any one of the methods of Reference Examples 8 to 10 or a combination of the methods was reacted with 2-methoxyethyl bromide. The Boc group was removed under acidic conditions as in Reference Example 11, and the secondary amine moiety was selectively protected with a Boc group to synthesize Intermediate L-1.

[Reference Example 26]

Intermediate M-1 was synthesized by esterifying the carboxylic acid moiety, dimethylating the α-position of the carbonyl group, reducing the ester moiety with LAH, acidifying the resulting alcohol moiety, aminating the moiety with methylamine reduction, protecting the moiety with a Boc group, aminating the 2-chloropyridine moiety in the presence of a Pd catalyst, and deprotecting the moiety.

[Reference Example 27]

5-Bromo-2-nitropyridine is reacted with tert-butyl cyanoacetate under alkaline conditions, and the tert-butyl group is removed and decarbonated under acidic conditions, followed by reduction of the cyano group, thereby synthesizing intermediate N-1.

[Reference Example 28]

5-bromo-2-nitropyridine is reacted with an alkyne derivative that has undergone nucleophilic substitution of an imide derivative under Sonogashira coupling reaction conditions, followed by hydrogen reduction in the presence of palladium hydroxide/activated carbon, followed by protection and deprotection to synthesize intermediate O-1.

[Reference Example 29]

Intermediate P-1 is synthesized by acylation of 2-(6-nitropyridin-3-yl)ethylamine and hydrogen reduction in the presence of palladium hydroxide/activated carbon.

The following intermediates P-2 to P-17 were synthesized using the corresponding amine derivatives synthesized according to the methods of Reference Examples 8 to 10 and the corresponding acylating agents, and appropriate deprotection was performed as needed according to the method of Reference Example 29. It should be noted that appropriate acylation conditions can be used, such as using an acyl chloride as the acylating agent instead of an acid anhydride, or a combination of a carboxylic acid and a condensing agent, depending on the introduced structure.

[Reference Example 30]

2-(6-nitropyridin-3-yl)ethylamine is subjected to mesylation and hydrogen reduction in the presence of palladium hydroxide/activated carbon to synthesize Intermediate Q-1.

The corresponding amine derivatives synthesized according to the methods of Reference Examples 8 to 10 were used, and appropriate deprotection was performed according to the method of Reference Example 29, to synthesize the following intermediates Q-2 to Q-9.

[Reference Example 31]

5-Bromo-2-nitropyridine is reacted with an alkyne derivative under Sonogashira coupling reaction conditions, protected, and then hydrogen reduced in the presence of palladium hydroxide/activated carbon, protected, and deprotected to synthesize the intermediate R-1.

According to the method of Reference Example 31, reactions 1) to 3) of Reference Example 31 were carried out using a halogenated pyridine derivative and a corresponding terminal alkyne derivative to synthesize the following intermediates R-2 to R-6.

[Reference Example 32]

R-1 synthesized in Reference Example 31 was subjected to mesylation and then reacted with an amide derivative under alkaline conditions for deprotection to synthesize intermediate S-1.

According to the method of Reference Example 32, the following intermediates S-2 and S-3 were synthesized using the corresponding alcohol derivative, the corresponding amide derivative, or the corresponding sulfonamide derivative.

[Reference Example 33]

6-((tert-Butoxycarbonyl)amino)nicotinic acid methyl ester was subjected to alkaline hydrolysis, condensation with morpholine, and deprotection to synthesize intermediate T-1.

The corresponding ester derivatives, or corresponding carboxylic acid derivatives, and corresponding amine derivatives synthesized according to the method of Reference Example 31, etc., are used, and appropriate protection and deprotection are performed as needed according to the method of Reference Example 33 to synthesize the following intermediates T-2 to T-17.

[Reference Example 34]

5-((3-((tert-butyldimethylsilyl)oxy)propyl)thio)-2-nitropyridine synthesized according to the method of Reference Example 15 was oxidized with m-chloroperbenzoic acid and hydrogen reduced in the presence of palladium hydroxide/activated carbon to synthesize Intermediate U-1.

[Reference Example 35]

5-Amino-2-nitropyridine is reacted with sodium azide and orthoformate, and then hydrogen reduced in the presence of palladium hydroxide/activated carbon to synthesize intermediate V-1.

[Reference Example 36]

Intermediate W-1 is synthesized by reacting tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate with benzophenone imine and sodium tert-butoxide in the presence of a Pd catalyst for deprotection.

The following intermediates W-2 to W-4 were synthesized according to the method of Reference Example 36 using the corresponding halogenated pyridine derivatives.

[Example 1]

Synthesis of 3-(4-formyl-2-methylthiopyrimidin-5-yl)-2-propynyl benzoate

A 1,4-dioxane solution (55 mL) _{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) was degassed and replaced with argon. Diisopropylamine (18.5 mL, 128.8 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 5 minutes. A mixture of 5-bromo-2-methylthiopyrimidine-4-carbaldehyde and (5-bromo-2-methylthiopyrimidin-4-yl)methoxymethanol (25 g, in bold) described in Reference Example 3 and a 1,4-dioxane solution (55 mL) of propynyl benzoate (20 g, 128.8 mmol) were slowly added dropwise. The reaction solution was then stirred at room temperature for 5 hours. The progress of the reaction was monitored by LC/MS. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (1 L), filtered through celite with suction, and the celite was washed with ethyl acetate. The resulting filtrate was concentrated under reduced pressure, and the resulting crude product was used directly in the next reaction.

[Example 2]

Synthesis of 6-((Benzoyloxy)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine 7-oxide

The crude product of 3-(4-formyl-2-methylsulfanylpyrimidin-5-yl)-2-propynyl benzoate synthesized in Example 1 was dissolved in ethanol (500 mL). Hydroxylamine hydrochloride (8.3 g, 120 mmol) and sodium acetate (10 g, 120 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 6 hours, then diluted with ethanol (1 L). Potassium carbonate (27.8 g, 200 mmol) was added and stirred at 50°C for 3 hours. The progress of the reaction was monitored by LC/MS. After completion of the reaction, the reaction solution was suction filtered through Celite, and the Celite was washed with ethyl acetate. The resulting filtrate was dried over anhydrous sodium 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 obtain the title compound (5.0 g, 16%).

[Example 3]

Synthesis of 8-chloro-2-methylthiopyrido[3,4-d]pyrimidin-6-ylbenzoate

6-((Benzoyloxy)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidine 7-oxide (5.0 g, 15.3 mmol) synthesized in Example 2 was dissolved in dichloromethane (60 mL) and cooled to 0°C. To this solution, thionyl chloride (25 mL, 343 mmol) was added dropwise at 0°C and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction solution was concentrated under reduced pressure and then azeotroped with toluene (20 mL) twice to remove the thionyl chloride. The resulting residue was crudely purified by neutral alumina column chromatography to obtain 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-6-yl)ethyl benzoate

(R)-1-(8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidin-6-yl)ethyl benzoate (360 mg, 1.0 mmol), synthesized using the method described in Example 3, (S)-tetrahydro-2H-pyran-3-amine hydrochloride (206 mg, 1.5 mmol), and potassium carbonate (415 mg, 3.0 mmol) were stirred in 1,4-dioxane (4.0 mL) at 100°C overnight. The progress of the reaction was monitored by TLC. After completion, the reaction solution was cooled to room temperature. The reaction solution was diluted with water and extracted twice with ethyl acetate (10 mL). The resulting organic phase was washed with brine and dried over 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 obtain the title compound (232 mg, 55%).

1H-NMR (CDCl3) δ: 8.97 (1H, s), 8.17-8.14 (2H, m), 7.62-7.57 (1H, m), 7.51-7.46 (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),1.76-1.65 (4H, m)

LC/MS: (M+H) ⁺ =425.2, C ₂₂ H ₂₄ N ₄ O ₃ S = 424.16.

[Example 5]

Synthesis of 2-methylthio-8-(propan-2-yl)aminopyrido[3,4-d]pyrimidin-6-ylmethanol

8-Isopropylamino-2-methylsulfanylpyrido[3,4-d]pyrimidin-6-yl benzoate (3.7 g, 10.0 mmol), synthesized by the method described in Example 4, was dissolved in methanol (20 mL) and THF (20 mL). A 10 mL aqueous solution of lithium hydroxide (0.96 g, 40 mmol) was added dropwise at room temperature. The reaction solution was stirred at room temperature for 1 hour. The progress of the reaction was monitored by LC/MS. After completion of the reaction, hydrochloric acid (2 mol/L) was added dropwise to neutralize the pH to 7. The resulting solid was isolated by filtration and dried under reduced pressure to obtain the title compound (2.55 g, 96%).

[Example 6]

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

2-Methylsulfanyl-8-(propan-2-yl)aminopyrido[3,4-d]pyrimidin-6-ylmethanol (3.1 g, 11.7 mmol) synthesized in Example 5 was dissolved in dichloromethane (30 mL) and stirred at 0°C. Dess-Martin periodinane (15 g, 35.2 mmol) was added in small amounts at 0°C, and the reaction solution was stirred at room temperature for 3 hours. The progress of the reaction was monitored by LC/MS. After completion, sodium thiosulfate aqueous solution was added to reduce the remaining reagents to terminate the reaction. The aqueous phase was extracted three times with dichloromethane (50 mL). The resulting organic phases were combined and dried over anhydrous sodium sulfate. After filtering to separate the solid, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (2.9 g, 94%).

[Example 7]

Synthesis of 6-difluoromethyl-2-methylsulfanyl-N-(propan-2-yl)pyrido[3,4-d]pyrimidin-8-amine

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

The following compounds Int-1 to Int-8 were synthesized using the method described in Example 4 or Examples 5 to 7 and using substituents in an appropriate order.

[Example 8]

Synthesis of (R)-1-(2-(methylsulfonyl)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)ethyl benzoate

(R)-1-(2-(methylthio)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)ethyl benzoate (232 mg, 0.55 mmol) synthesized in Example 4 and potassium hydrogen persulfate (R) (672 mg, 1.09 mmol) were stirred overnight at room temperature in THF (2.7 mL) and water (2.7 mL). The reaction was monitored by LC/MS. After completion, saturated aqueous sodium bicarbonate was slowly added, and the aqueous phase was extracted three times with ethyl acetate. The resulting organic phases were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering and separating the solid, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the crude title compound (245 mg, 98%).

1H-NMR (CDCl3) δ: 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).

LC/MS: (M+H) ⁺ =457.2, C ₂₂ H ₂₄ N ₄ O ₅ S = 456.15.

[Example 9]

Synthesis of (R)-1-(8-(1-methoxy-2-methylpropan-2-ylamino)-2-(methylsulfinyl)pyrido[3,4-d]pyrimidin-6-yl)ethyl benzoate

(R)-1-(8-(1-methoxy-2-methylpropan-2-ylamino)-2-(methylthio)pyrido[3,4-d]pyrimidin-6-yl)ethyl benzoate (1.9 g, 4.46 mmol), synthesized by the method described in Example 7, was dissolved in dichloromethane (30 mL) and stirred at 0°C. To this solution, m-CPBA (0.767 g, 4.46 mmol) was added in small amounts at 0°C, and the reaction solution was stirred at room temperature overnight. The progress of the reaction was monitored by LC/MS. After completion, aqueous sodium thiosulfate was added to reduce the remaining reagents to terminate the reaction. The aqueous phase was extracted three times with dichloromethane (30 mL). The resulting organic phases were combined and washed once with saturated aqueous sodium bicarbonate (50 mL) and once with saturated brine (50 mL). The organic phase was dried over anhydrous sodium 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 obtain the title compound (1.9 g, 96%).

The following compounds Int-9 to Int-16 were synthesized according to the method described in Example 8 or 9.

[Example 10]

Synthesis of (R)-1-(5-chloro-2-(methylsulfonyl)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)ethyl benzoate

(R)-1-(2-(methylsulfonyl)-8-(((S)-tetrahydro-2H-pyran-3-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)ethyl benzoate (268 mg, 0.587 mmol) and N-chlorosuccinimide (96 mg, 0.72 mmol) synthesized in Example 8 were dissolved in 1,2-dichloroethane (2.9 mL) and stirred at 65°C overnight. The reaction was monitored by LC/MS. After completion, the reaction solution was cooled to room temperature and purified directly by silica gel column chromatography to obtain the title compound (255 mg, 89%).

1H-NMR (CDCl3) δ: 9.70 (1H, s), 8.11-8.06 (2H, m), 7.60-7.53 (1H, m), 7.48-7.42 (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).

The compound Int-17 described below was synthesized according to the method described in Example 10.

[Example 11]

Synthesis of tert-butyl 4-[6-(6-difluoromethyl-8-isopropylaminopyrido[3,4-d]pyrimidin-2-ylamino)pyridin-3-yl]piperazine-1-carboxylate

tert-Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (88 mg, 0.316 mmol) synthesized in Reference Example 5 was dissolved in THF (3.5 mL). Sodium hydride (22.8 mg, 0.57 mmol, 60%) was added at 0°C and stirred for 10 minutes. A THF solution (3.5 mL) of (6-difluoromethyl-2-methylsulfonylpyrido[3,4-d]pyrimidin-8-yl)isopropylamine (Int-11, 100 mg, 0.316 mmol) synthesized in Example 8 was added to this suspension at room temperature and stirred at 35°C for 1 hour. The reaction was monitored by TLC and LC/MS. After completion, ice water (10 mL) was added to quench the reaction. The aqueous phase was extracted twice with ethyl acetate (25 mL). The resulting organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separating the solid by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 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)

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

The TFA salt (200 mg) was dissolved in methanol (0.625 mL) and dichloromethane (1.875 mL) and adsorbed onto a strongly acidic cation exchange resin (SCX) column. The SCX column was washed with a 1:3 mixture of methanol and dichloromethane. A 2.5% aqueous ammonia solution (2 mol/L, methanol solution) was then added to the 1:3 mixture of methanol and dichloromethane, and the resulting mixture was passed through the SCX column to elute the target compound. The resulting eluate was concentrated under reduced pressure to obtain the title compound (105 mg, purity >99%).

[Example 13]

Synthesis of tert-butyl (R)-4-(6-(6-(benzoyloxy)ethyl-8-(1-methoxy-2-methylpropan-2-ylamino)pyrido[3,4-d]pyrimidin-2-ylamino)pyridin-3-yl)piperazine-1-carboxylate

(R)-1-(8-(1-methoxy-2-methylpropan-2-ylamino)-2-(methylsulfinyl)pyrido[3,4-d]pyrimidin-6-yl)ethyl benzoate (1.9 g, 4.3 mmol) synthesized in Example 9 and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (3.59 g, 12.9 mmol) synthesized in Reference Example 5 were suspended in toluene (30 mL) and stirred at 120°C overnight. The reaction progress was monitored by LC/MS. The resulting reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 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)

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

The resulting crude product was dissolved in hydrogen chloride (20 mL, 4 mol/L, methanol solution) and stirred at room temperature for 4 hours. The progress of the reaction was monitored by LC/MS. After completion, the reaction solution was concentrated under reduced pressure. The residue was dissolved in methanol (30 mL) and concentrated aqueous ammonia (25%) was added dropwise to adjust the pH to above 10. Saturated brine (100 mL) was added to the solution and extracted three times with a 9:1 mixture of dichloromethane and methanol (30 mL). The resulting organic phases were combined and washed once with saturated brine (50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered to separate the solid, and concentrated under reduced pressure to obtain the crude form of the title compound. The crude form was then washed with methanol to obtain 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)

(R)-1-(8-(isopropylamino)-2-((6-(piperazin-1-yl)pyridazin-3-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)ethanol (Compound 261, 25 mg, 0.061 mmol), synthesized by the method described in Example 14, was dissolved in methanol (0.31 mL). After adding (S)-propylene oxide (3.5 mg, 0.061 mmol), the reaction solution was stirred at 55°C overnight. The progress of the reaction was monitored by LC/MS. After completion of the reaction, the solution was concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC (acetonitrile/water/TFA) and adsorbed onto a strongly acidic cation exchange resin (SCX) column. The SCX column was washed with methanol, and the target product was eluted with aqueous ammonia (2 mol/L, methanol). The resulting eluate was concentrated under reduced pressure to obtain 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)

(R)-1-(8-(isopropylamino)-2-((6-(piperazin-1-yl)pyridazin-3-yl)amino)pyrido[3,4-d]pyrimidin-6-yl)ethanol (Compound 261, 16.4 mg, 0.040 mmol), synthesized by the method described in Example 14, was dissolved in acetic acid (2.8 μL) and 1,2-dichloroethane (0.4 mL). 3-Oxetanone (2.8 μL, 0.048 mmol) and sodium triacetoxyborohydride (12.7 mg, 0.060 mmol) were added, and the reaction solution was stirred at 55°C for 2 hours. The progress of the reaction was monitored by LC/MS. After completion of the reaction, the reaction solution was returned to room temperature and quenched by the addition of water. The reaction solution was extracted with ethyl acetate, and the resulting organic layer was concentrated under reduced pressure. The resulting crude product was then purified by amine-modified column chromatography (ethyl acetate/methanol) to obtain the title compound (7.5 mg).

[Example 17]

Synthesis of (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)

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

[Example 18]

Synthesis of (R)-2-(4-(6-((8-(isopropylamino)-6-(1-methoxyethyl)pyrido[3,4-d]pyrimidin-2-yl)amino)pyridazin-3-yl)piperazin-1-yl)-2-methylpropanoic acid (Compound 678)

(R)-N8-isopropyl-6-(1-methoxyethyl)-N2-(6-(piperazin-1-yl)pyridazin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine (Compound 217, 42.3 mg, 0.10 mmol), synthesized by the method described in Example 14, was dissolved in acetonitrile (0.2 mL). 2-bromo-2-methylpropanoic acid tert-butyl ester (22.4 μL, 0.12 mmol) and potassium carbonate (16.6 mg) were added, and the reaction solution was stirred at 85°C overnight. The progress of the reaction was monitored by LC/MS. After completion, the reaction solution was returned to room temperature and quenched by the addition of water. The reaction solution 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), trifluoroacetic acid (1 mL) was added, and the reaction solution was stirred at room temperature for 24 hours. The progress of the reaction was monitored by LC/MS. After completion, the solution was concentrated under reduced pressure. The resulting crude product was adsorbed onto a strongly acidic cation exchange resin (SCX) column. The SCX column was washed with methanol, and the target product was eluted with aqueous ammonia (2 mol/L, methanol). The resulting eluate was concentrated under reduced pressure to obtain the title compound (8.5 mg).

[Example 19]

The following compounds 1 to 1239 were synthesized according to the synthesis methods described in Examples 11 to 18.

*: Optically active compounds were isolated by fractionation and purification using HPLC using a chiral column. However, the absolute configuration has not been determined.

abbreviation

DEA: diethylamine, TEA: triethylamine, DCM: dichloromethane, IPA: isopropyl alcohol,

(1) Compound 581: DAICEL CHIRALPAK AD 5μm, n-hexane/MeOH/IPA, RT = 12.31 min.: Optically active form with a short retention time

(1) Compound 582: DAICEL CHIRALPAK AD 5 μm, n-hexane/MeOH/IPA, RT = 15.35 min.: Optically active form with long retention time

(2) Compound 671: CHIRALPAK IA-3μm, 100% EtOH, RT = 4.388 min.: Optically active form with short retention time

(2) Compound 672: CHIRALPAK IA-3μm, 100% EtOH, RT = 6.490 min.: Optically active form with long retention time

(3) Compound 689: DAICEL CHIRALPAK AD-H 5 μm, n-hexane/EtOH, RT = 17.61 min.: Optically active form with short retention time

(3) Compound 690: DAICEL CHIRALPAK AD-H 5 μm, n-hexane/EtOH, RT = 20.71 min.: Optically active form with long retention time

(4) Compound 704: CHIRALPAK AD-3μm, hexane (0.2% TEA): EtOH = 50:50, RT = 6.446 min.: optically active form with long retention time

(4) Compound 705: CHIRALPAK AD-3μm, hexane (0.2% TEA): EtOH = 50:50, RT = 4.679 min.: Optically active form with short retention time

(5) Compound 713: CHIRALPAK IA-3 μm, 100% MeOH (0.1% DEA), RT = 3.628 min.: Optically active form with long retention time

(5) Compound 714: CHIRALPAK IA-3 μm, 100% MeOH (0.1% DEA), RT = 2.533 min.: Optically active form with short retention time

(6) Compound 724: CHIRALPAK AD-3, hexane (0.1% DEA)/EtOH = 50:50, RT = 4.32 min.: Optically active form with short retention time

(6) Compound 725: CHIRALPAK AD-3, hexane (0.1% DEA): EtOH = 50:50, RT = 5.06 min.: optically active form with long retention time

(7) Compound 729: CHIRALPAK IA-3, 0.46*5cm; 3μm, hexane (0.1%IPA)/EtOH = 50:50, RT = 4.01 min.: optically active form with long retention time

(7) Compound 730: CHIRALPAK IA-3, 0.46*5cm; 3μm, hexane (0.1%IPA)/EtOH = 50:50, RT = 1.68 min.: optically active form with short retention time

(8) Compound 735: DAICEL CHIRALPAK AD-H 5μm, Hexane/IPA = 90/10, RT = 9.18min.: Optically active form with short retention time

(8) Compound 736: DAICEL CHIRALPAK AD-H 5μm, Hexane/IPA = 90/10, RT = 10.65min.: Optically active form with long retention time

(9) Compound 773: DAICEL CHIRALPAK IA 5μm, MeOH/IPA = 6/4, RT = 17.90min.: Optically active form with short retention time

(9) Compound 774: DAICEL CHIRALPAK IA 5μm, MeOH/IPA = 6/4, RT = 21.84min.: Optically active form with long retention time

(10) Compound 775: DAICEL CHIRALPAK IA 5μm, Hexane/MeOH/IPA = 6/1/1, RT = 10.25 min.: Optically active form with short retention time

(10) Compound 776: DAICEL CHIRALPAK IA 5μm, Hexane/MeOH/IPA = 6/1/1, RT = 14.71 min.: Optically active form with long retention time

(11) Compound 809: DAICEL CHIRALPAK AD-H 5μm, 4.6×250mm, n-hexane/EtOH/MeOH = 70/15/15, RT = 21.62 min.: Optically active form with short retention time

(11) Compound 810: DAICEL CHIRALPAK AD-H 5μm, 4.6×250mm, n-hexane/EtOH/MeOH = 70/15/15, RT = 25.87 min.: Optically active form with long retention time

(12) Compound 865: CHIRALPAK IA-3; 0.46*5cm; 3μm; Hexane (0.1%DEA)/EtOH = 70:30, RT = 4.81 min.: Optically active form with short retention time

(12) Compound 866: CHIRALPAK IA-3; 0.46*5cm; 3μm; Hexane (0.1% DEA)/EtOH = 70:30, RT = 5.48 min.: Optically active form with long retention time

(13) Compound 869: CHIRALPAK IA-3; 0.46*5cm; 3μm; Hexane (0.1% DEA)/EtOH = 60:40, RT = 2.27 min.: Optically active form with short retention time

(13) Compound 870: CHIRALPAK IA-3; 0.46*5cm; 3μm; Hexane (0.1% DEA)/EtOH = 60:40, RT = 2.93 min.: Optically active form with long retention time

(14) Compound 875: DAICEL CHIRALPAK AD-H 5μm, Hexane/MeOH/EtOH = 80/10/10, RT = 22.30 min.: Optically active substance with short retention time

(14) Compound 876: DAICEL CHIRALPAK AD-H 5 μm, Hexane/MeOH/EtOH = 80/10/10, RT = 29.24 min.: Optically active form with long retention time

(15) Compound 938: DAICEL CHIRALPAK AD-H 5μm, (100% EtOH + 0.1% DEA), RT = 33.58 min.: Optically active form with short retention time

(15) Compound 939: DAICEL CHIRALPAK AD-H 5μm, (100% EtOH + 0.1% DEA), RT = 42.68 min.: optically active form with long retention time

(16) Compound 940: DAICEL CHIRALPAK AD-H 5 μm, (hexane/MeOH/EtOH + 0.1% DEA = 6/2/2), RT = 20.23 min.: optically active form with short retention time

(16) Compound 941: DAICEL CHIRALPAK AD-H 5 μm, (hexane/MeOH/EtOH + 0.1% DEA = 6/2/2), RT = 22.07 min.: optically active form with long retention time

(17) Compound 942: DAICEL CHIRALPAK AD-H 5 μm, (hexane/MeOH/EtOH + 0.1% DEA = 6/2/2), RT = 13.99 min.: optically active form with short retention time

(17) Compound 943: DAICEL CHIRALPAK AD-H 5 μm, (hexane/MeOH/EtOH + 0.1% DEA = 6/2/2), RT = 15.66 min.: optically active form with long retention time

(18) Compound 989: CHIRALPAK IA, n-hexane/EtOH = 70/30, RT = 13.32 min.: Optically active form with short retention time

(18) Compound 990: CHIRALPAK IA, n-hexane/EtOH = 70/30, RT = 16.69 min.: optically active form with long retention time

(19) Compound 992: CHIRALPAK IA-3: 0.46*5cm; 3μm, hexane (0.1%DEA)/EtOH = 50:50, 1.5ml/min, RT = 1.87 min.: Optically active form with short retention time

(19) Compound 993: CHIRALPAK IA-3: 0.46*5cm; 3μm, hexane (0.1%DEA)/EtOH = 50:50, 1.5ml/min, RT = 3.56 min.: optically active form with long retention time

(20) Compound 1025: CHIRALPAK IA, 0.46*25cm; 5μm, MeOH (0.1%DEA)/DCM = 75:25, 1.0mL/min., RT = 6.597 min.: Optically active form with short retention time

(20) Compound 1026: CHIRALPAK IA, 0.46*25cm; 5μm, MeOH (0.1%DEA)/DCM = 75:25, 1.0mL/min., RT = 8.199 min.: optically active form with long retention time

(21) Compound 1034: CHIRALPAK AS-3, 0.46*10cm; 3μm, hexane (0.1%DEA)/(MeOH/EtOH = 1:1) = 70:30, 1.0mL/min., RT = 6.23 min.: optically active form with short retention time

(21) Compound 1035: CHIRALPAK AS-3, 0.46*10cm; 3μm, hexane (0.1%DEA)/(MeOH/EtOH = 1:1) = 70:30, 1.0mL/min., RT = 9.94 min.: optically active form with long retention time

(22) Compound 1036: CHIRALPAK IC-3, 0.46*10cm; 3μm, DCM (0.1%DEA)/MeOH = 20:80, 1.0mL/min., RT = 5.10 min.: Optically active form with short retention time

(22) Compound 1037: CHIRALPAK IC-3, 0.46*10cm; 3μm, DCM (0.1%DEA)/MeOH = 20:80, 1.0mL/min., RT = 5.95 min.: optically active form with long retention time

(23) Compound 1066: CHIRALPAK IC-3, 0.46*10cm; 3μm, MeOH (0.1%DEA)/DCM =95:5, 1.0ml/min., RT = 5.421 min.: Optically active form with short retention time

(23) Compound 1067: CHIRALPAK IC-3, 0.46*10cm; 3μm, MeOH (0.1%DEA)/DCM =95:5, 1.0ml/min., RT = 6.00 min.: optically active form with long retention time

(24) Compound 1068: CHIRALPAK IC, 0.46*25cm; 5μm, MeOH (0.1%DEA)/DCM = 90:10, 1.0ml/min., RT = 17.429 min.: Optically active form with short retention time

(24) Compound 1069: CHIRALPAK IC, 0.46*25cm; 5μm, MeOH(0.1%DEA)/DCM = 90:10, 1.0ml/min., RT = 20.57 min.: Optically active form with long retention time

(25) Compound 1088: CHIRALPAK IA, n-hexane/EtOH/MeOH = 50/25/25, 1.0 mL/min., RT = 15.21 min.: Optically active form with short retention time

(25) Compound 1089: CHIRALPAK IA, n-hexane/EtOH/MeOH = 50/25/25, 1.0 mL/min., RT = 18.59 min.: Optically active form with long retention time

*: The compound was purified by reverse-phase HPLC to obtain a diastereomeric compound. However, the absolute configuration is not determined.

(1) Compound 831: C-18: RT = 1.67 min.: diastereomer with short retention time

(1) Compound 832: C-18: RT = 1.71 min.: diastereomer with long retention time

*: The following compounds show the relative configurations of two substituents.

Compounds 577, 607, 608, 609, 610, 618, 619, 621, 622, 645, 646, 647, 673, 708, 739, 742, 799, 801, 864

[Example 20]

Human CDK4/Cyclin D3 inhibitory activity

The CDK4/Cyclin D3 inhibitory activity of the compounds was measured using an assay kit (QSS AssistCDK4/Cyclin D3_FP Kit) purchased from Kalna Biosciences Co., Ltd. This assay is based on Kalna Biosciences' IMAP technology and measures kinase activity by quantifying changes in fluorescence polarization caused by the binding of a fluorescent substrate, phosphorylated by the kinase, to the IMAP binding reagent.

The 10x assay buffer provided with the kit or a homemade assay buffer of the same composition is used for solution preparation. Prepare the assay buffer by diluting the 10x assay buffer provided with the kit 10-fold with purified water. The assay buffer contains 20 mM HEPES (pH 7.4), 0.01% Tween 20, and 2 mM dithiothreitol. For the test compound solution, the test compound is diluted with dimethyl sulfoxide (DMSO) to a final concentration of 100-fold, then diluted 25-fold with assay buffer to a final concentration of 4-fold. Prepare the ATP/substrate/metal solution by diluting the 5x ATP/substrate/metal solution provided with the kit 5-fold with assay buffer. Prepare the enzyme solution by diluting the CDK4/cyclin D3 solution provided with the kit with assay buffer to a final concentration of 2-fold (the final CDK4/cyclin D3 concentration is 12.5 to 25 ng/well). 5× IMAP Binding Buffer A and 5× IMAP Binding Buffer B were diluted 5-fold with purified water, mixed at a ratio of IMAP Binding Buffer A:IMAP Binding Buffer B = 85:15, and added to the mixture to achieve a 400-fold dilution of the IMAP Binding Reagent to prepare the detection reagent.

To a 384-well plate, add 5 μL of the test compound solution and 5 μL of the ATP/substrate/metal solution, followed by 10 μL of the enzyme solution or assay buffer, mix, and initiate the enzyme reaction. The total reaction volume is 20 μL/well, and the reaction mixture consists of 20 mM HEPES (pH 7.4), 0.01% Tween 20, 2 mM dithiothreitol, 100 nM FITC-labeled peptide substrate (the substrate peptide sequence information has not been disclosed by Carna Biosciences), 100 μM ATP, 1 mM magnesium chloride, 1% DMSO, and 12.5–25 ng/well of CDK4/cyclin D3. After incubation at room temperature for 45 minutes, add 60 μL of the detection reagent to each well and incubate at room temperature in the dark for an additional 30 minutes. Fluorescence polarization is then measured using a microplate reader at an excitation wavelength of 485 nm and a measurement wavelength of 535 nm.

The enzyme activity when DMSO was added instead of the test compound solution was set to 100%. The enzyme activity when DMSO was added instead of the test compound solution was set to 0%. The enzyme activity inhibition rate of the test compound was calculated and matched to the dose-response curve to calculate the 50% inhibitory concentration for CDK4/cyclin D3.

The inhibitory activity of each compound on CDK4/cyclin D3 activity is shown in the table below.

The activity strengths in the table show that +++ represents an _IC50 value < 10 nM, ++ represents an _IC50 value < 10 nM, and + represents an _IC50 value < 100 nM.

[Example 21] CDK2/Cyclin A2 Inhibitory Activity

The CDK2/Cyclin A2 inhibitory activity of the compounds was measured using an assay kit (QSS AssistCDK4/Cyclin D3_FP Kit) purchased from Kalna Biosciences Co., Ltd. This assay is based on Kalna Biosciences' IMAP technology and measures kinase activity by quantifying changes in fluorescence polarization caused by the binding of a fluorescent substrate, phosphorylated by the kinase, to the IMAP binding reagent.

The assay buffer provided with the kit was prepared by diluting the 10× assay buffer 10-fold with purified water. This buffer contained 20 mM HEPES (pH 7.4), 0.01% Tween 20, and 2 mM dithiothreitol. For the test compound solution, the test compound was diluted with dimethyl sulfoxide (DMSO) to a final concentration of 100-fold, then diluted 25-fold with assay buffer to a final concentration of 4-fold. The ATP/substrate/metal solution was prepared by diluting the 5× ATP/substrate/metal solution provided with the kit 5-fold with assay buffer. The enzyme solution was prepared by diluting the CDK2/cyclin A2 solution provided with the kit with assay buffer to a final concentration of 2-fold (the final CDK2/cyclin A2 concentration was 2.5 ng/well). The detection reagent was prepared by diluting the 5× IMAP binding buffer A 5-fold with purified water and adding it to a 400-fold dilution of the IMAP binding reagent.

To a 384-well plate, add 5 μL of test compound solution and 5 μL of ATP/substrate/metal solution, followed by 10 μL of enzyme solution or assay buffer, mix, and initiate the enzyme reaction. The total reaction volume is 20 μL/well, and the reaction mixture consists of 20 mM HEPES (pH 7.4), 0.01% Tween 20, 2 mM dithiothreitol, 100 nM FITC-labeled peptide substrate (information regarding the substrate peptide sequence has not been released by Carna Biosciences), 30 μM ATP, 5 mM magnesium chloride, 1% DMSO, and 2.5 ng/well of CDK2/cyclin A2. After incubation at room temperature for 60 minutes, add 60 μL of detection reagent to each well and incubate at room temperature in the dark for an additional 30 minutes. Fluorescence polarization is then measured using a microplate reader at an excitation wavelength of 485 nm and a measurement wavelength of 535 nm.

The enzyme activity when DMSO was added instead of the test compound solution was set to 100%, and the enzyme activity when DMSO was added instead of the enzyme solution was set to 0%. The enzyme activity inhibition rate of the test compound was calculated and matched to the dose-response curve to calculate the 50% inhibitory concentration for CDK2/cyclin A2.

The inhibitory activity of each compound on CDK2/cyclin A2 activity is shown in the table below.

The activity strengths in the table show that +++ represents an _IC50 value < 10 nM, ++ represents an _IC50 value < 10 nM, and + represents an IC50 value < 100 nM, and + represents an IC50 value < 100 _nM .

[Example 22]

Human CDK6/Cyclin D3 inhibitory activity

CDK6/cyclin D3 inhibitory activity was measured using the Off-Chip Mobility Shift Assay (MSA). The MSA method utilizes the differences in mobility during electrophoresis due to differences in protein molecular weight and charge to separate proteins. In the kinase activity assay, the substrate generated by kinase phosphorylation changes its charge to negative, which is then separated using the principle of electrophoresis. The degree of phosphorylation is quantified to determine kinase activity.

An assay buffer containing 20 mM HEPES (pH 7.5), 0.01% Triton X-100, and 2 mM dithiothreitol was used to prepare each solution. For the test compound solution, the test compound was prepared at a 100-fold final concentration using dimethyl sulfoxide (DMSO) and then diluted 25-fold in assay buffer to a final concentration of 4-fold. The ATP/substrate/metal solution was prepared at a 4-fold final concentration. The enzyme solution was prepared at a 2-fold final concentration. The enzyme concentration was set appropriately based on the enzyme activity signal and the inhibitory activity of the positive control compound.

To a 384-well plate, add 5 μL of test compound solution and 5 μL of ATP/substrate/metal solution, followed by 10 μL of enzyme solution or assay buffer and mix to initiate the enzyme reaction. The total reaction volume is 20 μL/well, and the reaction mixture composition is 20 mM HEPES (pH 7.5), 0.01% Triton X-100, 2 mM dithiothreitol, 1000 nM peptide substrate (DYRKtide-F), 300 μM ATP, 5 mM magnesium chloride, 1% DMSO, and the specified concentrations of CDK6/cyclin D3. After incubation at room temperature for 5 hours, 60 μL of stop buffer (QuickScout Screening Assist MSA; Calbiosciences) is added to each well to terminate the reaction. Next, the substrate peptide and phosphorylated peptide in the reaction solution were separated and quantified using a LabChip 3000 from Computer Science. The kinase reaction was evaluated using the product ratio (P/(P+S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P).

The enzyme activity when DMSO was added instead of the test compound solution was set to 100%, and the enzyme activity when DMSO was added instead of the enzyme solution was set to 0%. The enzyme activity inhibition rate of the test compound was calculated and matched to the dose-response curve to calculate the 50% inhibitory concentration for CDK6/cyclin D3.

The inhibitory activity of each compound on CDK6/cyclin D3 activity is shown in the table below.

The activity strengths in the table show that +++ represents an _IC50 value < 10 nM, ++ represents an _IC50 value < 10 nM, and + represents an IC50 value < 100 nM, and + represents an IC50 value < 100 _nM .

[Example 23]

Mice in the CAIA (collagen antibody-induced arthritis) group (vehicle/+, drug-treated group) were intraperitoneally administered with 250 μl/head of a 4.8 mg/ml cocktail of monoclonal antibodies against type II collagen (Arthritogenic MoAb Cocktail (Chondrex #53100)) (set as day one). Disease was induced on day 4 by intraperitoneal administration of LPS (LPS solution (E. coli 0111:B4) (Chondrex #9028) 0.5 mg/ml) at 100 μl/head. Disease scores were assessed daily until day 9. The drug was administered orally once daily from day 4 to day 8.

The non-diseased group (vehicle/- group) was intraperitoneally administered with PBS pH 7.2 (Gibco #20012-027) at 250 μl/head on the first day, and LPS was similarly administered on the fourth day.

The disease is scored on a scale of 0 to 4 for all four limbs, with the total score for all four limbs used for evaluation. The scoring criteria are: 0: No change, 1: Swelling in one limb only, 2: Swelling in the wrists and ankles, or multiple limbs, 3: Swelling in the wrists and ankles and one or more limbs, and 4: Swelling in the wrists and ankles and all four limbs.

Figure 1 shows the scoring results on the final day, day 9.

Claims (27)

1. A compound of general formula (I) or a pharmaceutically permissible salt thereof, [Chemistry 1] In the formula, L represents -NR ⁵ -, -O-, or -S-; R ⁵ represents a hydrogen atom, or a C _1-6 alkyl group substituted with [0-2 -OH, 0-2 C _1-8 alkoxy, and 0-6 fluorine atoms]; R ¹ represents C _1-8 alkyl, C _3-12 cycloalkyl, (C _3-12 cycloalkyl)C _1-6 alkyl, 4-12 heterocyclic group, (4-12 heterocyclic group)C _1-6 alkyl, C _6-10 aryl, (C _6-10 aryl)C _1-6 alkyl, 5-10 heteroaryl, (5-10 heteroaryl)C _1-6 alkyl, C _1-8 alkylsulfonyl, or C _1-8 acyl; the heteroatoms in R ¹ are independently selected from 1 to 4 heteroatoms from oxygen, sulfur, and nitrogen atoms in each group; R1 may be substituted with ¹ to 6 substituents selected from halogens, =O, -OH, -CN, -COOH, ^-COOR6 , -R7, ^C3-6 cycloalkyl groups substituted with [0-2 -OH, _{0-2 C1-8} alkoxy groups, and 0-6 fluorine atoms], 3- to 10-membered heterocyclic groups substituted with [0-2 -OH, 0-2 _C1-8 alkoxy groups, and 0-6 fluorine atoms], _C1-8 acyl groups substituted with [0-2 -OH, 0-2 _C1-8 alkoxy groups, and 0-6 fluorine atoms], and _C1-8 alkoxy groups substituted with [0-2 -OH, 0-2 _C1-8 alkoxy groups, and 0-6 fluorine atoms]. ^R6 and ^R7 independently represent _C1-6 alkyl groups substituted with [0-2 -OH, 0-2 _C1-8 alkoxy, and 0-6 fluorine atoms]; R ² represents C _1-8 alkyl, C _3-8 cycloalkyl, 4-6 membered heterocyclic group, C _1-8 acyl group, -COOR ⁸ , or -CONR ⁹ R ¹⁰ ; The _C1-8 alkyl and _C3-8 cycloalkyl groups of ^R2 are independently substituted by 0-1 -OH, 0-2 _C1-8 alkoxy groups substituted by [0-1 -OH, 0-1 _C1-4 alkoxy group, and 0-3 fluorine atoms], and 0-5 fluorine atoms, respectively; Wherein, ^R2 is not an unsubstituted _C1-8 alkyl, an unsubstituted _C3-8 cycloalkyl, or a trifluoromethyl; ^R8 , ^R9 , and ^R10 each independently represent a hydrogen atom or a _C1-8 alkyl group; The 4-6 membered heterocyclic group of ^R2 may be optionally substituted by 1-4 substituents selected from fluorine atom, -OH, _C1-4 alkyl, and _C1-4 alkoxy. The _C1-8 acyl group, -COOR ⁸ , and ^{-CONR 9} of ^R2 are optionally and independently substituted by 1 to 4 substituents selected from fluorine atom, -OH, and _C1-4 alkoxy group; ^{R9 and R10 in R2 can} optionally form a ring containing ^the nitrogen atom they are bonded to by a single bond or -O- bond. In the heterocyclic group of ^R2 , the heteroatom is one oxygen atom in a 4-5 membered ring and one to two oxygen atoms in a 6-membered ring; R ³ represents a hydrogen atom, a _C1-8 alkyl group, or a halogen atom; X represents CR ¹¹ or a nitrogen atom; Y represents CR ¹² or a nitrogen atom; Z represents CR ¹³ or a nitrogen atom; ^R11 to ^R13 independently represent hydrogen atom, fluorine atom, chlorine atom, _C1-6 alkyl group, or _C1-6 alkoxy group; ^R4 is represented by ^{-A1 -A2 -A3} ; ^A1 represents a single bond, a _C1-8 alkylene group, a _C2-8 alkenylene group, or a _C2-8 ynylene group; One to two ^sp3 carbon atoms at any position in ^A1 are optionally substituted with one to two structures selected from [-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- ]. When two sp ³ carbon atoms are substituted, structures such as -OO-, -O-NR ^14- , -NR ¹⁴ -O-, -O-CH ₂ -O-, -O-CH _2- NR 14-, and -NR ¹⁴ -CH ² _- O- are not formed. ^A2 represents a single bond, _C1-7 alkylene group, _C3-12 cycloalkylene group, _C3-12 cycloalkylidene group, 4-12 membered heterocyclic group, 4-12 membered heterocyclic alkylidene group, _C6-10 membered aryl group, or 5-10 membered heterocyclic group; A ³ represents halogen, -CN, -NO ₂ , -R ²⁵ , -OR ²⁶ , -NR ²⁷ R ²⁸ , -C(=O)R ²⁹ , -C(=O)-OR ³⁰ , -OC(=O)R ³¹ , -OC(=O)-NR ³² R ³³ , -C(=O)-NR ³⁴ R ³⁵ , -NR ³⁶ -C (＝O) R ³⁷ , -NR ³⁸ -C (＝O) -OR ³⁹ , -S (＝O) ₂ -R ⁴⁰ , -S (＝O) ₂ -NR ⁴¹ R ⁴² , or -NR ⁴³ -S (＝O) ₂ R ⁴⁴ ; Wherein, the ^A1 terminal on the ^A2 side is a structure selected from [-O-, ^-NR14- , -C(=O)-, -C(=O)-O-, -OC(=O)-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 when ^A2 is a single bond, ^A3 represents ^-R25 ; ^R14 , ^R32 , ^R34 , ^R36 , ^R38 , ^R41 , and ^R43 independently represent a hydrogen atom, a _C1-8 alkyl group, a _C1-8 acyl group, a _C1-8 alkylsulfonyl group, a 4-12 membered heterocyclic group, a _C3-12 cycloalkyl group, a _C6-10 aryl group, a 5-10 membered heteroaryl group, a (4-12 membered heterocyclic group) _C1-3 alkyl group, a ( _C3-12 cycloalkyl group) _C1-3 alkyl group, a ( _C6-10 aryl group) _C1-3 alkyl group, or a (5-10 membered heteroaryl group) _C1-3 alkyl group. ^R15 to ^R31 , ^R33 , ^R35 , ^R37 , ^R39 , ^R40 , ^R42 , and ^R44 independently represent a hydrogen atom, a _C1-8 alkyl group, a 4-12 membered heterocyclic group, a _C3-12 cycloalkyl group, a _C6-10 aryl group, a 5-10 membered heteroaryl group, a (4-12 membered heterocyclic group) _C1-3 alkyl group, a ( _C3-12 cycloalkyl group) _C1-3 alkyl group, a ( _C6-10 aryl group) _C1-3 alkyl group, or a (5-10 membered heteroaryl group) _C1-3 alkyl group. ^A1 , ^A2 , ^A3 , and ^R14 to ^R44 of ^A1 , ^A2 , and ^A3 are each independently selected from -OH, =O, -COOH, -SO3H, _-PO3H2 , _-CN , _-NO2 , halogens, C1-8 alkyl groups substituted with [0-2 -OH, _0-2 ^-OR45 , and 0-6 fluorine atoms], _C3-12 cycloalkyl groups substituted with [0-2 -OH, 0-2 ^-OR46 , and 0-6 fluorine atoms], _C1-8 alkoxy groups substituted with [ _0-2 -OH, 0-2 ^-OR47 , and 0-6 fluorine atoms], and groups substituted with [0-2 -OH, 0-2 ^-OR49]. Substitution of 1 to 4 substituents in a 4 to 12-membered heterocyclic group with 0 to 6 fluorine atoms; ^R14 to ^R44 can be selected to form a ring by bonding within ^A1 , ^A2 , ^A3 , [between ^A1 and ^A2 ], [between ^A1 and ^A3 ], or [between ^A2 and ^A3 ], through [single bond, -O-, -NR ^50- , or -S (=O) _p- ]. ^R11 or ^R13 may be selected to form a ring by bonding with [ ^A1 , ^A2 , or ^A3 ] through [single bond, -O-, ^-NR51- , or -S(=O) _p- ]. R ⁴⁵ to R ⁵¹ represent hydrogen atoms, or C _1-4 alkyl groups substituted with [0 to 1 -OH and 0 to 6 fluorine atoms]; P represents an integer from 0 to 2; The heteroatoms in ^A1 , ^A2 , and ^A3 are independently selected from 1 to 4 heteroatoms from oxygen, sulfur, and nitrogen atoms in each group. 2. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein L represents -NH-. 3. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein R ¹ represents a C _1-8 alkyl, a C _3-12 cycloalkyl, a (C _3-12 cycloalkyl) C _1-6 alkyl, a 4- to 12-membered heterocyclic group, or a (4- to 12-membered heterocyclic) C _1-6 alkyl. 4. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^R2 is a _C1-8 alkyl group substituted with 1 to 4 fluorine atoms. 5. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^R2 is a _C1-8 alkyl group substituted with 0 to 1 -OH and 0 to 2 _C1-8 alkoxy groups substituted with [0 to 1 -OH, 0 to 1 _C1-4 alkoxy group, and 0 to 3 fluorine atoms]. 6. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^R2 is a 4- to 6-membered heterocyclic group optionally substituted with 1 to 4 substituents selected from fluorine atom, -OH, _C1-4 alkyl, and _C1-4 alkoxy. 7. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^R2 is a _C1-8 acyl group, ^-COOR8 , or ^{-CONR9R10 ,} optionally substituted with 1 to 4 substituents selected from fluorine atom, -OH, and _C1-4 alkoxy. 8. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein X represents CR ¹¹ , Y represents CR ¹² , and Z represents CR ¹³ . 9. The compound according to claim 1 or 2, or a pharmaceutically permissible salt thereof, wherein X represents a nitrogen atom, Y represents CR ¹² , and Z represents CR ¹³ . 10. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein X represents CR ¹¹ , Y represents a nitrogen atom, and Z represents CR ¹³ . 11. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein X represents CR ¹¹ , Y represents CR ¹² , and Z represents a nitrogen atom. 12. The compound according to claim 1 or 2, or a pharmaceutically permissible salt thereof, wherein ^A1 is a single bond. 13. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^A1 represents a _C1-8 alkylene group, and all ^sp3 carbon atoms of ^A1 are not substituted by other structures. 14. The compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^A1 represents a _C1-8 alkylene group, and one ^sp3 carbon atom at any position of ^A1 is substituted with -O-. 15. The compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^A1 represents a _C1-8 alkylene group, and one ^sp3 carbon atom at any position of ^A1 is substituted with ^-NR14- . 16. The compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^A1 represents a _C1-8 alkylene group, one ^sp3 carbon atom at any position of ^A1 is substituted with ^-NR14- , and further wherein one ^sp3 carbon atom at any position of ^A1 is optionally substituted with -O-. 17. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein ^A2 represents a 4- to 12-membered heterocyclic group; ^A2 is optionally substituted with 1 to 4 substituents selected from -OH, -COOH, _-SO3H , _-PO3H2 , _-CN , _-NO2 , halogens, _C1-8 alkyl groups substituted with [0-2 -OH, 0-2 ^-OR45 , and 0-6 fluorine atoms], _C3-12 cycloalkyl groups substituted with [0-2 -OH, 0-2 ^-OR46 , and 0-6 fluorine atoms], _C1-8 alkoxy groups substituted with [0-2 -OH, 0-2 ^-OR47 , and 0-6 fluorine atoms], and 4- to 12-membered heterocyclic groups substituted with [0-2 -OH, 0-2 ^-OR49 , and 0-6 fluorine atoms]. 18. The compound according to claim 1 or 2, or a pharmaceutically permissible salt thereof, wherein ^A2 represents a 4- to 12-membered heterocyclic group substituted with =O; ^A2 is optionally selected from -OH, = _O , -COOH, -SO3H, _-PO3H2 , -CN, _-NO2 , halogen, _C1-8 alkyl group substituted with [ _0-2 -OH, 0-2 ^-OR45 , and 0-6 fluorine atoms], _C3-12 cycloalkyl group substituted with [0-2 -OH, 0-2 ^-OR46 , and 0-6 fluorine atoms], _C1-8 alkoxy group substituted with [0-2 -OH, 0-2 ^-OR47 , and 0-6 fluorine atoms], and group substituted with [0-2 -OH, 0-2 ^-OR49]. Substitution of 1 to 4 substituents in a 4 to 12-membered heterocyclic group with 0 to 6 fluorine atoms. 19. The compound of claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein X represents CR ¹¹ , Y represents CR ¹² , and Z represents CR ¹³ , and R ¹¹ or R ¹³ forms a ring by bonding with [A ¹ , A ² , or A ³ ] via [single bond, -O-, -NR ^51- , or -S (=O) _p- ]. 20. The compound according to claim 1 or 2, or a pharmaceutically permissible salt thereof, wherein ^A3 is a hydrogen atom. 21. The compound according to claim 1 or 2 ^, or a pharmaceutically permissible salt thereof, wherein ^A3 is a halogen, -CN, -R25, ^-OR26 , ^-NR27R28 , -C(=O) ^R29 , or -C(=O) ^-OR30 , and ^R25 to ^R30 independently represent a hydrogen atom, a _C1-8 alkyl group, a 4- to ¹² -membered heterocyclic group, a _C3- to 12-membered cycloalkyl group, a (4- to 12-membered heterocyclic group)C1- to _3- alkyl group, or a (C3- to ₁₂ -membered cycloalkyl group)C1- _{to 3-} alkyl group. ^R25 to ^R30 are optionally and independently substituted by 1 to 4 substituents selected from -OH, =O, _-COOH , _-SO3H , _-PO3H2 , -CN, _-NO2 , halogens, C1-8 alkyl groups substituted with [0 to 2 -OH, 0 to 2 ^-OR45 , and 0 to 6 fluorine atoms], _{C3-12 cycloalkyl} groups substituted with [0 to 2 -OH, 0 to 2 ^-OR46 , and 0 to 6 fluorine atoms], _C1-8 alkoxy groups substituted with [0 to 2 -OH, 0 to 2 ^-OR47 , and 0 to 6 fluorine atoms], and 4 to 12 heterocyclic groups substituted with [0 to 2 -OH, 0 to 2 ^-OR49 , and 0 to 6 fluorine atoms]. 22. The compound according to claim 1 or 2, or a pharmaceutically permissible salt thereof, wherein ^R3 is a hydrogen atom. 23. The compound according to claim 1 or 2 or a pharmaceutically permissible salt thereof, wherein R ³ represents a _C1-4 alkyl group, a fluorine atom, or a chlorine atom. 24. Selected from the following compounds or their pharmaceutically permissible salts, 6-(difluoromethyl)-N8-isopropyl-N2-(5-piperazin-1-yl-2-pyridine)pyrido[3,4-d]pyrimidine-2,8-diamine (1R)-1-[8-(isopropylamino)-2-[(5-piperazin-1-yl-2-pyridine)amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol 1-[2-[(5-piperazin-1-yl-2-pyridine)amino]-8-(tetrahydrofuran-3-ylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol 1-[2-[(5-piperazin-1-yl-2-pyridine)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-pyridine]pyrido[3,4-d]pyrimidin-2,8-diamine 1-[6-[[6-[(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]piperazin-2-one 1-[6-[[5-chloro-6-[(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]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-pyridine]amino]-8-(tetrahydropyran-4-ylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[5-(piperazin-1-ylmethyl)-2-pyridine]amino]-8-[[(3S)-tetrahydropyran-3-yl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[5-(piperazin-1-ylmethyl)-2-pyridine]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-pyridine]methyl]piperazin-2-one 6-[(1R)-1-methoxyethyl]-N2-[5-(piperazin-1-ylmethyl)-2-pyridine]-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-pyridine]-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]pyrimidin-2,8-diamine N8-Isopropyl-6-[(1R)-1-methoxyethyl]-N2-[6-[(2S)-2-methylpiperazin-1-yl]pyridazin-3-yl]pyrido[3,4-d]pyrimidin-2,8-diamine N8-Isopropyl-6-[(1R)-1-methoxyethyl]-N2-[6-[(2R)-2-methylpiperazin-1-yl]pyridazin-3-yl]pyrido[3,4-d]pyrimidin-2,8-diamine (1R)-1-[2-[[6-(4,7-diazaspiro[2.5]octane-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]octane-7-ylmethyl)-2-pyridine]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-pyridine]methyl]-4-piperidinyl]propane-2-ol (1R)-1-[2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridine]amino]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[5-[2-(dimethylamino)ethoxy]-2-pyridine]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]acetone 1-[6-[[8-(isopropylamino)-6-[(2S)-tetrahydrofuran-2-yl]pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]piperazin-2-one (1R)-1-[8-(isopropylamino)-2-(5,6,7,8-tetrahydro-1,6-naphthidin-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-pyridine]methyl]piperazin-1-yl]-2-methyl-propane-1-ol 4-[6-[[6-[(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]-1-[(2S)-2-hydroxypropyl]-1,4-diazacycloheptane-5-one 4-[6-[[6-[(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]-1-[(2R)-2-hydroxypropyl]-1,4-diazacycloheptane-5-one N8-Isopropyl-N2-[5-(piperazin-1-ylmethyl)-2-pyridine]-6-[(2S)-tetrahydrofuran-2-yl]pyrido[3,4-d]pyrimidin-2,8-diamine 1-[6-[[6-[(1R)-1-hydroxyethyl]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-2-yl]amino]-2-methyl-3-pyridin]piperazin-2-one 1-[6-[[8-(isopropylamino)-6-[(3S)-tetrahydrofuran-3-yl]pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]piperazin-2-one (1R)-1-[2-(5,6,7,8-tetrahydro-1,6-naphthidin-2-ylamino)-8-[[(3S)-tetrahydropyran-3-yl]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol 1-[6-[[8-(isopropylamino)-6-(3-methyloxetane-3-yl)pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]piperazin-2-one (1R)-1-[2-[[5-[4-(dimethylamino)cyclohexyloxy]-2-pyridine]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-pyridine]-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-pyridine]methyl]piperidine-4-carboxylic acid (1R)-1-[8-(ethylamino)-2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridine]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridine]amino]-8-(propylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol N8-Isopropyl-6-(3-Methyloxetane-3-yl)-N2-(6-piperazin-1-ylpyridazin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine N8-Isopropyl-6-(3-methyloxetane-3-yl)-N2-[5-(piperazin-1-ylmethyl)-2-pyridine]pyrido[3,4-d]pyrimidin-2,8-diamine 6-(3-methyloxetane-3-yl)-N2-[5-(piperazin-1-ylmethyl)-2-pyridine]-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-pyridine]-1,4-diazacycloheptan-5-one (1R)-1-[8-(isopropylamino)-2-[(6-methyl-5-piperazin-1-yl-2-pyridine)amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[2-[[6-(2-hydroxyethyl)-7,8-dihydro-5H-1,6-naphthidin-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-naphthidin-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-pyridine]-6-[(3R)-tetrahydrofuran-3-yl]-N8-[(3S)-tetrahydropyran-3-yl]pyrido[3,4-d]pyrimidin-2,8-diamine (1R)-1-[2-[[6-[2-(dimethylamino)ethyl]-7,8-dihydro-5H-1,6-naphthidin-2-yl]amino]-8-(isopropylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol (2S)-1-[4-[[6-[[8-(ethylamino)-6-[(1R)-1-hydroxyethyl]pyridino[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]methyl]piperazin-1-yl]propane-2-ol] (2R)-1-[4-[[6-[[8-(ethylamino)-6-[(1R)-1-hydroxyethyl]pyridino[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]methyl]piperazin-1-yl]propane-2-ol] (1R)-1-[8-(isopropylamino)-2-[[5-[(2R)-2-methylpiperazin-1-yl]-2-pyridine]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[8-(isopropylamino)-2-[[5-[(2S)-2-methylpiperazin-1-yl]-2-pyridine]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol N8-Isopropyl-N2-(5-piperazin-1-yl-2-pyridine)-6-[(2S)-tetrahydrofuran-2-yl]pyrido[3,4-d]pyrimidin-2,8-diamine (1R)-1-[8-(cyclobutylamino)-2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridine]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol (1R)-1-[8-(cyclopropylmethylamino)-2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-2-pyridine]amino]pyrido[3,4-d]pyrimidin-6-yl]ethanol 6-(3-methyloxetane-3-yl)-N2-(5-piperazin-1-yl-2-pyridine)-N8-propyl-pyrido[3,4-d]pyrimidine-2,8-diamine 6-(3-methyloxetane-3-yl)-N2-[5-(piperazin-1-ylmethyl)-2-pyridine]-N8-propyl-pyrido[3,4-d]pyrimidine-2,8-diamine N2-(5-piperazin-1-yl-2-pyridine)-N8-propyl-6-tetrahydrofuran-3-yl-pyrido[3,4-d]pyrimidine-2,8-diamine N2-[5-(piperazin-1-ylmethyl)-2-pyridine]-N8-propyl-6-tetrahydrofuran-3-yl-pyrido[3,4-d]pyrimidine-2,8-diamine N8-Isopropyl-6-(3-Methyloxetane-3-yl)-N2-(5-piperazin-1-yl-2-pyridine)pyrido[3,4-d]pyrimidine-2,8-diamine N8-Isopropyl-N2-(5-piperazin-1-yl-2-pyridine)-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-pyridine]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-pyridine]methyl]piperazin-1-yl]ethanol (1R)-1-[2-[[5-[[4-(hydroxymethyl)-1-piperidinyl]methyl]-2-pyridine]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-pyridine]methyl]piperidin-4-ol 1-[[6-[[8-(tert-butylamino)-6-[(1R)-1-hydroxyethyl]pyrido[3,4-d]pyrimidin-2-yl]amino]-3-pyridine]methyl]piperidin-4-ol (1R)-1-[8-(tert-butylamino)-2-[[5-[[4-(hydroxymethyl)-1-piperidinyl]methyl]-2-pyridine]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-pyridine]methyl]piperidin-4-ol (1R)-1-[2-[[5-[[4-(hydroxymethyl)-1-piperidinyl]methyl]-2-pyridine]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-pyridine]piperazin-2-one (1R)-1-[2-[[5-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-6-methyl-2-pyridine]amino]-8-(propylamino)pyrido[3,4-d]pyrimidin-6-yl]ethanol. 25. A pharmaceutical composition comprising any one of claims 1 to 24, or a pharmaceutically permissible salt thereof, and a pharmaceutically permissible carrier. 26. A pharmaceutical composition having CDK4/6 inhibitory activity, comprising the compound of any one of claims 1 to 24 or a pharmaceutically permissible salt thereof as an active ingredient. 27. A preventive or therapeutic agent for rheumatoid arthritis, arteriosclerosis, pulmonary fibrosis, cerebral infarction, or cancer, comprising the compound of any one of claims 1 to 24 or a pharmaceutically permissible salt thereof as an active ingredient.