TW201704227A - Novel heteroarylamino-3-pyrazole derivative and pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention provides a compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein X is nitrogen atom or CR5; Y is hydrogen atom, C1-6 alkyl, etc.; R<SP>1a</SP>, R<SP>1b</SP>, R<SP>1c</SP>, R<SP>1d</SP>, and R<SP>1e</SP> are the same or different, hydrogen atom, halogen atom, hydroxy, etc.; R4 is hydrogen atom, cyano, C1-6 alkyl, etc.; R2, R3 and R5 are the same or different, hydrogen atom, halogen atom, hydroxy, C1-6 alkyl, etc.; and Ar is monocyclic or polycyclic C6-10 aryl or monocyclic or polycyclic 5- to 10-membered heteroaryl, which exhibits antitumor activity by inhibiting plural kinases/signals such au CDK1, CDK2, CDK5, AURKA, AURKB, and JAK2 that are necessary for cell cycle, cell growth and survival of cancer stem cell, and has low side effect and high safety.

Description

Novel heteroarylamino-3-pyrazole derivatives and pharmacologically acceptable salts thereof

The present invention relates to a novel heteroarylamino-3-pyrazole derivative useful as a medicament and a pharmacologically acceptable salt thereof. More specifically, it relates to a heteroarylamino-3-pyrazole derivative and a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the above derivative or a salt thereof, and a kinase comprising the same A therapeutic agent for a related condition.

In the process of normal somatic cell carcinoma, abnormalities in cell division control are known as one of the fundamental features. Cell division is divided into 4 cycles, which are related to G1 phase, S phase, G2 phase, and mitosis (M) phase. Different proteins are related to the control of the period.

The anticancer agents currently used in the control of cell division are mostly those which inhibit the activity of one or a plurality of related proteins of the cell cycle, and their clinical effectiveness has been proved by various studies. On the other hand, it has also been reported that most of the anticancer agents currently involved in cell division control exhibit various side effects of unknown causes in addition to the side effects derived from the obstruction mechanism. Therefore, there is a case where the anticancer agent cannot be sufficiently administered, and the limit of treatment is generated. Based on these circumstances, the industry is looking forward to the development of anticancer agents with excellent therapeutic effects and few side effects.

In cell cycle control, the cyclin-dependent kinase (CDK) line is synchronized with the cyclin as its regulatory subunit, after G1, S Phases, G2 phase and M phase are controlled in four phases to control the cell cycle. At least 13 CDKs are known in mammalian cells, and it has been determined that CDK1 (CDC2), CDK2, CDK3, CDK4 and CDK6 are involved in cell cycle progression. In addition, although all CDKs are related to the transition from G1 phase to S phase, especially CDK1 and CDK2 will form complex with cyclin E or cyclin A, respectively, and undertake the transition from G1 phase to S phase or from S phase. The necessary role for the transition to the G2 phase.

Moreover, it has been clarified that in mitosis, in addition to CDK1, a few specific kinases also control one of the complex series of mitosis. It has been clarified that as a minority of specific kinases, serine-threonine kinase plays an important role (Non-Patent Document 1), and it is known that Aurora kinase is used to give chromosomes a higher fidelity to the child. The manner in which the cells are distributed is controlled (Non-Patent Document 2). There are three known Aurora kinases in mammalian cells, and it has been determined that at least AURKA (Aurora kinase-A) and AURKB (Aurora kinase-B) are involved in chromosome segregation or cytoplasmic separation.

It has been reported that CDK5 plays an important role in the generation of nerves or the formation of brain functions (Non-Patent Document 3). Further, it has been reported that CDK5 is associated with a neurodegenerative disease such as Alzheimer's disease and Parkinson's disease (Non-Patent Document 4), and there is a report indicating that CDK5 is associated with cancer (Non-Patent Document 5).

It has been reported that by blocking the function of CDK and Aurora kinase, it promotes cell cycle inhibition, cell proliferation inhibition, apoptosis, and differentiation or aging, and exhibits an anti-tumor effect. Further, it has been reported that CDK1, cyclin A, cyclin E, AURKA, and AURKB are excessively expressed in various human solid cancers or blood cancers, and their expression or activity is associated with poor prognosis (Non-Patent Document 6, Non-Patent Document 7) Non-Patent Document 8, Non-Patent Document 9, and Non-Patent Document 10) are considered to have high use value as an anticancer agent for a low molecular compound targeting CDK or Aurora.

On the other hand, there are reports that cancer stem cells exist in several types of cancers such as blood cancer, brain tumor, colorectal cancer, and breast cancer. Cancer stem cells are defined as cancer cells A few cells with high nature and high tumor formation ability. Further, from the viewpoint of the main cause of cancer deterioration, there is also a case called a tumor (Cancer)-Initiating Cell. In recent years, the role of a specific kinase signal in cancer stem cells has become clear (Non-Patent Document 11). For example, it has been reported that the JAK2/STAT3 signal is necessary for the survival of cancer stem cells of breast cancer or prostate cancer (Non-Patent Document 12), and that the TGF-beta signal is activated in cancer stem cells of breast cancer which shows resistance to chemotherapy. (Non-Patent Document 13).

Further, Myc, which is known as a proto-oncogene, is considered to be one of the main causes of cancer deterioration, and the prognosis of breast cancer patients whose Myc signal is activated is extremely poor. Further, based on the discovery of a target molecule for induction of lethal synthesis using a Myc signal-constantized cancer cell line, it is considered that an inhibitor of CDK1, CDK2, AURKA, and AURKB is a cell for inhibiting or selective proliferation of a cancer cell dependent on Myc signal. The induction of death is effective (Non-Patent Document 14).

Heretofore, as the arylaminopyrazole derivative, Patent Document 1 discloses, for example, the following compounds.

[wherein, Z ¹ or Z ² means a nitrogen atom, Q is -S- or the like, R ^x and R ^y are -TR ³ , -LZR ³ , and R ¹ is -T-(D ring) [D ring is 5 From a member to a single member of a member, etc.], T is a valence bond, Z is a C _1-4 alkylene chain, etc., L is -O-, etc., and R ² and R ^2' are -R, -TWR ^6, etc. R ³ is -R or the like, R is a hydrogen atom or the like, W is -C(R ⁶ ) ₂ O- or the like, and R ⁶ is a hydrogen atom or the like]

Further, Patent Document 2 discloses, for example, the following compounds.

[Chemical 2]

Wherein K is NH, O, S or the like, A is an aryl group, m is 0 or the like, X is O or S, R ¹ is a hydrogen atom or the like, R ² is an amine group or the like, and R ³ is an aryl oxygen. Base, etc., R ⁴ is an alkyl group, etc.]

Further, Patent Document 3 discloses, for example, the following compounds.

In the formula, R ¹ is a hydrogen atom or the like, R ² is a hydroxyl group or the like, R ³ is an alkyl group or the like, R ⁴ is a hydrogen atom or the like, R ⁵ is a hydrogen atom or the like, R ⁶ is a halogen or the like, and R ⁷ is a halogen or the like. n is 0~4, p is 0~5]

Further, Patent Document 4 discloses, for example, the following compounds.

However, none of the patent documents 1, 2, 3 and 4 discloses the compound represented by the formula (1) of the present invention.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2002/066461

[Patent Document 2] International Publication No. 2013/033862

[Patent Document 3] International Publication No. 2010/099379

[Patent Document 4] International Publication No. 2013/130600

[Non-patent literature]

[Non-Patent Document 1] Lim S, Kaldis P. Development. 140 (15): 3079 - 93 (2013)

[Non-Patent Document 2] Cheung CH, et al., Expert Opin Ther Pat. 24 (9): 1021 - 38 (2014)

[Non-Patent Document 3] Nikolic M, et al., Genes Dev 10: 816 - 825, (1996)

[Non-Patent Document 4] Wilkaniec A, et al., J Neurochem. 136 (2): 222 - 33 (2016)

[Non-Patent Document 5] Liang Q, et al., Sci Rep. 3: 2932 (2013)

[Non-Patent Document 6] Chen X, et al., Med Oral Patol Oral Cir Bucal. 20 (1): e7 - e12 (2015)

[Non-Patent Document 7] Jansen MP, et al., Breast Cancer Res Treat. 133 (3): 937 - 47 (2012)

[Non-Patent Document 8] Yasmeen A, et al., Expert Rev Mol Diagn. 3 (5): 617 - 33 (2003)

[Non-Patent Document 9] Pacaud R, et al., Theranostics. 5 (1): 12 - 22 (2015)

[Non-Patent Document 10] Fu J, et al., Mol Cancer Res. 5 (1): 1 - 10 (2007)

[Non-Patent Document 11] Pattabiraman DR, Weinberg RA. Nat Rev Drug Discov. 13 (7): 497 - 512 (2013)

[Non-Patent Document 12] Marotta LL, et al., J Clin Invest. 121 (7): 2723 - 35 (2011)

[Non-Patent Document 13] Bhola NE, et al., J Clin Invest. 123 (3): 1348 - 58 (2013)

[Non-Patent Document 14] Horiuchi D, et al., Am Soc Clin Oncol Educ Book. e497 - 502 (2014)

The problem to be solved by the present invention is to provide a compound which inhibits plurals of CDK1, CDK2, AURKA, AURKB, JAK2, CDK5, etc., which are necessary for the cell cycle, cell proliferation or cancer stem cell survival as described above. Kinase and signal play an anti-cancer effect, reduce side effects, and have higher safety. Further, there is provided a compound which exhibits a cancer stem cell control action by inhibiting a kinase and which has a side effect and is highly safe.

As a result of intensive studies, the present inventors have found that a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof (hereinafter also referred to as "the compound of the present invention") is selected from CDK1. The kinases in CDK2, AURKA, AURKB, JAK2, CDK5 and the like have a high inhibitory effect and do not exhibit antagonistic activity against the Adenosine A3 receptor, but have excellent antitumor effects. Furthermore, for the preferred compounds of the compounds of the invention, it is confirmed that the compound has a PK (Pharmacokinetics) type based on suitable solubility and metabolic stability, and/or weak cardiotoxicity and against ordinary cells. The toxicity is weaker, thereby completing the present invention.

That is, the present invention is as follows.

[item 1]

A compound or a pharmacologically acceptable salt thereof, which is represented by the following formula (1), [Chem. 5]

[In the formula (1), X represents a nitrogen atom or CR ⁵ ; Y represents a hydrogen atom, a C _1-6 alkyl group (the group may also be selected from a halogen atom, a hydroxyl group, a C _1-6 alkoxy group, and C _{3 - a} 1 to 3 substituent in the _10- cycloalkyl group, or a C _3-10 cycloalkyl group (the group may also be selected from a halogen atom, a hydroxyl group, a C _1-6 alkyl group, and a C _1-6 alkane group). a saturated heterocyclic ring of the same or different 1-4 in the oxy group) or a member of 3 to 8 members (the group may also be selected from a halogen atom, a hydroxyl group, a C _1-6 alkyl group, and a C _1-6 alkane) 1 to 4 substituents which are the same or different in the oxy group; R ^1a , R ^1b , R ^1c , R ^1d and R ^{1e are the} same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, C _{a 1-6} alkyl group (the group may also be substituted by the same or different one to three groups selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group), a C _1-6 alkoxy group (the group is also Substituted by the same or different 1 to 3 groups selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group, an amine group, a C _1-6 alkylamino group (the group may also be selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group of 1 to 3 identical or different substituents), C _2-12 dialkylamino group (the group may also be selected by a halogen atom, a hydroxyl And a C _1-6 alkoxy group of 1 to 6 identical or different substituents), the 3 to 6-membered cyclic amino group (the group may also be selected by a halogen atom, a hydroxyl group, C _1-6 alkyl And the same or different 1 to 4 substituents in the C _1-6 alkoxy group) or a C _1-6 alkylcarbonyl group (the group may also be selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group) 1 or 3 substituents which are the same or different); R ⁴ represents a hydrogen atom, a cyano group, a hydroxyl group, a C _1-6 alkyl group (the group may also be selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group). The same or different 1-3 substituents or C _3-10 cycloalkyl groups (the group may also be the same or different from the halogen atom, the hydroxyl group and the C _1-6 alkoxy group) R ² , R ³ and R ^{5 are the} same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C _1-6 alkyl group (the group may also be selected from a halogen atom, a hydroxyl group) , C _1-6 alkoxy and C _3-10 cycloalkyl, the same or different 1-3 substituents, C _1-6 alkoxy (this group may also be the same or different 1~3 halogen atoms), are the same or different amino, C _1-6 alkyl group (the group may also be selected by a halogen atom, a hydroxyl group and the C _1-6 alkoxy group 1 to 3 substituents), C _2-12 dialkylamino group (the group may also be selected by a halogen atom, a hydroxyl group and a C _1-6 alkoxy group in the same or different 1 to 6 substituents) a cyclic amine group of 3 to 6 members (the group may also be substituted by the same or different 1 to 4 groups selected from the group consisting of a halogen atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) , C _1-6 alkylcarbonyl (the group may also be substituted by the same or different 1-3 halogen atoms), C _3-10 cycloalkyl (this group may also be selected from a halogen atom, a hydroxyl group, C _{1- a} saturated heterocyclic ring of 3 to 8 members, which may be the same or different from the _6- alkyl group and the C _1-6 alkoxy group (the group may also be selected from a halogen atom, a hydroxyl group, C _{1- a 1-6} alkyl group which is the same or different in a ₆ alkyl group and a C _1-6 alkoxy group), a C _6-10 aryl group (the group may also be selected from a halogen atom, a C _1-6 alkyl group and a C group) a monocyclic or polycyclic heteroaryl group of the same or different _1-4 alkoxy groups) or a 5- to 10-membered heteroaryl group (the group may also be selected from a halogen atom, C _{1 1-6} alkyl and C _1-6 alkoxy in the same or different 1 to 4 substituents); Ar represents the C _6-10 monocyclic or polycyclic aromatic group of five or ten of ~ Single or multi-ring Yl].

[item 2]

A compound according to item 1, or a pharmacologically acceptable salt thereof, wherein Ar is a phenyl group or a pyridyl group.

[item 3]

The compound of Item 1 or 2, or a pharmacologically acceptable salt thereof, wherein Ar is a phenyl group.

[item 4]

The compound according to any one of items 1 to 3, wherein X is CR ⁵ ; R ⁵ is a hydrogen atom, a halogen atom or a C _1-6 alkyl group (the group may also be subjected to 1~), or a pharmacologically acceptable salt thereof. 3 fluorine atoms are substituted).

[item 5]

The compound according to any one of items 1 to 3, wherein X is a nitrogen atom, or a pharmacologically acceptable salt thereof.

[item 6]

The compound according to any one of items 1 to 5, wherein the Y is a hydrogen atom or a C _1-6 alkyl group (the group may be substituted by 1 to 3 fluorine atoms), or a pharmacologically acceptable salt thereof.

[item 7]

The compound according to any one of items 1 to 6 or a pharmacologically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, a C _1-6 alkyl group (the group may also be substituted by 1 to 3 fluorine atoms) or C _3-10 cycloalkyl (this group may also be substituted by 1 to 4 fluorine atoms).

[item 8]

The compound of any one of items 1 to 7 or a pharmacologically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, a C _1-6 alkyl group (the group may also be substituted with 1 to 3 fluorine atoms) or C _3-4 cycloalkyl (this group may also be substituted by 1 to 4 fluorine atoms).

[item 9]

The compound or a pharmacologically acceptable salt thereof, wherein R ² and R ^{3 are the} same or different and are a hydrogen atom, a halogen atom or a C _1-6 alkyl group (the group may also be a 1~3 fluorine atoms are substituted).

[item 10]

The compound of any one of items 1 to 9 or a pharmacologically acceptable salt thereof, wherein R ^1a , R ^1b , R ^1c , R ^1d and R ^{1e are the} same or different and are a hydrogen atom, a halogen atom, C _{1- a 6} alkyl group (the group may also be substituted by the same or different one to three groups selected from a fluorine atom and a C _1-6 alkoxy group) or a C _1-6 alkoxy group (the group may also be subjected to 1~) 3 fluorine atoms are substituted).

[item 11]

The compound or a pharmacologically acceptable salt thereof, wherein R ^1a , R ^1b , R ^1c , R ^1d and R ^{1e are the} same or different and are a hydrogen atom, a halogen atom or C _{1- 6} alkyl (this group can also be substituted by 1 to 3 fluorine atoms).

[item 12]

The compound of any one of items 1 to 11, or a pharmacologically acceptable salt thereof, wherein R ⁴ is a C _1-6 alkyl group (the group may also be substituted with 1 to 3 fluorine atoms) or a cyclopropyl group.

[item 13]

The compound according to any one of items 1 to 12, wherein the at least one of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e is a halogen atom, or a pharmacologically acceptable salt thereof.

[item 14]

The compound according to any one of items 1 to 13 or a pharmacologically acceptable salt thereof, wherein at least two of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are a halogen atom.

[item 15]

The compound according to any one of items 1 to 14, or a pharmacologically acceptable salt thereof, wherein at least two of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are a fluorine atom.

[item 16]

A compound according to claim 1 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: (4-methyl-6-((5-methyl-1H-pyrazole-3-) (amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 14 etc.], (4-((5-methyl-1H-pyrazol-3-yl)) Amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 10 and the like], (4-((5-methyl-1H-pyrazol-3-yl))amine Pyrimidine-2-yl)(2,3,4-trifluorophenyl)methanol [Example 21 and the like], (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,4-trifluorobenzene) Methanol) [Example 31, etc.], (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) (3,4,5- Trifluorophenyl)methanol [Example 9], (4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) (3,4,5-trifluoro Phenyl)methanol [Example 8 etc.], (3,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 1 and the like], (3,4-difluorophenyl)(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) Methanol [Example 11], (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorobenzene Methanol) [Example 27], (4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol [Example 26], (2,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 29] (2,4-difluorophenyl)(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 30] (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,6-trifluorophenyl)methanol, (4 -((5-methyl-1H-pyridyl) 3-yl)amino)pyrimidin-2-yl)(2,4,6-trifluorophenyl)methanol [Example 20], (2,3-difluorophenyl)(4-((5- Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 35], (2,3-difluorophenyl)(4-methyl-6-((5- Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) Methanol, (4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(pentafluorophenyl)methanol [Example 22, etc.], (4-methyl- 6-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(pentafluorophenyl)methanol, (3,4-difluorophenyl)(5-fluoro- 4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 24], (3,4-difluorophenyl) (5-fluoro-4) -Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (5-fluoro-4-methyl-6-((5-A) -1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol, (5-fluoro-4-((5-methyl-1H-) Pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 33], (5-fluoro-4-methyl-6-((5) -methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol, (5-fluoro-4-((5-methyl-) 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol [Example 25], (5-chloro-4-((5-methyl) -1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 36], (5-chloro-4-methyl-6- ((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol, 1-(3,4-difluorophenyl )-1-(4-((5-methyl-1H-pyrazol-3-yl)amine Pyrimido-2-yl)ethane-1-ol [Example 49], 1-(3,4-difluorophenyl)-1-(4-methyl-6-((5-methyl-) 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)ethane-1-ol, (4-((3-ethyl-1H-pyrazol-5-yl)amino)pyrimidine-2 -yl)(3,4,5-trifluorophenyl)methanol [Example 54], (4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol [Implementation Example 53], (4-((3-Cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 57 , 1-(4-((3-Cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)-1-(2,4,5-trifluorophenyl)ethane -1-ol [Example 72], (4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(4-fluoro-3-methylphenyl) Methanol [Example 61], (4-chloro-3-fluorophenyl)(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)methanol [ Example 59], 1-(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)-1-(4-fluoro-3-methylphenyl) Ethyl-1-ol [Example 79], and 1-(4-chloro-3-fluorophenyl)-1-(4-((3-cyclopropyl-1H-pyrazol-5-yl)) Amino)pyrimidin-2-yl)ethane-1-ol [Example 73]. [Item 17] The compound of Item 1, or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: (4-methyl-6-((5-methyl-1H-pyrazole) 3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 14 etc.], (4-((5-methyl-1H-pyrazole-3) -amino)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 10, etc.], (4-((5-methyl-1H-pyrazol-3-yl) Amino)pyrimidin-2-yl)(2,3,4-trifluorophenyl)methanol [Example 21, etc.], (4-methyl-6-((5-methyl-1H-pyrazole-) 3-yl)amino)pyrimidin-2-yl)(2,3,4-trifluorophenyl)methanol [Example 31, etc.] (4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol [Example 9 ], (4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol [Example 8, etc.] (3,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 1 etc.], (3, 4-difluorophenyl)(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 11], (4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol [Example 27], ( 4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol [Example 26], (2, 4 -difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 29], (2,4-difluorophenyl) (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 30], (4-methyl-6-( (5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,6-trifluorophenyl)methanol, (4-((5-methyl-1H-) Pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,6-trifluorophenyl)methanol [Example 20], (2,3-difluorophenyl) (4-(( 5-methyl-1H-pyrazol-3-yl)amine Pyrimidine-2-yl)methanol [Example 35], (2,3-difluorophenyl)(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino) Pyrimidine-2-yl)methanol, 1-(3,4-difluorophenyl)-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino) Pyrimidine-2-yl)ethane-1-ol, (4-((3-ethyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol [Example 54], (4- ((3-Cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol [Example 53], (4-(( 3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 57], 1-(4-(( 3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)-1-(2,4,5-trifluorophenyl)ethane-1-ol [Example 72] (4-((3-Cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(4-fluoro-3-methylphenyl)methanol [Example 61], ( 4-chloro-3-fluorophenyl)(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)methanol [Example 59], 1-(4 -((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)-1-(4-fluoro-3-methylphenyl)ethane-1-ol [implementation Example 79], and 1-(4-chloro-3-fluorophenyl)-1-(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl) Ethyl-1-ol [Example 73].

[item 18]

A pharmaceutical composition comprising a compound according to any one of items 1 to 17 or 52, or a pharmacologically acceptable salt thereof.

[item 19]

A kinase inhibitor comprising the compound according to any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[item 20]

An anticancer agent containing the compound of any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[item 21]

The anticancer agent according to Item 20, wherein the cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer, pancreatic cancer, gastric cancer, osteosarcoma , myeloma, or blood cancer.

[item 22]

A method for treating and/or preventing cancer, which comprises administering a therapeutically effective amount of a compound according to any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof to a patient in need of treatment. .

[item 23]

The method for treating and/or preventing according to Item 22, wherein the cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer, pancreas Cancer, stomach cancer, osteosarcoma, myeloma, or blood cancer.

[item 24]

A use of a compound according to any one of items 1 to 17 or 52, or a pharmacologically acceptable salt thereof, for the manufacture of a therapeutic and/or prophylactic agent for cancer.

[item 25]

The use of item 24, wherein the cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer, pancreatic cancer, gastric cancer, osteosarcoma, bone marrow Tumor, or blood cancer.

[item 26]

The compound of any one of items 1 to 17 or 52, or a pharmacologically acceptable salt thereof, for use in the treatment and/or prevention of cancer.

[item 27]

The compound of Item 26 or a pharmacologically acceptable salt thereof, wherein the cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer, Pancreatic cancer, gastric cancer, osteosarcoma, myeloma, or blood cancer.

[item 28]

The anticancer agent according to Item 20, the method for treating and/or preventing the item 22, the use of the item 24, or the compound of the item 26 or a pharmacologically acceptable salt thereof, wherein the cancerous blood cancer, the myeloma, the liver cancer , ovarian cancer, prostate cancer, lung cancer, osteosarcoma, colorectal cancer, breast cancer, skin cancer or epithelial cell carcinoma.

[item 29]

A cell cycle terminator comprising the compound of any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[item 30]

A proliferative inhibitor of cancer stem cells, which comprises the compound of any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[item 31]

The anticancer agent according to Item 20 or Item 21, which has an inhibitory effect on the expression of a stem cell gene.

[item 32]

The anticancer agent according to Item 31, wherein the stem cell gene is any one selected from the group consisting of Nanog, Sox2, b-chain protein and Oct4.

[item 33]

The anticancer agent according to item 31, wherein the stem cell gene is Nanog.

[item 34]

An expression inhibitor of a stem cell gene, which comprises the compound of any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[item 35]

An anticancer agent containing a compound which inhibits three or more kinases.

[item 36]

The anticancer agent according to item 35, wherein the kinase system is selected from the group consisting of CDK2, CDK5, JAK2, AURKA, AURKB and CDK1.

[item 37]

An anticancer agent comprising a compound which blocks two or more kinases selected from the group consisting of CDK2, CDK5 and JAK2.

[item 38]

An anticancer agent comprising a compound which blocks all of CDK2, CDK5 and JAK2.

[item 39]

A method of treating cancer comprising inhibiting three or more kinases.

[item 40]

The method of item 39, wherein the kinase is selected from the group consisting of CDK2, CDK5, JAK2, AURKA, AURKB, and CDK1.

[item 41]

A method of treating cancer comprising blocking a kinase selected from two or more of the group consisting of CDK2, CDK5 and JAK2.

[item 42]

A method of treating cancer comprising blocking all of CDK2, CDK5 and JAK2.

[item 43]

A method of treating cancer comprising inhibiting the performance of a stem cell gene.

[item 44]

A method for inhibiting the expression of a stem cell gene, which comprises blocking CDK5.

[item 45]

A therapeutic agent for the treatment of cancer resistant to a chemotherapeutic agent, which comprises the compound according to any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[item 46]

The therapeutic agent according to Item 45, wherein the chemotherapeutic agent is a taxane-based anticancer agent.

[item 47]

The anticancer agent according to Item 20 or Item 21, which has a cell cycle termination effect.

[ite 48]

The anticancer agent according to any one of items 20, 21 or 47, which has a proliferation inhibitory effect of cancer stem cells.

[item 49]

The anticancer agent according to any one of items 20 to 21 or 47 to 48, which has a recurrence preventing effect of cancer.

[item 50]

The anticancer agent according to any one of items 20 to 21 or 47 to 49, which has a cancer metastasis suppressing action.

[item 51]

A method for inhibiting the expression of a stem cell gene, which comprises blocking a kinase selected from two or more of the group consisting of CDK2, CDK5 and JAK2.

[ite 52]

A compound according to item 1, or a pharmacologically acceptable salt thereof, which is selected from the group consisting of (-)-(3,4-difluorophenyl)(4-((5-methyl)) -1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 2], (+)-(3,4-difluorophenyl)(4-((5-methyl-) 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol [Example 3], (+)-(4-methyl-6-((5-methyl-1H-pyrazole-3) -yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 4], (-)-(4-methyl-6-((5-methyl-) 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol [Example 5], (-)-(6-((5-methyl) -1H-pyrazol-3-yl)amino)pyridin-2-yl)(3,4,5-trifluorophenyl) A Alcohol [Example 6], (+)-(6-((5-Methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)(3,4,5-trifluorophenyl) Methanol [Example 7], (+)-{4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl} (2,3, 4-Trifluorophenyl)methanol [Example 32], and (-)-{4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2- (}, 2,3,4-trifluorophenyl)methanol [Example 31].

[ite 53]

A pharmaceutical composition comprising a compound according to any one of items 1 to 17 or 52, or a pharmacologically acceptable salt thereof, and a (1) hormonal therapeutic agent, (2) a chemotherapeutic agent, (3) An immunotherapeutic agent, and (4) one or more agents selected from the group consisting of agents that inhibit the receptor action of cell proliferating factors or cell proliferating factors.

[item 54]

An anticancer agent comprising the compound according to any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof as an active ingredient, and for use in combination with a therapeutic agent selected from the group consisting of (1) a hormonal therapeutic agent, (2) A chemotherapeutic agent, (3) an immunotherapeutic agent, and (4) one or more agents selected from the group consisting of agents that inhibit the action of a cell proliferating factor or a cell proliferating factor.

[item 55]

A method for treating and/or preventing cancer, which comprises administering a therapeutically effective amount of a compound according to any one of items 1 to 17 or 52 or a pharmacologically acceptable salt thereof to a patient in need of treatment. And a group selected from the group consisting of (1) a hormonal therapeutic agent, (2) a chemotherapeutic agent, (3) an immunotherapeutic agent, and (4) a drug that blocks the action of a cell proliferating factor or a cell proliferating factor. More than one of the above agents.

a compound represented by the formula (1), or a pharmacologically acceptable salt thereof (also referred to as a compound of the present invention) by CDK1, CDK2, CDK5, JAK2, AURKA or AURKB, or interaction with other kinases, has an excellent inhibitory effect, and can be applied to the prevention and treatment of various symptoms associated with kinases, such as cancer. Further, since cardiotoxicity or toxicity to normal cells is weak, it is particularly useful as an anticancer agent having excellent therapeutic effects and few side effects, and is applied to prevention and treatment of various diseases related to kinases and the like.

Figure 1 is a graph of a powder X-ray diffraction pattern of the compound of Example 89.

2 is a graph showing DSC-TGA (differential scanning calorimetry-thermogravimetric analysis) of the compound of Example 89.

Fig. 3 is a perspective structural view of the crystal obtained in Example 90 obtained by X-ray crystal analysis.

Figure 4 is a graph of the powder X-ray diffraction pattern of the compound of Example 91.

Figure 5 is a graph of the DSC-TGA of the compound of Example 91.

Fig. 6 shows the results of measurement of the tumor diameter after the test shown in Test Example 7 of the compound obtained in Example 4. The vertical axis represents the change in tumor volume. The horizontal axis represents the number of days after tumor transplantation. The curve and the error bar represent the mean and standard error of the tumor volume, respectively. # indicates the result of the meaningful difference test (ρ<0.05, Dunnett's check).

Fig. 7 shows the results of measurement of the body weight after the test shown in Test Example 7 for the compound obtained in Example 4. The vertical axis represents the change in body weight. The horizontal axis represents the number of days after tumor transplantation. The curve and the error bar represent the mean and standard error of the body weight, respectively. # indicates the result of the meaningful difference test (ρ<0.05, student t test).

Fig. 8 shows the results of measurement of the tumor diameter after the test shown in Test Example 8 of the compound obtained in Example 4. The vertical axis represents the change in tumor volume. The horizontal axis represents the number of days after tumor transplantation. The curve and the error bar represent the mean and standard error of the tumor volume, respectively. # indicates the result of the meaningful difference check (ρ<0.025, Williams test).

Figure 9 shows the test shown in Test Example 8 for the compound obtained in Example 4. The result of the measurement of the body weight afterwards. The vertical axis represents the change in body weight. The horizontal axis represents the number of days after tumor transplantation. The curve and the error bar represent the mean and standard error of the body weight, respectively. # indicates the result of the meaningful difference check (ρ<0.025, Williams test).

Fig. 10 shows the results of the Nanog performance level after the test shown in Test Example 13 for the compound obtained in Example 4. The results of the control compound Palbociclib and European docetaxel are also shown.

Fig. 11 shows the results of performing the Nanog expression level after the test shown in Test Example 13 for the compound obtained in Example 72.

Hereinafter, the present invention will be described in more detail.

In the present specification, the radicals which are defined by "substitutable" are unsubstituted and substituted. The number of substituents in the radical, unless otherwise stated, is not specified as long as it can be substituted. The limit is one or plural. Further, the description of each base applies to a portion or substituent of another base of the base, except where otherwise indicated.

In the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. It is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

The "C _1-6 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, 1-methylpropyl, and 1,1-dimethylethyl. Pentyl, 3-methylbutyl, 2-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methyl Butyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl and the like. The preferred "C _1-6 alkyl group" may, for example, be a C _1-4 alkyl group, and more preferably a C _1-3 alkyl group.

Specific examples of the "C _1-4 alkyl group" include a methyl group, an ethyl group, a propyl group, and a 1-methyl group having 1 to 4 carbon atoms in a specific example of "C _1-6 alkyl group". Base, butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl and the like. Specific examples of the "C _1-3 alkyl group" include a methyl group, an ethyl group, a propyl group, and a 1-methylethyl group having 1 to 3 carbon atoms in a specific example of "C _1-6 alkyl group". Wait.

In the present specification, for example, C _1-6 indicates that the carbon number is 1 to 6, and C _1-4 indicates that the carbon number is 1 to 4, and C _1-3 indicates that the carbon number is 1 to 3, or so-called C ₆ represents a carbon number of 6. The same is true for other numbers.

The "C _3-10 cycloalkyl group" means a cyclic alkyl group having 3 to 10 carbon atoms, and also includes a part of the crosslinked structure. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, a cyclodecyl group, an adamantyl group, and the like. The preferred "C _3-10 cycloalkyl group" is a C _3-8 cycloalkyl group, and more preferably a C _3-6 cycloalkyl group.

The "C _3-8 cycloalkyl group" means a cyclic alkyl group having 3 to 8 carbon atoms. Specific examples of the "C _3-10 cycloalkyl group" include a cyclopropyl group having 3 to 8 carbon atoms, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Wait.

The "C _3-6 cycloalkyl group" means a cyclic alkyl group having 3 to 6 carbon atoms. Specific examples thereof include a cyclopropyl group having 3 to 6 carbon atoms, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group in a specific example of the "C _3-10 cycloalkyl group".

The so-called "C _1-6 alkoxy" means "C _1-6 alkyl group", the same "C _1-6 alkyl" portion of the above-mentioned "C _1-6 alkyl" meaning. Specific examples include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy, and 1,1. - dimethylethoxy, pentyloxy, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1 - dimethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethyl Butyloxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy and the like. Preferred examples of the "C _1-6 alkoxy group" include a C _1-4 alkoxy group.

Specific examples of the "C _1-4 alkoxy group" include a methoxy group, an ethoxy group, a propoxy group having 1 to 4 carbon atoms in a specific example of the "C _1-6 alkoxy group". 1-methylethoxy, butoxy, and the like.

The "C _1-6 alkyl group" in the "C _1-6 alkylcarbonyl group" has the same meaning as the above "C _1-6 alkyl group". Specific examples of the "C _1-6 alkylcarbonyl group" include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, a 1-methylethylcarbonyl group, a butylcarbonyl group, a 2-methylpropylcarbonyl group, and 1 -methylpropylcarbonyl, 1,1-dimethylethylcarbonyl, and the like. Preferred examples of the "C _1-6 alkylcarbonyl group" include a C _1-4 alkylcarbonyl group.

Specific examples of the "C _1-4 alkylcarbonyl group" include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, a 1-methylethylcarbonyl group, a butylcarbonyl group, and a 2-methylpropylcarbonyl group.

The "C _1-6 alkyl group" in the "C _1-6 alkylamino group" has the same meaning as the above "C _1-6 alkyl group". Specific examples of the "C _1-6 alkylamino group" include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, and an isobutylamino group. A third butylamino group, a pentylamino group, a hexylamino group, and the like. A preferred "C _1-6 alkylamino group" is a "C _1-4 alkylamino group".

Specific examples of the "C _1-4 alkylamino group" include a methylamino group having 1 to 4 carbon atoms and an ethylamino group in a specific example of the "C _1-6 alkylamino group". A propylamino group, an isopropylamino group, a butylamino group or the like.

The "C _2-12 dialkylamino group" means "an amine group having two identical or different C _1-6 alkyl groups bonded", and the C _1-6 alkyl group has the same meaning as described above. Specific examples of the "C _2-12 alkylamino group" include a dimethylamino group, a diethylamino group, an ethylmethylamino group, a methylpropylamino group, and an ethylpropylamino group. , dipropylamino, isopropylmethylamino, isopropylethylamino, diisopropylamino, methylbutylamino, ethylbutylamino, dibutylamino, Diisobutylamino group, di-tert-butylamino group, dipentylamino group, dihexylamino group and the like. Preferred examples of the "C _2-12 dialkylamino group" include a "C _2-8 dialkylamino group".

Specific examples of the "C _2-8 dialkylamino group" include dimethylamino group, diethylamino group, ethylmethylamino group, methylpropylamino group, and ethylpropylamine. Base, dipropylamino, isopropylmethylamino, isopropylethylamino, diisopropylamino, methylbutylamino, ethylbutylamino, dibutylamino , diisobutylamino group, di-t-butylamino group and the like.

The "cyclic amine group of 3 members to 6 members" includes a monocyclic cyclic amine group of 3 to 6 members containing at least one nitrogen atom. The "3 to 6 member cyclic amine group" may further have one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom or a sulfur atom. Further, the bond to the bond of the group is a nitrogen atom constituting a ring in the "cyclic amine group of 3 to 6 members". Further, the group also includes a cyclic amine group in which a part of the ring contains an unsaturated bond. Specific examples of the "cyclic amine group of 3 to 6 members" include an aziridine group, an azetidinyl group, a pyrrolidinyl group, and an imidazolidinyl group. Zyridinyl, thiazolyl, piperid Base, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyridyl and the like. As a preferred "cyclic amine group of 3 to 6 members", "a cyclic amine group of 5 to 6 members" can be cited.

Specific examples of the "cyclic amine group of 5 members to 6 members" include pyrrolidinyl group and imidazolidinyl group. Zyridinyl, thiazolyl, piperid Base, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyridyl and the like.

"Acyclic amine group of 3 to 6 members" and "cyclic amine group of 5 or 6 members" may also be combined with C _3-6 cycloalkyl, 6-membered aryl or 5 or 6 members. The base forms a condensed ring. Specific examples of the condensed ring include the "base" shown below.

[Chemical 6]

The "saturated heterocyclic ring of 3 to 8 members" means composed of 3 to 8 atoms including one or two atoms independently selected from a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. A monocyclic or 2-ring saturated heterocyclic ring. A portion of the base can also be crosslinked or spiro cyclized. Further, in the group, a C _6-10 aryl group or a C _5-10 heteroaryl group may also be condensed. Further, in this group, the nitrogen atom constituting the ring does not become a "base" bonding bond. That is, the group does not include a concept such as a 1-pyrrolidinyl group. Specific examples include agbatidine, pyrrolidine, piperidine, and piperidin. , morpholine, homopiperidine, tetrahydrofuran, tetrahydropyranyl and the like. The "saturated heterocyclic ring of 3 to 8 members" is preferably a saturated heterocyclic group of 5 to 6 members of a single ring ("5 to 6 membered monocyclic saturated heterocyclic ring").

Specific examples of the "single-ring saturated heterocyclic ring of 5 to 6 members" include pyrropyridine, piperidine, and piperidin of 5 to 6 members of a single ring in a specific example of "saturated heterocyclic ring of 3 to 8 members". , morpholine, tetrahydrofuran, tetrahydropyran, and the like.

The "C _6-10 monocyclic or polycyclic aryl group" means an aromatic hydrocarbon having 6 to 10 carbon atoms. Specific examples thereof include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. Phenyl is preferred.

In the group, a C _4-6 cycloalkyl group or a heterocyclic group of 5 to 6 members having 1 to 3 atoms of the same or different kinds selected from a nitrogen atom, an oxygen atom or a sulfur atom may also be condensed. Further, the bond to the bond of the group is a carbon atom constituting a ring in the "C _6-10 monocyclic or polycyclic aryl group". As a specific example, the base etc. shown below are mentioned, for example.

The "monocyclic or polycyclic heteroaryl group of 5 to 10 members" means a monocyclic ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. An aromatic heterocyclic group of 5 to 6 membered rings or an aromatic heterocyclic group of 8 to 10 members of 2 rings. Specific examples include pyridyl groups and hydrazines. Base, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, Azolyl, different Azolyl, pyridyl Base, three Base, triazolyl, imidazolidinyl, Diazolyl, triazolyl, tetrazolyl, fluorenyl, oxazolyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzo Azolyl, benzothiazolyl, benzopyrene Azolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, or 6,11-dihydrodibenzo[b,e]thiazepine Base. As a preferred "monocyclic or polycyclic heteroaryl group of 5 to 10 members", a monocyclic heteroaryl group of 5 to 6 members can be cited.

Specific examples of the monocyclic heteroaryl group of 5 to 6 members include, for example, a single ring in a specific example of "a monocyclic or polycyclic heteroaryl group of 5 to 10 members".

More preferably, it is a monocyclic aromatic heterocyclic ring having a 5- to 6-membered ring having one or more nitrogen atoms in the ring. Specific examples thereof include a pyridyl group and a pyrimidinyl group, and more preferably a pyridyl group.

Some or all of the atoms of the compounds of the present invention may also be substituted with isotopic elements (for example, D, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ³⁵ S, ¹⁸ F, ¹²⁵ I, etc. These compounds are also included in the compounds of the invention.

Further preferred embodiments of the invention are described.

Hereinafter, preferred R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , X, Y and Ar among the compounds represented by the formula (1) are disclosed. The technical scope of the invention is not limited to these and the like.

The pyrazole moiety of the compound represented by the formula (1) may be a tautomer such as the following formulas (1a) and (1b), and all tautomers are contained in the compound of the present invention.

As "X", a nitrogen atom or CR ^{5 is} preferable. More preferably, a nitrogen atom is mentioned.

The "Y" is preferably a hydrogen atom or a C _1-6 alkyl group (the group may be substituted by 1 to 3 fluorine atoms). More preferably, a hydrogen atom is mentioned.

As "R ^1a ", "R ^1b ", "R ^1c ", "R ^1d " or "R ^1e ", it is preferably the same or different and is a hydrogen atom, a halogen atom or a C _1-6 alkyl group. The group may also be substituted by the same or different 1 to 3 groups selected from a fluorine atom and a C _1-6 alkoxy group) or a C _1-6 alkoxy group (the group may also be substituted by 1 to 3 fluorine atoms) ). More preferably, the same or different ones are a hydrogen atom, a halogen atom or a C _1-6 alkyl group (the group may be substituted by 1 to 3 fluorine atoms). More preferably, it is the same or different and is a hydrogen atom or a halogen atom.

The "R ² " and "R ³ " are preferably the same or different and are a hydrogen atom, a halogen atom or a C _1-6 alkyl group (the group may be substituted by 1 to 3 fluorine atoms).

As "R ⁴ ", a hydrogen atom, a C _1-6 alkyl group (which may be substituted by 1 to 3 fluorine atoms) or a C _3-10 cycloalkyl group (which may be substituted by 1 to 4 fluorine atoms) is preferable. ). More preferably, it is a C _1-6 alkyl group (which may be substituted by 1 to 3 fluorine atoms) and a C _3-6 cycloalkyl group (which may be substituted by 1 to 4 fluorine atoms). Further, a C _1-3 alkyl group (which may be substituted by 1 to 3 fluorine atoms) and a cyclopropyl group are more preferable.

The "R ⁵ " is preferably a hydrogen atom, a halogen atom or a C _1-6 alkyl group (the group may be substituted by 1 to 3 fluorine atoms or a C _1-6 alkoxy group). More preferably, it is a hydrogen atom or a C _1-6 alkyl group (this group may be substituted by 1 to 3 fluorine atoms). More preferably, a hydrogen atom is mentioned.

As "Ar", a phenyl group or a pyridyl group is preferable. More preferably, it is a phenyl group.

Examples of the "pharmacologically acceptable salt" include an acid addition salt and a base addition salt. For example, examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, or citrate, oxalate, acetate, and An acid salt such as a salt, a propionate, a benzoate, a trifluoroacetate, a methanesulfonate, a besylate, a p-toluenesulfonate or a camphorsulfonate; and a base addition salt, An inorganic base salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt or an ammonium salt, or an organic alkali salt such as a triethylammonium salt, a triethanolammonium salt, a pyridinium salt or a diisopropylammonium salt, etc. Amino acid salts such as arginine, aspartic acid, glutamic acid and the like, such as basic or acidic amino acids.

When the compound of the present invention is obtained in the form of a salt, when the compound of the present invention is obtained in the form of a salt, it can be directly purified, and when the compound of the present invention is obtained in a free form, it is dissolved or The salt may be suspended in a suitable organic solvent and added with an acid or a base to form a salt by a usual method.

The compound of the present invention is sometimes also present in the form of an adduct (hydrate, solvate) with water or various solvents, and such adducts are also included in the present invention. Furthermore, the invention also encompasses all tautomers of the compounds of the invention and all crystalline forms.

The compound of the present invention also includes a prodrug of the compound represented by the formula (1) or a pharmacologically acceptable salt thereof. Further, solvates such as these hydrates and ethanol solvates are also included.

The term "pre-drug-removing of the compound represented by the formula (1)" in the present specification means conversion to a compound represented by the formula (1) by a reaction using an enzyme or gastric acid under physiological conditions in vivo. A compound, for example, a compound which is converted into a compound represented by the formula (1) by enzymatic oxidation, reduction, hydrolysis or the like.

The compounds of the invention also contain compounds having one or a plurality of asymmetric carbon atoms in the molecule. Accordingly, the compounds of the invention also include optical isomers, racemates, non-image isomers, and the like. Further, the compounds of the present invention also include cis-trans isomers, isomers based on axial chirality, and the like. As indicated above, the compounds of the invention also comprise all of the isomers present and mixtures thereof.

The kinase which exhibits an inhibitory activity as a compound of the present invention includes various tyrosine kinases, various serine kinases, and various sulphonic acid kinases. Preferred examples thereof include CDK1, CDK2, CDK5, AURKA, AURKB, and JAK2.

Hereinafter, the compound represented by the formula (1) or a method for producing the pharmacologically acceptable salt thereof will be exemplified, but is not limited thereto.

The compound of the present invention can be produced by appropriately combining, for example, the following production methods, methods according thereto, or synthetic methods known to those skilled in the art from known compounds.

Production method:

The compound represented by the formula (1) can be synthesized, for example, by the following method.

[Chemistry 9]

[wherein, LG and LG' are the same or different from each other, and mean a leaving group, and examples thereof include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, and a phenoxy group. , trifluorophenoxy, tetrafluorophenoxy, pentafluorophenoxy, nitrophenoxy, etc.; other definitions are the same as those described in item 1 above]

Method 1 for the compound represented by formula (A-3) step 1: Step 1-1:

The compound of the formula (A-3) can be synthesized by reacting a compound of the formula (A-2) wherein X is a nitrogen atom with a compound of the formula (A-1) in the presence of a base. The base is not particularly limited, and examples thereof include triethylamine, diisopropylethylamine, tributylamine, and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). , 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, dimethylaminopyridine, methylpyridine, N-methylmorpholine (NMM), etc. An alkali; or an inorganic base such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

The solvent may be any solvent which does not react under the reaction conditions of this step. Specific examples thereof include alcohol solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), and third butanol; for example, diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, and benzene. Methyl ether, 1,4-two An ether solvent such as an alkane; an aromatic hydrocarbon solvent such as benzene, toluene, chlorobenzene or xylene; an ester solvent such as ethyl acetate or methyl acetate; N,N-dimethylformamide, N,N-di An aprotic solvent such as methyl acetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or dimethyl hydrazine or water; or a mixture thereof.

The reaction temperature is carried out under reflux from heating at -80 ° C, usually from 25 ° C to 90 ° C. The reaction time is usually from 30 minutes to 12 hours.

Step 1-2:

The compound of the formula (A-3) can be synthesized by using Ulmann-type conditions in the presence of a metal catalyst (for example, in DMF (N, N-Dimethyl Formamide, N, N-dimethylmethyl). In aprotic solvents such as guanamine), a metal catalyst such as copper (II) acetate is used for heating and refluxing, or Buchwald type conditions (for example, in the presence of a carbonate such as cesium carbonate, BINAP (2, 2') is used. -bis(diphenylphosphino)-1,1'-binaphthyl,2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), palladium such as Pd ₂ (dba) ₃ or Pd(OAc) ₂ Catalyst, such as dppf (1,1'-Bis(diphenylphosphino)ferrocene, 1,1'-bis(diphenylphosphino)ferrocene), Xantphos (4,5-bisdiphenylphosphine-9,9 a compound of the formula (A-2) wherein X is a carbon atom and a compound of the formula (A-1), such as a ligand such as -dimethyl oxazepine or the like, which is heated under reflux in an inert solvent such as toluene or the like. The compound is reacted.

The solvent may be any solvent which does not react under the reaction conditions of this step. Specifically, for example, tetrahydrofuran or 1,4-di An ether solvent such as an alkane.

The reaction temperature is carried out under reflux from heating at -80 ° C, usually at 25 ° C to 150 ° C. The reaction time is usually from 30 minutes to 12 hours.

Method for producing a compound represented by formula (A-3) 2 Step 2 (Preparation of the compound represented by the formula (A-5)):

The compound of the formula (A-5) can be synthesized by reacting a compound of the formula (A-4) wherein X is a nitrogen atom with a compound of the formula (A-1) in the presence of a base. The base is not particularly limited, and examples thereof include triethylamine, diisopropylethylamine, tributylamine, and 1,5-di. Azabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), pyridine, dimethylaminopyridine, An organic base such as methylpyridine or N-methylmorpholine (NMM); or an inorganic base such as sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

The solvent may be any solvent which does not react under the reaction conditions of this step. Specific examples thereof include an alcohol solvent such as methanol, ethanol, 2-propanol or tert-butanol; for example, diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1, 4-two An ether solvent such as an alkane; an aromatic hydrocarbon solvent such as benzene, toluene, chlorobenzene or xylene; an ester solvent such as ethyl acetate or methyl acetate; N,N-dimethylformamide, N,N-di An aprotic solvent such as methyl acetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or dimethyl hydrazine or water; or a mixture thereof.

The reaction temperature is carried out under reflux from heating at -80 ° C, usually from 25 ° C to 90 ° C. The reaction time is usually from 30 minutes to 12 hours.

Step 3 (Preparation of the compound represented by the formula (A-3)):

The compound of the formula (A-3) can be synthesized by reacting a compound of the formula (A-5) wherein X is a nitrogen atom with a cyanide ion in the presence of a base.

The base is not particularly limited, and examples thereof include triethylamine, diisopropylethylamine, tributylamine, and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). , 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, dimethylamine Organic bases such as pyridine, methylpyridine and N-methylmorpholine (NMM).

The solvent may be any solvent which does not react under the reaction conditions of this step. Specific examples thereof include an alcohol solvent such as methanol, ethanol, 2-propanol or tert-butanol; for example, diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1, 4-two An ether solvent such as an alkane; an aromatic hydrocarbon solvent such as benzene, toluene, chlorobenzene or xylene; an ester solvent such as ethyl acetate or methyl acetate; N,N-dimethylformamide, N,N-di An aprotic solvent such as methyl acetamide, N-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone or dimethyl hydrazine or water; or a mixture thereof.

The reaction temperature is usually from 25 ° C to 150 ° C. The reaction time is usually from 30 minutes to 12 hours.

Method for preparing a compound represented by formula (A-6) Step 4:

The compound of the formula (A-6) can be synthesized by reacting a compound of the formula (A-3) wherein X is a carbon atom or a nitrogen atom with an organic metal species such as a substituted aryl group reagent in an inert solvent.

The inert solvent may be any solvent which does not react under the reaction conditions of this step. Specific examples thereof include an ether solvent such as tetrahydrofuran or diethyl ether.

The reaction temperature is carried out under reflux from heating at -80 ° C, usually from -10 ° C to 25 ° C. The reaction time is usually from 30 minutes to 24 hours.

Method for preparing compound represented by formula (1) Step 5: Step 5-1:

The compound represented by the formula (1) can be synthesized by reacting a compound of the formula (A-6) wherein X is a carbon atom or a nitrogen atom with a reducing agent, an alkyl group reagent, an alkylating agent or the like.

Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, and diisobutylaluminum hydride. Examples of the alkyl group-containing sub-reagent include methyl magnesium bromide and isopropyl magnesium bromide. Examples of the alkylating agent include trifluoromethyltrimethylnonane and the like.

The solvent may be any solvent which does not react under the reaction conditions of this step. Specifically, for example, when a reducing agent is used, an alcohol-based solvent such as methanol or ethanol may be used, and when an alkyl group-containing reagent is used, an ether solvent such as tetrahydrofuran or diethyl ether may be used, and when an alkylating agent is used, Examples of the aprotic solvent include dimethylacetamide or N-methyl-2-pyrrolidone.

With respect to the reaction temperature, it is usually from -10 ° C to 50 ° C from -80 ° C under heating under reflux. The reaction time is usually from 10 minutes to 48 hours.

Step 5-2:

The synthesis can be carried out by reacting a compound of the formula (A-6) wherein X is a carbon atom or a nitrogen atom with hydrogen in the presence of a catalyst, in the absence or absence of a ligand, in the presence or absence of a base. (1) The compound represented.

As the catalyst, and the like salts of transition metals include palladium or nickel, ruthenium chloride or palladium acetate, ruthenium acetate, BINAP complexes like ^{complexes, (R) -RUCY TM -Xylbinap,} (S) -RUCY Negative catalysts such as ^TM- Xylbinap.

As a ligand, in addition to a phosphorus ligand such as diphenylphosphine ethane, BIAP (N, N-bis(2-ethyl-5-methyl-imidazol-4-ylmethyl)aminopropane, N, N can also be used. a chiral ligand such as bis(2-ethyl-5-methyl-imidazol-4-ylmethyl)aminopropane).

Examples of the base include potassium third potassium methoxide, sodium third potassium hydride, sodium ethoxide, sodium methoxide, and the like.

As a hydrogen source, in addition to hydrogen, ammonium formate or the like can also be mentioned.

The solvent may be any solvent which does not react under the reaction conditions of this step. Specific examples thereof include an alcohol solvent such as isopropyl alcohol, methanol or ethanol; and an ether solvent such as tetrahydrofuran or diethyl ether.

With respect to the reaction temperature, it is usually from -10 ° C to 50 ° C from -80 ° C under heating under reflux. The reaction time is usually from 10 minutes to 48 hours.

In the respective reactions of the above-described production methods, even if the use of a protecting group is not specifically indicated, any function other than the reaction point changes depending on the illustrated reaction conditions, or is not suitable for the implementation. In the case of the method, the target compound can also be obtained by protecting the reaction site as needed, and after performing the reaction or after performing a series of reactions.

As the protecting group, a literature (for example, in Protective Groups in Organic Synthesis, 3rd ed., T. W. Greene, John Wiley & Sons Inc. (1999), etc.) can be used. The protective group which is a normal group, more specifically, the protecting group of the amine group may, for example, be a benzyloxycarbonyl group, a third butoxycarbonyl group, an ethyl fluorenyl group or a benzyl group, and further, as a protecting group for a hydroxyl group, For example, a trialkylalkylene group such as a trimethylsulfanyl group or a tert-butyldimethylsilyl group, an ethenyl group or a benzyl group can be mentioned.

The introduction and detachment of the protective group can be carried out by a method commonly used in organic synthetic chemistry (for example, referring to the above-mentioned Protective Groups in Organic Synthesis) or a method according to the same.

In the present specification, a protecting group, a condensing agent, and the like are sometimes referred to as abbreviations prescribed by IUPAC-IUB (International Union of Pure and Applied Chemistry - International Union of Biochemistry).

Preferred salts of the starting compound and the target compound and non-toxic salts which are conventionally used as pharmaceutically acceptable salts, and examples thereof include organic acid salts (for example, acetate, trifluoroacetate, maleate). , fumarate, citrate, tartrate, methanesulfonate, besylate, formate, tosylate, etc.) and inorganic acid salts (eg hydrochloride, hydrobromide, Acid addition salts such as hydroiodide, sulfate, nitrate, phosphate, etc., salts with amino acids (eg, arginine, aspartic acid, glutamic acid, etc.), alkali metal salts ( For example, sodium salts, potassium salts, etc., alkali metal salts (such as calcium salts, magnesium salts, etc.) and other metal salts, ammonium salts, organic base salts (such as trimethylamine salt, triethylamine salt, pyridinium salt, methyl group) Pyridinium salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.).

The intermediate or final product in the above production method can also be subjected to various conversions by appropriately converting its functional groups (for example, protecting, deprotecting, functionally, based on an amine group, a hydroxyl group, a carbonyl group, a halogen group, etc.) Instead, it is directed to another compound encompassed by the invention. The conversion of the functional group can be carried out by a usual method generally carried out (for example, referring to Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999), etc.).

The intermediate and the target compound in each of the above production methods may be subjected to isolation purification according to a purification method commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, and the like. Further, the intermediate may be subjected to a subsequent reaction without special purification.

In the compound (1) of the present invention, there may be an optical isomer based on an optically active center, a rotary enantiomer based on an axial or surface chirality due to intermolecular rotation, and other stereoisomers. The inclusion of all possible isomers and mixtures thereof, including such materials, tautomers, and geometric isomers, are included within the scope of the invention.

In particular, the optical isomer or the polar enantiomer can be obtained in the form of a racemate or, alternatively, an optically active starting material or intermediate can be used in the form of an optically active body. Further, at a suitable stage of the above-described production method, the corresponding raw material, intermediate or final material may be a physical or chemical racemic body by a known separation method such as an optically active column method or a fractional crystallization method. It is resolved analytically to its optical mirror image isomer. For example, a racemic body can be reacted with an optically active resolving agent to synthesize two kinds of non-image areomers, and the physical properties are different, and the analysis is carried out by a method such as fractional crystallization (non-image isomer method).

When a pharmaceutically acceptable salt of the compound of the present invention is to be obtained, when the compound represented by the formula (1) is obtained as a pharmacologically acceptable salt, the purification may be carried out as it is, and When the compound represented by the formula (1) is obtained in a free form, it may be formed by dissolving or suspending it in a suitable organic solvent, and adding an acid or a base to form a salt by a usual method.

The raw materials and intermediates in the various production methods described above are not specifically described as being produced by a commercially available compound, or may be a commercially available compound by a method known to a practitioner or a method according to the method. synthesis.

The compound of the present invention is provided, for example, in the form of an anticancer agent, and the type of cancer to which it is applied is not limited. Specific examples thereof include breast cancer, ovarian cancer, head and neck cancer, lung cancer, and large intestine. Cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer, pancreatic cancer, stomach cancer, osteosarcoma, myeloma, or blood cancer. Examples of preferred cancer types include breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, or endometrial cancer, and more preferred cancer types are listed. Breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, or prostate cancer.

As another preferred aspect when the compound of the present invention is used as an anticancer agent, examples of the cancer type to be used include blood cancer, myeloma, liver cancer, osteosarcoma, skin cancer, and midline carcinoma. , breast cancer, lung cancer, ovarian cancer, uterine cancer, colorectal cancer, prostate cancer or pharyngeal cancer. Examples of preferred cancer types include blood cancer, myeloma, liver cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, colon cancer, prostate cancer, and pharyngeal cancer. As a better cancer type, breast cancer, lung cancer, and ovary are mentioned. Cancer, uterine cancer, colon cancer, prostate cancer or pharyngeal cancer.

In the present invention, the term "blood cancer" includes the concept of lymphoma and leukemia.

In the present invention, the "anticancer agent" has an effect of reducing or eliminating a cancerous tumor or causing a cancerous tumor to no longer increase when administered for the purpose of preventing/treating cancer.

In the present invention, the term "prevention" refers to the act of administering the active ingredient of the present invention to a healthy person who is not afflicted, for example, for the purpose of preventing the onset of the disease. The term "treatment" refers to the act of administering the active ingredient of the present invention to a human (patient) diagnosed by a doctor as an onset, for example, to alleviate the disease or symptom, to prevent the cancer tumor from growing or returning to the state before the onset of the disease. The purpose of the act. Further, the purpose of administration is to prevent the deterioration of the disease or the symptoms or to prevent the increase of the cancerous tumor, and is also included in the therapeutic behavior.

When the compound of the present invention is used in the treatment, it can be administered as a pharmaceutical composition orally or parenterally (for example, intravenously, subcutaneously or intramuscularly, topically, rectally, transdermally or nasally). Examples of the composition for oral administration include a tablet, a capsule, a pill, a granule, a powder, a liquid, a suspending agent and the like. These preparations can be used in the past The techniques described are prepared to contain non-toxic and inactive carriers or excipients commonly used in the art of formulation.

In the case of administering the compound of the present invention, the amount used varies depending on the symptoms, age, administration method, etc., for example, in the case of oral administration, it is preferred to cast the symptoms once or several times per day for an adult. The lower limit is 0.01 mg (preferably 1 mg), and the upper limit is 5000 mg (preferably 500 mg). In the case of intravenous injection, the adult is administered once or several times a day according to the symptoms, and the lower limit is 0.01 mg (preferably 0.1 mg), and the upper limit is 1000 mg (preferably 30 mg). Expect results. Further, when oral or intravenous injection is performed depending on the symptoms of the patient, it is also preferable to perform intermittent administration.

The compound of the present invention can be used together with other agents for the purpose of enhancing the effect and/or reducing the side effects. Specifically, the compound of the present invention can be used together with a hormonal therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, a drug which inhibits the action of a cell proliferating factor or a receptor for a cell proliferating factor. Hereinafter, the agent which can be used together with the compound of the present invention is simply referred to as a concomitant agent.

Examples of the hormone therapeutic agent include: phosphoestrol, diethylstilbestrol, chloroethreethanol, medroxyprogesterone acetate, megestrol acetate, chlorgestrel acetate, cyproterone acetate, acetylene maleoxazole, Allylestrenol, gestrinone, mepafloxacin, raloxifene, omexixifen, dextromethafen, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.) ), oral contraceptive preparations, megestrol, testosterone, omepridine, LH-RH agonist (such as goserelin acetate, buserelin, leuprolide, etc.), droloxifene, ring Thiostrenol, ethinyl estradiol sulfonate, aromatase inhibitors (eg fadrozole hydrochloride, anastrozole, letrozole, exemestane, fluconazole, formestane, etc.), anti-androgen (eg Flunaramide, bicalutamide, nilutamide, etc., adrenocortical hormone agents (such as dexamethasone, prednisolone, betamethasone, prednisolone, etc.), and male synthesizing inhibitors ( For example, abiraterone, etc., retinoids and agents that delay the metabolism of retinoids (for example, liazodazole, etc.).

As the chemotherapeutic agent, for example, an alkylating agent, a metabolic antagonist, an anticancer antibiotic, a plant-derived anticancer agent, or the like can be used. Representative examples are described below.

Examples of the alkylating agent include nitrogen mustard, hydrochloric acid mustard-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, triamine, carbopol, toluene. Acid acesulfame, busulfan, nimustine hydrochloride, dibromomannitol, melphalan, carbazolamide, ramustine, estramustine sodium phosphate, tri-ethyl melamine, camo Statin, lomustine, streptozotocin, piperacin, itoglyzate, carboplatin, cisplatin, dibromospironium chloride, formoterol, prednisolone, cuminidine Futin, temozolomide, tromethamine, trosamine, net statin, adoline, cysteamine nitrosourea, dexamethasone and its DDS (4,4'-Diamino Diphenyl Sulphone, 4,4'-diaminodiphenyl hydrazine) preparation, and the like.

Examples of the metabolic antagonist include mercaptopurine, 6-mercaptopurine nucleoside, sulpho-inosine, methotrexate, enalapril, enoxabine, cytarabine, and cytarabine octadecyl Phosphate, cyclocytidine hydrochloride, 5-FU-based agents (eg, fluorouracil, tegafur, UFT (eufos), deoxyfluorouridine, carmofur, galoxibine, ethidium fluoride, cape Hebin, etc., Aminoguanidine, Nairabine, Hyperthyroid tetrahydrofolate, Thioguanine, Glycosyl thiocyanate, calcium leucovorin, calcium leucovorin, cladribine, ethidium fluoride, fluoride DDS preparations such as Rabin, gemcitabine, hydroxyurea, pentastatin, pyridoxine, iodine deoxyuridine, mitoxantrone, thiazolidine nucleoside, azurestatin, bendamustine and the like Wait.

Examples of the anticancer antibiotic include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, penicillin sulfate, and hydrochloric acid. Daunorubicin, doxorubicin hydrochloride, aclarithine hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neosuppressant, serotonin, saxmycin, carbendazim, mitre Tan, doxorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and the like DDS preparations.

Examples of the plant-derived anticancer agent include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, and yew. Alcohol, European paclitaxel, vinorelbine and the like DDS preparations, and the like.

Examples of the immunotherapeutic agent include: Bianji Youshu, Keshen Town, Xizuran, Lentinus edodes, Ubumex, Interferon, Interleukin, Macrophage Colony Stimulating Factor, Granulocyte Colony Stimulating Factor, Erythropoietin, lymphotoxin, BCG (Bacille Calmette-Guerin) vaccine, Corynebacterium parvum, levamisole, polysaccharide K, propiconazole, anti-CTLA4 antibody, PD-1 antibody, Toll-like Receptors (Toll Like receptors) agonists (eg TLR7 agonists, TLR8 agonists, TLR9 agonists, etc.).

The cell proliferating factor in the agent which inhibits the action of the cell proliferating factor and the cell proliferating factor may be any substance which promotes cell proliferation, and generally, a peptide having a molecular weight of 20,000 or less is used, and A factor that acts at a low concentration in combination with a receptor. Specific examples thereof include EGF (epidermal growth factor) or a substance having substantially the same activity (for example, TGFalpha or the like), insulin, or a substance having substantially the same activity as the substance (for example, insulin, IGF (insulin) -like growth factor, insulin-like proliferative factor-1, IGF-2, etc., FGF (fibroblast growth factor) or a substance having substantially the same activity (eg acidic FGF, basic FGF, KGK (keratinocyte growth factor), FGF-10, etc., and other cell proliferative factors (such as CSF (colony stimulating factor), EPO (erythropoietin, erythropoietin), IL-2 (interleukin) -2, interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGF-beta (transforming growth factor beta) , HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), regulatory proteins, EPO tube, etc.).

The administration period of the compound of the present invention and the concomitant drug is not limited, and it may be administered to the subject to be administered at the same time, or may be administered at intervals. Moreover, the invention can also be made into a combination a mixture of the substance and the combined agent. The dosage of the pharmaceutical agent can be appropriately selected based on the dose used clinically. Further, the ratio of the compound of the present invention to the concomitant agent can be appropriately selected depending on the administration target, the administration route, the target disease, the symptom, the combination, and the like. For example, when the administration target is a human, it is sufficient to use 0.01 to 100 parts by weight of the compound for use with 1 part by weight of the compound of the present invention. Further, in order to suppress the side effects, it may be used in combination with an agent such as an antiemetic agent, a hypnotic agent or an anticonvulsant (which is also included in the concomitant drug).

The compound of the present invention, as shown in the test examples and the like in the present specification, has a high inhibitory effect on a kinase selected from the group consisting of CDK1, CDK2, AURKA, AURKB, JAK2, CDK5 and the like, and can be applied to various symptoms associated with kinases, for example, Prevention and treatment of cancer and the like. In particular, a preferred one of the compounds of the present invention exhibits an inhibitory effect on the expression of a stem cell gene by blocking CDK5 (for stem cell genes, which will be described later). By using a substance which inhibits CDK5 other than the compound of the present invention (for example, siRNA which can directly block CDK5 of CDK5, etc.), the inhibition of the expression of the stem cell gene of the CDK5 inhibitor can be confirmed. Furthermore, by confirming the expression of stem cell genes in cells that have abolished or inhibited the expression of CDK5 (CDK5 weakened, CDK5 dominant negative, etc.), it is also confirmed that CDK5 inhibits the correlation with the inhibition of stem cell gene expression. .

The so-called stem cell gene line can induce genes that self-replicate and/or differentiate into different cells. Examples of the stem cell gene include Nanog, Sox2, β-chain protein, and Oct4. The preferred one of the compounds of the present invention has an inhibitory effect on the expression of a stem cell gene (Test Example 11). Further, the preferred one of the compounds of the present invention exhibits a spheroid formation inhibitory action, and thus the proliferation inhibitory action of cancer stem cells can be expected.

By these effects, the preferred one of the compounds of the present invention can also be expected to be useful as an anticancer agent having a relapse prevention effect against cancer.

Further, a preferred one of the compounds of the present invention is also useful as a therapeutic agent for cancers which are therapeutically resistant to chemotherapeutic agents. As the chemotherapeutic agent herein, preferably, for example, A taxane-based anticancer agent. The taxane-based anticancer agent in the present specification may, for example, be an anticancer agent having a taxane skeleton, and examples thereof include paclitaxel and paclitaxel.

In recent years, the relationship between G protein (G protein-coupled receptor) and tumor formation has gradually become clear.

(Refer to G protein-coupled receptors: novel targets for drug discovery in cancer. Lappano R, Maggiolini M. Nat Rev Drug Discov. 2011 Jan; 10(1): 47-60, Differential effect of adenosine receptors on growth of human colon cancer HCT 116 and HT-29cell lines. Sakowicz-Burkiewicz M, Kitowska A, Grden M, Maciejewska I, Szutowicz A, Pawelczyk T. Arch Biochem Biophys. 2013 May; 533 (1 2): 47-54, The adenosinergic system in cancer: Key therapeutic target. Sorrentino R, Pinto A, Morello S. Oncoimmunology. 2013 Jan 1; 2(1): e22448).

It is considered that the compound of the present invention is a compound which is less potent and less antagonistic to GPCR, and has little effect on GPCR and on tumor formation via GPCR.

[Examples]

Hereinafter, the present invention will be specifically described by way of Reference Examples, Examples and Test Examples, but the present invention is of course not limited thereto. Further, the following reference examples and the names of the compounds shown in the examples are not necessarily in accordance with the IUPAC nomenclature.

In this specification, the following abbreviations are used.

THF: tetrahydrofuran

TFA: trifluoroacetic acid

NaBH(OAc) ₃ : sodium triethoxy borohydride

DMAP: N,N-dimethyl-4-aminopyridine

(Boc) ₂ O: di-tert-butyl dicarbonate

DMF: N,N-dimethylformamide

DIEA: N-ethyldiisopropylamine

WSCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

WSCI. HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBt: 1-hydroxybenzotriazole

HOBt. H ₂ O: 1-hydroxybenzotriazole monohydrate

Me: methyl

Et: ethyl

DMA: N,N-dimethylacetamide

NMP: 1-methyl-2-pyrrolidone

Boc: third butoxycarbonyl

Cbz or Z: benzyloxycarbonyl

(R)-RUCY ^TM -XylBINAP:RuCl[(R)-daipena][(R)-xylbinap], CAS number:1384974-38-2

(S)-RUCY ^TM -XylBINAP:RuCl[(S)-daipena][(S)-xylbinap], CAS No.: 1312713-39-5

N: equivalent (for example, 2N HCl means 2 equivalents of hydrochloric acid)

M: molar concentration (mol/L) (for example, 2M methylamine means 2 mol/L methylamine solution)

t _R : hold time

Obs MS[M+1]: observed molecular mass

Purification by reverse phase HPLC (High Performance Liquid Chromatography) was carried out as follows.

Purification was performed using a Gilson HPLC system. The column was a YMC CombiPrep ODS-A column (5 μm, 50 × 20 mm ID), and the solvent system was a mixed solvent system of CH ₃ CN (containing 0.035% TFA) and water (containing 0.05% TFA). UV (ultraviolet) detection was carried out at various wavelengths of 210 nm, 220 nm, and 254 nm.

The conditions for elution are as follows.

Preparation device: Gilson HPLC system

Column: YMC CombiPrep ODS-A 5μm, 50×20mm I.D.

Solvent: CH ₃ CN (containing 0.035% TFA), water (containing 0.05% TFA)

Flow rate: 35mL/min

Gradient: Linear gradient from 1:99 (v/v) CH ₃ CN/water to 95:5 (v/v) CH ₃ CN/water at 35 mL/min over 13 minutes

The powder X-ray diffraction measurement was carried out under the following conditions.

‧Device: X'pert-MPD (manufactured by Spectris)

‧X-ray: Cu Kα ₁ /45kV/40mA

‧Injection slit: 15mm (automatic) / anti-diffusion slit: 15mm (automatic)

‧ Sample plate: anti-reflective Si plate

‧Step size: 0.017°

‧Scanning range: 4~40° (2θ)

‧Accumulated time: 100 seconds / step

In addition, the diffraction peak at the diffraction angle 2θ (°) described in the present specification may cause a slight measurement error due to measurement equipment, measurement conditions, and the like. Specifically, the measurement error may be in the range of ±0.2, preferably ±0.1.

The differential scanning calorimetry (DSC) measurement was carried out under the following conditions.

‧Device: DSCQ1000 (manufactured by TA Instruments)

‧Measurement temperature range: 10~250°C

‧ Heating rate: 10 ° C / min

‧Container: Aluminum gas pan (Pin hole)

‧ Ambient gas flow: dry nitrogen, about 50mL / min

Thermogravimetric measurement (TGA) was carried out under the following conditions.

‧Device: TGAQ500 (manufactured by TA Instruments)

‧Measurement temperature range: room temperature ~250 °C

‧ Heating rate: 10 ° C / min

‧Container: Platinum pot

‧ Ambient gas flow: dry nitrogen, sample flow rate of about 60mL / min, equilibrium flow rate of about 40mL / min

The X-ray diffraction measurement was carried out under the following conditions.

‧X-ray diffraction device: R-AXIS RAPID-R Rigaku

(Control software: RAPID AUTO Ver.3.11 Rigaku,

Analysis software: Crystal Structure Ver.4.01 Rigaku, Mercury Ver.3.1 Development (Build RC5) CCDC)

‧Measurement conditions (X-ray: CuKα ray, output: 50kV-100mA, temperature: 93±1K)

The LC/MS (liquid chromatography/mass spectrometry) analysis conditions for compound identification are as follows.

LC/MS assay:

Testing equipment: ACQUITY (registered trademark) SQ deteceter (Waters)

HPLC: ACQUITY UPLC (registered trademark) system

Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm)

Solvent: Liquid A: 0.06% formic acid / H ₂ O, B solution: 0.06% formic acid / MeCN

Gradient conditions: linear gradient from B 2% to 96% in 0.0~1.3min

Flow rate: 0.8mL/min

UV: 220nm and 254nm

Reference Example 1: 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine

[化10]

Add 2,4-dichloropyrimidine (25.0 g) and N-ethyl-diisopropylamine (30.6 mL) to a solution of 5-methyl-pyrazol-3-amine (18.0 g) in ethanol (500 mL) Stir at 70 ° C for 9 hours. After standing to cool to room temperature, the precipitated solid was filtered, washed with ethanol and hexane, and dried under reduced pressure to give the title compound (14.9 g).

^{1 H-NMR (300MHz, DMSO} -d 6) δ 12.1 (s, 1H), 10.3 (s, 1H), 8.14 (d, 1H), 5.76 (br-s, 1H), 2.21 (s, 3H).

Reference Example 2: 6-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidine-2-carbonitrile

To a solution of the compound (4.8 g) obtained in Reference Example 1 in DMSO (Dimethylsulfoxide, dimethylhydrazine) (100 mL), sodium cyanide (2.24 g) and 1,4-diazabicyclo[2.2.2. ] octane (1.28 g) was stirred at 120 ° C for 3 hours. After cooling to room temperature, water was added to the reaction liquid, and the insoluble matter was removed by filtration. Ethyl acetate was added to the obtained filtrate, and the target was extracted into an organic layer, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced vacuoielielielieliel

^{1 H-NMR (300MHz, DMSO} -d 6) δ 12.20 (s, 1H), 10.48 (s, 1H), 8.35 (s, 1H), 2.22 (s, 3H).

Reference Example 3: (3-methoxyphenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanone

To a solution of the compound (3.40 g) obtained in EtOAc (EtOAc m. After adding 2N hydrochloric acid (70 mL) to the reaction liquid and stirring at room temperature for 18 hours, 6 N aqueous sodium hydroxide solution (12 mL) was added, and THF was distilled off under reduced pressure. The precipitated solid was collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure to give the title compound (4.5 g).

¹ H-NMR (300MHz, DMSO-d ₆ ) δ 12.07 (s, 1H), 10.19 (s, 1H), 8.40 (d, 1H), 7.48-7.39 (m, 3H), 7.29-7.25 (m, 1H) ), 3.80 (s, 3H), 2.16 (s, 3H).

Reference Example 4: (3,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanone

To a solution of the compound obtained in Reference Example 2 (100 mg) in THF (10 mL), EtOAc (3 mL) The mixture was stirred under cooling for 45 minutes. After adding 2 equivalents of hydrochloric acid (1 mL), the mixture was warmed to room temperature and stirred for 45 minutes. After adding 6 equivalents of aqueous sodium hydroxide solution (0.5 mL) and water to the reaction liquid, ethyl acetate was further added, and the target substance was extracted to the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the organic layer under reduced pressure was added hexane/ethyl acetate (1/1, 3 mL), and washed with an ultrasonic cleaner, and the precipitated solid was collected by filtration. (1/1) Washing (1 mL × 4) gave the title compound (91 mg).

^{1 H-NMR (400MHz, DMSO} -d 6) δ 12.10 (s, 1H), 10.24 (s, 1H), 8.43 (s, 1H), 8.07-8.01 (m, 1H), 7.93 (d, 1H), 7.84-7.82 (m, 1H), 2.18 (s, 3H).

Reference Example 5: (3,5-Dimethoxyphenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanone

To a solution of the compound (4.0 g) obtained in EtOAc (EtOAc) (EtOAc) After adding 2 equivalents of hydrochloric acid (80 mL), it was stirred at room temperature for 13 hours. After adding 6 equivalents of aqueous sodium hydroxide solution (15 mL) and water to the reaction liquid, ethyl acetate was further added, and the target substance was extracted to the organic layer. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Hexane/ethyl acetate (1/1, 40 mL) was added to the residue obtained by concentrating the organic layer under reduced pressure, and the mixture was washed with an ultrasonic cleaner, and the precipitated solid was collected by filtration. /ethyl acetate (1/1) was washed (10 mL × 2) to give the title compound (4.73 g).

^{1 H-NMR (300MHz, DMSO} -d 6) δ 12.08 (s, 1H), 10.19 (s, 1H), 8.39 (d, 1H), 7.00 (s, 2H), 6.83 (s, 1H), 3.77 ( s, 6H), 2.16 (s, 3H).

Reference Example 6: 5-Amino-3-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester

Boc ₂ O (15.26 g) was added to a solution of 3-methyl-1H-pyrazol-5-amine (6.79 g) in chloroform (200 mL). After stirring for 7 hours, the solvent was distilled off under reduced pressure, and hexane (50 mL) was added to the residue and stirred. The precipitated solid was filtered to give the title compound (12.3 g).

^{1 H-NMR (300MHz, DMSO} -d 6) δ 6.24 (br-s, 2H), 5.13 (s, 1H), 1.99 (s, 3H), 1.53 (s, 9H).

Reference Example 7: 3-(6-Cyanopyridin-2-ylamino)-5-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester

The compound obtained in Reference Example 6 (3.94 g), 2-chloro-6-cyanopyridine (2.76 g), Pd(OAc) ₂ (448 mg), Xantphos (1.15 g), cesium carbonate (16.25 g) and two The alkane (100 mL) was combined and heated to reflux for 3 hours. After standing to cool to room temperature and filtering through celite, the filtrate was concentrated under reduced pressure. The residue was purified by EtOAcjjjjjjjjjj

^{1 H-NMR (300MHz, DMSO} -d 6) δ 10.4 (s, 1H), 7.82 (dd, 1H), 7.45 (d, 1H), 7.42 (d, 1H), 6.57 (s, 1H), 2.47 ( s, 3H), 1.56 (s, 9H).

Reference Example 8: 3-((6-(3,4-difluorobenzylidinyl)pyridin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester

To a solution of the compound (1.8 g) obtained in EtOAc (EtOAc m. After stirring at room temperature for 2 hours, a 10% aqueous potassium hydrogensulfate solution (30 mL) was added. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added to make it neutral, and ethyl acetate was added to the reaction mixture, and the target was extracted into an organic layer, and the organic layer was washed with saturated brine. Drying was carried out using anhydrous sodium sulfate. The residue obtained by concentrating the organic layer (yield: hexane)

¹ H-NMR (300MHz, DMSO-d ₆ ) δ 10.2 (s, 1H), 8.09 (m, 1H), 7.89-7.82 (m, 2H), 7.69-7.60 (m, 1H), 7.48-7.41 (m) , 2H), 6.32 (s, 1H), 2.33 (s, 3H), 1.55 (s, 9H).

Reference Example 9: (3,4-difluorophenyl)(6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methanone

[化18]

Methylene chloride (0.5 mL) and trifluoroacetic acid (0.2 mL) were added to the obtained compound (19 mg), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced vacuo.

^{1 H-NMR (300MHz, DMSO} -d 6) δ 9.47 (s, 1H), 8.13 (m, 1H), 7.89 (m, 1H), 7.76 (m, 1H), 7.63 (m, 1H), 7.42- 7.33 (m, 2H), 5.94 (s, 1H), 2.11 (s, 3H).

Reference Example 10: (4-ethoxyphenyl)(6-((5-methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)methanone

To a solution of the compound (250 mg) in THF (8 mL), EtOAc (EtOAc) Stir for 10 minutes and stir at room temperature for 18.5 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was stirred at room temperature for 3 hours. 2 equivalents of hydrochloric acid (4 mL) were added to the reaction solution. It was stirred at room temperature for 2 hours, after which a saturated aqueous sodium hydrogencarbonate solution was added. Ethyl acetate was added to the reaction mixture, and the target was extracted into an organic layer. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Methylene chloride (4 mL) and trifluoroacetic acid (2 mL) were added to the residue obtained by concentrating the organic layer under reduced pressure, and the mixture was stirred at room temperature for 2 hr. To the obtained residue, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added, and the title compound was extracted to the organic layer, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and hexane/ethyl acetate (1/1, 6 mL) was added to the obtained residue, and washed with an ultrasonic washing machine, and the precipitated solid was collected by filtration, and then hexane/acetic acid was used. The ethyl ester (3/1) was washed (2 mL × 2) to give the title compound (187 mg).

_{LC / MS, t R 0.77min,} obs MS [M + 1] 323.2.

Reference Example 11: (6-((5-Methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)(3,4,5-trifluorophenyl)methanone

To a solution of the compound obtained in Reference Example 7 (250 mg) in THF (15 mL), THF (15 mL) The mixture was stirred under ice cooling for 10 minutes and at room temperature for 18.5 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid (4 mL) was added to the reaction liquid, and the mixture was stirred at room temperature for 2 hours, and a saturated aqueous sodium hydrogencarbonate solution was added. Ethyl acetate was added to the reaction mixture, and the target was extracted into an organic layer. After washing the machine layer, it was dried using anhydrous sodium sulfate. Methylene chloride (4 mL) and trifluoroacetic acid (2 mL) were added to the residue obtained by concentrating the organic layer under reduced pressure, and the mixture was stirred at room temperature for 3 hours. The organic layer was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to the residue, and the title compound was extracted to the organic layer, washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the organic layer (yield: hexanes)

_{LC / MS, t R 0.87min,} obs MS [M + 1] 333.1.

Reference Example 12: (4-Chloro-3-fluorophenyl)(6-((5-methyl-1H-pyrazole)amino)pyridin-2-yl)methanone

A solution of 3-fluoro-4-chlorophenylmagnesium bromide in 0.5 M in THF (5 mL) was added to a solution of THF (8 mL). The mixture was stirred for 10 minutes under cooling and at room temperature for 18.5 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction mixture, the mixture was stirred at room temperature for 3 hours. 2N hydrochloric acid (4 mL) was added to the reaction liquid, and the mixture was stirred at room temperature for 2 hours, and a saturated aqueous sodium hydrogencarbonate solution was added. Ethyl acetate was added to the reaction mixture, and the target was extracted into an organic layer. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Methylene chloride (4 mL) and trifluoroacetic acid (2 mL) were added to the residue obtained by concentrating the organic layer under reduced pressure, and the mixture was stirred at room temperature for 3 hr. To the obtained residue, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added, and the title compound was extracted to the organic layer, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced vacuo.

_{LC / MS, t R 0.87min,} obs MS [M + 1] 331.1.

Reference Example 13: 3-((6-(3,5-dimethoxybenzimidyl)pyridin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylic acid III Butyl ester

To a solution of the compound (500 mg) obtained in EtOAc (EtOAc, EtOAc, EtOAc The mixture was stirred under ice cooling for 10 minutes and at room temperature for 18.5 hours. After adding a saturated aqueous ammonium chloride solution to the reaction liquid, the mixture was stirred at room temperature for 3 hours, and a saturated aqueous sodium hydrogencarbonate solution was further added. Ethyl acetate was added to the reaction mixture, and the target was extracted into an organic layer. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced vacuo.

_{LC / MS, t R 1.07min,} obs MS [M + 1] 439.6.

Reference Example 14: 3-((6-(3-methoxybenzylidenyl)pyridin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester

The title compound (466 mg) was obtained from the title compound (m.

_{LC / MS, t R 1.08min,} obs MS [M + 1] 409.3.

Reference Example 15: (4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanone

To a suspension of the compound (4.80 g) obtained in Reference Example 2 in THF (40 mL), EtOAc (3 mL) ). After stirring at room temperature for 2 hours, 2N hydrochloric acid (200 mL) was added, and the mixture was warmed to room temperature and stirred for 14 hours. A 6 N aqueous solution of sodium hydroxide (55 mL) was added and the mixture was evaporated. The precipitated solid was filtered, washed with water (40 mL×2), ethyl acetate (40 mL×3) and THF (10 mL×3), and dried under reduced pressure to give the title compound (6.50 g).

^{1 H-NMR (300MHz, DMSO} -d 6) δ 12.1 (s, 1H), 10.2 (s, 1H), 8.42 (d, 1H), 7.97-7.90 (m, 2H), 2.18 (s, 3H).

Reference Example 16: 2-Chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine

[化25]

To a solution of 5-methyl-pyrazol-3-amine (1.6 g) in ethanol (19.2 mL) was added 2,4-dichloro-6-methylpyrimidine (1.35 g) and sodium bicarbonate (2.47 g). Stir at 110 ° C for 8 hours. After standing to cool to room temperature, water and ethyl acetate were added to the reaction liquid, and the target substance was extracted to the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced vacuo.

^{1 H-NMR (400MHz, DMSO} -d 6) δ 12.0 (s, 1H), 10.1 (s, 1H), 6.00 (br-s, 1H), 2.25 (s, 3H), 2.20 (s, 3H).

Reference Example 17: 4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2-carbonitrile

To a solution of the compound (1.24 g) obtained in Reference Example 16 in DMSO (100 mL) / isopropyl alcohol (3 mL), sodium hydride (0.31 g) and 1,4-diazabicyclo[2. The alkane (0.32 g) was stirred at 90 ° C for 5 hours. After cooling to room temperature, water was added and the insoluble matter was removed by filtration. Ethyl acetate was added to the obtained filtrate, and the target was extracted into an organic layer, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure toiel

^{1 H-NMR (400MHz, DMSO} -d 6) δ 12.13 (s, 1H), 10.29 (s, 1H), 2.32 (s, 3H), 2.21 (s, 3H).

Reference Example 18: (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl) A ketone

To a solution of the compound obtained in Reference Example 17 (0.2 g) in THF (4 mL), EtOAc (3 mL) ). After stirring at room temperature for 3 hours, a 10% aqueous potassium hydrogensulfate solution (30 mL) was added under ice-cooling, and then warmed to room temperature and stirred for 16 hours. Saturated aqueous sodium hydrogencarbonate solution and ethyl acetate were added to the reaction mixture, and the title compound was extracted into an organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the precipitated solid was filtered. Furthermore, after washing with chloroform and hexane, it was dried under reduced pressure to obtain the title compound (0.22 g).

^{1 H-NMR (400MHz, DMSO} -d 6) δ 12.0 (s, 1H), 10.0 (s, 1H), 7.93 (t, 2H), 2.36 (s, 3H), 2.17 (s, 3H).

Reference Example 19: (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4-difluorophenyl)methanone

To a solution of the compound (0.2 g) in THF (5 mL), EtOAc (5 mL) Stir at room temperature for 15 hours. 2N hydrochloric acid (3.1 mL) was added to the reaction liquid, and the mixture was stirred at room temperature for 50 minutes. A saturated aqueous sodium carbonate solution and ethyl acetate were added to the reaction mixture, and the title compound was extracted into an organic layer. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained solid was filtered, washed with hexane and ethyl acetate, and dried under reduced pressure to give the title compound (0.28 g).

_{LC / MS, t R 0.75min,} obs MS [M + 1] 330.6.

Reference Example 20: Bromine (2,4,5-trifluorophenyl)magnesium

THF (12 mL) and 1,2-dibromoethane (51 μL) were added to the crumbly magnesium (0.35 g) which was dried at 120 ° C for 40 minutes under reduced pressure, and stirred at room temperature for 20 minutes. To the reaction mixture was slowly added a solution of 2,4,5-trifluorophenyl bromide (2.5 g) in THF (6 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour to give the title compound (1M THF solution 12 mL).

Reference Example 21: (4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanone

[化30]

The solution of the compound (4.2 g) obtained in Reference Example 2 in THF (30 mL) was slowly added to the bromo 2,4,5-trifluorophenyl magnesium (1M) obtained in Reference Example 20 under ice-cooling. The THF solution (120 mL) was stirred at room temperature for 2 hours and 50 minutes. 2N hydrochloric acid (7 mL) was added to the reaction liquid, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium carbonate solution and ethyl acetate were added to the reaction mixture, and the title compound was extracted into an organic layer. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography (chloroform/methanol) to afford the title compound (2.49 g).

_{LC / MS, t R 0.74min,} obs MS [M + 1] 349.2.

Reference Example 22: (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl) A ketone

The solution of the compound (0.5 g) obtained in Reference Example 17 in THF (15 mL) was slowly added to the bromo 2,4,5-trifluorophenyl magnesium (1M) obtained in Reference Example 20 under ice-cooling. The THF solution (10 mL) was stirred at room temperature for 2 hours and 50 minutes. 2N hydrochloric acid (7 mL) was added to the reaction liquid, and the mixture was stirred at room temperature for 2 hours. Adding saturated sodium carbonate to the reaction mixture The aqueous solution and ethyl acetate were extracted to the organic layer, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained solid was filtered, washed with hexane and ethyl acetate, and dried under reduced pressure to give the title compound (0.62 g).

_{LC / MS, t R 0.74min,} obs MS [M + 1] 349.2.

Reference Example 23: 3-((6-((3,4-Difluorophenyl)(hydroxy)methyl)pyridin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate Tert-butyl acid

Sodium borohydride (113 mg) was added to a solution of the compound (1. After adding water and ethyl acetate to the reaction liquid, the target was extracted into an organic layer, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the organic layer (yield: hexane)

_{LC / MS, t R 0.84min,} obs MS [M + 1] 417.3.

Reference Example 24: 2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-4-amine

Add 2,4-dichloropyrimidine (1.21 g) and N-ethyl-diisopropylamine (1.49 mL) to a solution of 5-cyclopropyl-pyrazol-3-amine (1.10 g) in ethanol (30 mL) ), stirring at 70 ° C for 11 hours. After standing to cool to room temperature, water was added and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated using an evaporator. The residue was purified by EtOAc EtOAc EtOAc.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 5.6 Hz, 1H), 7.96 (br-s, 1H), 7.05 (br-s, 1H), 5.87 (br-s, 1H), 1.80-1.87 (m, 1H), 0.94-1.01 (m, 2H), 0.72-0.74 (m, 2H).

LC/MS, t _R 0.67 min, obs MS [M+1] 236.1

Reference Example 25: 6-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidine-2-carbonitrile

To a suspension of the compound (364 mg) obtained in Reference Example 24 in DMSO (1.4 mL) / isopropyl alcohol (0.70 mL), sodium cyanide (106 mg) and 1,4-diazabicyclo[2.2.2] Octane (87 mg) was stirred at 90 ° C for 6 hours. After cooling to room temperature, water was added to the reaction liquid, and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated using an evaporator. The residue was diluted with ethyl acetate and then diluted 10 times with hexane. The resulting solid was filtered and dried to give the title compound (0.309 g).

^{1 H-NMR (400MHz, DMSO} -d 6) δ 12.12 (s, 1H), 10.38 (s, 1H), 8.30 (s, 1H), 1.82-1.88 (m, 1H), 0.86-0.91 (m, 2H ), 0.62-0.66 (m, 2H).

LC/MS, t _R 0.673 min, obs MS [M+1] 227.1

Reference Example 26: 2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylpyrimidin-4-amine

Add 2,4-dichloro-6-methylpyrimidine (1.34 g) and N-ethyl-diisopropyl to a solution of 5-cyclopropyl-pyrazol-3-amine (1.11 g) in ethanol (30 mL) The amine (1.50 mL) was stirred at 70 ° C for 5 hours. After standing to cool to room temperature, water was added and extracted three times with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated using an evaporator. The residue was purified by EtOAc EtOAc EtOAc.

^{1 H-NMR (400MHz, CDCl} 3) δ 7.53 (br-s, 1H), 6.95 (br-s, 1H), 5.87 (br-s, 1H), 2.37 (s, 3H), 1.81-1.88 (m , 1H), 0.97-1.02 (m, 2H), 0.72-0.76 (m, 2H).

_{LC / MS, t R 0.70min,} obs MS [M + 1] 250.1.

Reference Example 27: 4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)-6-methylpyrimidine-2-carbonitrile

To a solution of the compound (0.32 g) obtained in Reference Example 26 in DMSO (1.4 mL) / isopropyl alcohol (0.70 mL), sodium cyanide (75 mg) and 1,4-diazabicyclo[2.2.2] Octane (72 (mg), stirred at 90 ° C for 6 hours. After cooling to room temperature, water was added to the reaction liquid, followed by filtration. The obtained residue was washed three times with water, and washed twice with ethyl acetate / hexane = 1/10 solvent, and dried under reduced pressure to give the title compound (0.24 g).

^{1 H-NMR (400MHz, DMSO} -d 6) δ 12.15 (br-s, 1H), 10.23 (br-s, 1H), 7.30 (br-s, 1H), 5.95 (br-s, 1H), 2.28 (s, 3H), 1.81-1.86 (m, 2H), 0.86-0.90 (m, 2H), 0.62-0.66 (m, 2H).

_{LC / MS, t R 0.72min,} obs MS [M + 1] 241.1.

Reference Example 28: 2-Chloro-N-(5-ethyl-1H-pyrazol-3-yl)pyrimidine-4-amine

Add 2,4-dichloropyrimidine (0.405 g) and N-ethyl-diisopropylamine (0.497 mL) to a solution of 5-ethyl-pyrazol-3-amine (0.332 g) in ethanol (10 mL) It was stirred at 70 ° C for 6 hours. After standing to cool to room temperature, the residue was purified and purified mjjjjjjj

¹ H-NMR (400MHz, CDCl ₃ ) δ 8.18 (d, J = 5.2 Hz, 1H), 7.74 (br-s, 1H), 7.11 (br-s, 1H), 6.10 (br-s, 1H), 2.69 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H).

_{LC / MS, t R 0.65min,} obs MS [M + 1] 224.1.

Reference Example 29: 4-((5-Ethyl-1H-pyrazol-3-yl)amino)pyrimidine-2-carbonitrile

[化38]

To a suspension of the compound (171 mg) obtained in Reference Example 28 in DMSO (1.4 mL) / isopropyl alcohol (0.70 mL), sodium cyanide (50 mg) and 1,4-diazabicyclo[2.2.2] Octane (47.7 mg) was stirred at 90 ° C for 6 hours. After cooling to room temperature, water was added to the reaction liquid, and the mixture was diluted with ethyl acetate / hexane = 1 / 1. The mixture was extracted twice with ethyl acetate, and the organic phase was washed with brine and dried over sodium sulfate. The obtained residue was suspended and filtered using ethyl acetate / hexane = 1/10. The obtained residue was washed twice with ethyl acetate / hexane = 1/10 solvent, and dried under reduced pressure to give the title compound (102 mg).

_{LC / MS, t R 0.66min,} obs MS [M + 1] 215.2.

Reference Example 30: (4-((5-Cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanone

To a solution of the compound (87 mg) in THF (10 mL), m. m. . After stirring at room temperature for 2 hours, 2M hydrochloric acid (200 mL) was added, and the mixture was warmed to room temperature and stirred for 14 hours. Water (2.0 mL) and acetic acid (1.0 mL) were added and stirred for 1 hour. After extracting three times with ethyl acetate, the organic phase was washed with saturated brine and used. The sodium sulfate was dried and concentrated by means of an evaporator. The residue was purified by EtOAc EtOAc EtOAc.

¹ H-NMR (400MHz, CDCl ₃ ) δ 8.40-8.55 (m, 2H), 7.86-7.89 (m, 2H), 7.31 (br-s, 1H), 5.92 (br-s, 1H), 1.84-1.89 (m, 1H), 0.99-1.02 (m, 2H), 0.71-0.73 (m, 2H).

_{LC / MS, t R 0.90min,} obs MS [M + 1] 360.2.

Reference Example 31: (4-((5-ethyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanone

To a suspension of the compound (62 mg) obtained in Reference Example 29 in THF (4 mL), THF (3 mL) of THF (3,4,5-trifluorophenyl magnesium) in THF (2.4 mL) ). After stirring at room temperature for 2 hours, 2M hydrochloric acid (200 mL) was added, and the mixture was warmed to room temperature and stirred for 14 hours. Water (2.0 mL) and acetic acid (1.0 mL) were added and stirred for 1 hour. After extracting three times with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated with an evaporator. The residue was purified by EtOAc EtOAc EtOAc.

^{1 H-NMR (400MHz, CDCl} 3) δ 9.23 (br-s, 1H), 8.41 (d, J = 5.6Hz, 1H), 7.87-7.95 (m, 2H), 7.28 (br-s, 1H), 6.03 (br-s, 1H), 2.71 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

_{LC / MS, t R 0.90min,} obs MS [M + 1] 348.2.

Reference Example 32: 6-Methyl-4-thio-3,4-dihydropyrimidin-2(1H)-one

To a solution of 6-methylpyrimidine-2,4(1H,3H)-dione (12.6 g) in pyridine (100 mL) was added to a solvent (22.3 g), and the mixture was stirred at 140 ° C for 2 hours. After standing to cool to room temperature, water (300 mL) was added to the solid obtained by concentration under reduced pressure, and the mixture was stirred at 110 ° C for 10 minutes. After standing to cool to room temperature, the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (13.1 g).

¹ H-NMR (DMSO-d ₆ ) δ 2.00 (s, 3H), 6.13 (s, 1H), 11.5 (s, 1H), 12.3 (s, 1H).

Reference Example 33: 6-Methyl-4-(methylthio)pyrimidin-2(1H)-one

The compound (13.1 g) obtained in Reference Example 32 was added to a 1 M aqueous sodium hydroxide solution (287 mL), and the mixture was cooled to 0° C., and then, methylene chloride (6.0 mL) was added dropwise, and the mixture was stirred at 0° C. for 2 hours. Further, the mixture was stirred at room temperature for 2.5 hours, and then cooled to 0 ° C, and then acetic acid (130 mL) was added and concentrated under reduced pressure. Water was added to the obtained solid, and the mixture was heated to 100 ° C to be dissolved, and then cooled to room temperature to be recrystallized. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (10.5 g).

¹ H-NMR (DMSO-d ₆ ) δ 2.10 (s, 3H), 2.40 (s, 3H), 6.19 (s, 1H), 11.4 (br-s, 1H).

Reference Example 34: 2-Chloro-4-methyl-6-(methylthio)pyrimidine

The compound (442 mg) obtained in Reference Example 33 was added to chlorobenzene (4 mL) and stirred at 100 ° C for 1.5 hr. After standing to cool to room temperature, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution were added to the solid obtained by concentration under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate.

¹ H-NMR (CDCl ₃ ) δ 2.40 (s, 3H), 2.54 (s, 3H), 6.93 (s, 1H).

Reference Example 35: 4-methyl-6-(methylthio)pyrimidine-2-carbonitrile

To a solution of the compound obtained in Reference Example 34 (490 mg) in DMSO (3 mL) / isopropyl alcohol (1.7 mL), sodium hydride (165 mg), 1,4-diazabicyclo[2.2.2] octane (157 mg), stirred at room temperature for 23 hours. Saturated aqueous sodium hydrogencarbonate solution, saturated brine and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine and dried over sodium sulfate.

¹ H-NMR (CDCl ₃ ) δ 2.45 (s, 3H), 2.56 (s, 3H), 7.15 (s, 1H).

Reference Example 36: 4-Chloro-6-methylpyrimidine-2-carbonitrile

After cooling a solution of the compound (165 mg) obtained in Example 35 (yield: EtOAc) (EtOAc), EtOAc (EtOAc) A saturated aqueous sodium carbonate solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with brine and dried over sodium sulfate.

_{^{1 H-NMR (CDCl 3)}} δ 2.59 (s, 3H), 7.40 (s, 1H).

Reference Example 37: 4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2-carbonitrile

To a solution of the compound (154 mg) in DMSO (4 mL), EtOAc (EtOAc, EtOAc) Stir at room temperature for 67 hours. Water was added, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (162 mg).

¹ H-NMR (DMSO-d ₆ ) δ 2.22 (s, 3H), 2.33 (s, 3H), 5.98 (br-s, 1H), 7.55 (br-s, 1H), 10.3 (s, 1H), 12.1(s, 1H).

Reference Example 38: 2,4-dibromo-6-methyl-pyrimidine

A solution of 2,4-dichloro-6-methylpyrimidine (40 g) in acetic acid (40 g) and methanesulfonic acid (160 g) was poured into a 30% hydrogen bromide/acetic acid solution (662 g) at 45 °C. After stirring at 45 ° C for 15 minutes, cooled toluene (200 g) was added and cooled to an internal temperature of 0 °C. Water (320 g), triethylamine (248 g) and 37.5% potassium carbonate aqueous solution (640 g) were added dropwise at an internal temperature of 5 ° C or less to prepare an organic layer. The aqueous layer was extracted twice with isopropyl acetate (200 g), combined with the original organic layer, and concentrated to 148 g. The operation of adding isopropanol (148 g) twice and concentrating again until the content amount became 148 g was repeated. Isopropanol (40 g) was added and the temperature was raised to 50 °C. Water (200 g) was added dropwise at 50 ° C, cooled to 0 ° C over 5 hours, and stirred overnight. The crystals were filtered, washed with chilled isopropyl alcohol/water (30 g / 120 g), and dried under reduced pressure at 40 ° C to give the title compound (45 g).

LC/MS, t _R 0.803 min, obs MS [M+1] 252.9.

Reference Example 39: 2-bromo-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-4-amine

To a solution of 2,4-dibromo-6-methyl-pyrimidine (40 g) and 5-methyl-pyrazol-3-amine (22 g) in 2-pyrrolidone (120 g) obtained in Reference Example 38 Water (280 g) and sodium hydrogencarbonate (16 g) were added, and the mixture was stirred at 60 ° C for 16 hours. After cooling to 0 ° C for 6 hours, the mixture was stirred overnight at 0 ° C, and the crystals obtained by filtration were cooled by cooling acetonitrile (80 g) at 40-50. Drying under reduced pressure at °C gave the title compound (36 g).

_{LC / MS, t R 0.635min,} obs MS [M + 1] 270.0.

Reference Example 40: 4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2-carbonitrile

2-Bromo-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (30 g) obtained in Reference Example 39 was suspended in DMF (240 g) / Sodium cyanide (7.4 g) was added to propanol (30 g), and the temperature was raised to 70 °C. 1,4-Diazabicyclo[2.2.2]octane (4 g) was added, and the mixture was heated to 90 ° C and stirred for 11 hours. After cooling to 50 ° C, water (900 g) was added and cooled to 0 °C. The crystals were filtered, washed with water (60 g) and EtOAc (30 g).

^{1 H-NMR (400MHz, DMSO} -d 6) δ 12.13 (s, 1H), 10.29 (s, 1H), 2.32 (s, 3H), 2.21 (s, 3H).

Example 1: (3,4-Difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol

(Synthesis Method A)

Boron was added to a solution of the compound (30 mg) obtained in Reference Example 4 in methanol (2 mL) Sodium hydride (3.6 mg) was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction liquid, and the target was extracted to the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography (ethyl acetate).

^{1 H-NMR (400MHz, DMSO} -d 6) δ 11.98 (s, 1H), 9.88 (s, 1H), 8.22 (d, 1H), 7.51-7.46 (m, 1H), 7.40-7.33 (m, 1H ), 7.28-7.25 (m, 1H), 5.77 (d, 1H), 5.56 (d, 1H), 2.19 (s, 3H).

Example 2: (-)-(3,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, and implementation Example 3: (+)-(3,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol

(Synthesis Method B)

(3,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl as a racemate obtained in Example 1. Methanol (20 mg) was dissolved in hexane:isopropyl alcohol:methanol = 7:3:5 (1.5 mL), and the HPLC system containing Shimadzu CR-6A CHROMATOPAC, HITACHI L-6000 PUMP, Shimadzu SPD-6A was used twice. , in the tube column Daicel Chiral PAK AD-H, 20mm The compound was subjected to optical analysis under the conditions of a solvent of hexane: isopropyl alcohol = 70:30 and a flow rate of 10 mL/min, and a compound of Example 2 (10.9 mg) and Example 3 (10.7 mg) was obtained.

Example 2: Hold time 19.9 min, [α] _D ²⁰ = -22.8 ( c = 0.50, MeOH)

Example 3: Hold time 36.3 min, [α] _D ²⁰ = +21.9 ( c = 1.00, MeOH)

Example 4: (+)-(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluoro Phenyl)methanol

[化51]

(Synthesis Method C)

(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) was obtained in the same manner as in Reference Example 22 under a nitrogen atmosphere. isopropanol 2,4,5-trifluorophenyl) methanone (2.0g) of (10 mL) was added potassium t-butoxide group of 0.01M isopropanol solution (30mL) and a solution of (R) -RUCY ^TM -Xylbinap (0.2g). The reaction mixture was stirred under a stream of hydrogen (5 Torr) at 40 ° C for 3 hr. After the hydrogen gas in the reaction vessel was replaced with nitrogen, the residue was evaporated to dryness crystals crystals crystals

^{1 H-NMR (400MHz, DMSO} -d 6) δ 11.89 (s, 1H), 9.70 (s, 1H), 7.50-7.64 (m, 1H), 7.43-7.48 (m, 1H), 6.09 (s, 1H ), 5.87 (s, 1H), 5.70 (s, 1H), 2.27 (S, 1H), 2.14 (s, 3H).

LC/MS, t _R 0.58 min, obs MS [M+1] 351.3.

[α] _D ²⁰ = -29.5 ( c = 1.0, MeOH)

LC analysis (column Daicel Chiral PAK AD-H, 4.6mm ×25 cm, hexane: isopropanol: methanol: triethylamine: acetic acid = 70:25:5:0.1:0.05, flow rate 1 mL/min) retention time 11.37 min.

Example 5: (-)-(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluoro Phenyl)methanol

(Synthesis Method D)

Using (S) -RUCY ^TM -Xylbinap as a catalyst, with the embodiment of Example 4 of the same embodiment from (4-methyl-6 - ((5-methyl -1H- pyrazol-3-yl) amine Pyrimidine-2-yl)(2,4,5-trifluorophenyl)methanone (100 mg) gave the title compound (54 mg).

LC/MS, t _R 0.58 min, obs MS [M+1] 351.3.

LC analysis (column Daicel Chiral PAK AD-H, 4.6mm ×25 cm, hexane: isopropanol: methanol: triethylamine: acetic acid = 70:25:5:0.1:0.05, flow rate 1 mL/min) retention time 8.66 min.

Example 6: (-)-(6-((5-Methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)(3,4,5-trifluorophenyl)methanol and Example 7: (+)-(6-((5-Methyl-1H-pyrazol-3-yl)amino)pyridin-2-yl)(3,4,5-trifluorophenyl)methanol

Sodium borohydride (23 mg) was added to a solution of the compound (m. Water and ethyl acetate were added to the reaction liquid, and the target was extracted into an organic layer, and the organic layer was washed with saturated brine and dried over sodium sulfate. The residue obtained by concentrating the organic layer under reduced pressure was purified by ethylamine-hexane column chromatography (ethyl acetate/methanol) to afford (6-((5-methyl-1H-) Pyrazol-3-yl)amino)pyridin-2-yl)(3,4,5-trifluorophenyl)methanol (130 mg).

_{LC / MS, t R 0.63min,} MS [M + 1] 334.9.

The racemic form obtained by DAICEL in the same manner (6-((5-methyl-) 1H-pyrazol-3-yl)amino)pyridin-2-yl)(3,4,5-trifluorophenyl)methanol (28.7 g) was subjected to optical analysis to obtain Example 6 (10.3 g) and Example 7 (9.6 g) of the compound.

Will be the column Daicel Chiral PAK OJ-H, 4.6mm ×25 cm, solvent: hexane:ethanol:methanol:ethylenediamine=40:40:20:0.1, flow rate 1.0 mL/min The retention time obtained by analyzing the compounds of Example 6 and Example 7 is shown below.

Example 6: 3.69 min

Example 7: 5.90 min

Example 8~44

The compounds of Examples 8 to 44 shown in the following tables were obtained by the same methods as in Examples 1, 2, 3, 4 or 5 (Synthesis methods A, C, and D) using the corresponding starting compounds. LC analysis using a chiral column was carried out under the following conditions to reveal the retention time.

Column Daicel Chiral PAK AD-H, 4.6mm ×25 cm, hexane: isopropanol: methanol: triethylamine: acetic acid = 70:25:5:0.1:0.05, flow rate 1 mL/min

Example 45: (3,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methane-d-ol

To a solution of the compound (47 mg) obtained in m. Three equivalents of HCl and 5 equivalents of NaOH were added to the reaction liquid, and the pH of the reaction liquid was adjusted to 8, and then concentrated under reduced pressure. Water was added to the residue, and the precipitated solid was filtered, washed with water and hexane, and dried under reduced pressure to give the title compound (44 mg).

^{1 H-NMR (400MHz, DMSO} -d 6) δ11.9 (s, 1H), 9.84 (s, 1H), 8.21 (s, 1H), 7.50-7.26 (m, 3H), 5.84 (s, 1H) , 5.53 (d, 1H), 2.18 (s, 3H).

Example 46: 1-(3-Methoxyphenyl)-1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)ethane-1 -alcohol

Methylmagnesium bromide (0.98 M, 0.2 mL) was added to a THF (1 mL) solution of Compound (20 mg). Thereafter, methylmagnesium bromide (0.98 M, 1.5 mL) was added, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, and the title compound was extracted into an organic layer. Then, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced vacuo.

¹ H-NMR (300MHz, DMSO-d ₆ ) δ 12.10 (s, 1H), 10.00 (s, 1H), 8.29 (s, 1H), 7.12-7.30 (m, 3H), 6.82 (d, 1H), 5.72 (s, 1H), 3.77 (s, 3H), 2.28 (s, 3H), 1.87 (s, 3H).

Examples 47~52

The compounds of Examples 47 to 52 shown in the following tables were obtained by the same methods as in Example 46 using the corresponding starting materials.

[化56]

Examples 53~70

The compounds of Examples 53 to 70 shown in the following Table were obtained by the same method as in Example 1 (Synthesis Method A) using the corresponding starting compound.

Examples 71~86

Using the corresponding starting compound, the following method was obtained in the same manner as in Example 46. The compounds of Examples 71-86 shown in the Table.

Example 87: (+)-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl} (2,4,5-trifluoro Phenyl)methanol

To (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl) under a nitrogen atmosphere methanone (3.0g) and the isopropyl alcohol (60mL) / tetrahydrofuran (60 mL) was added potassium tertiary butoxide (58.2 mg) and ^{(R) -RUCY TM -Xylbinap (40.9mg} ) solution. The reaction mixture was stirred under a hydrogen stream (5 Torr) at 40 ° C for 2.5 hr. After the hydrogen in the reaction vessel was replaced with nitrogen, 3-mercaptopropyl phthalocyanine (4.0 g) and activated carbon (2.0 g) were added to the reaction liquid. After stirring for 1 hour, the mixture was filtered through Celite, and the residue was washed with ethanol. The filtrate was concentrated using an evaporator to give a crude material (3.1 g). Ethanol (5 mL) was added thereto, and the mixture was stirred by an ultrasonic cleaner to confirm the precipitation of a solid. The mixture was stirred with heating at 90 ° C for 30 minutes, then slowly cooled to room temperature, and further cooled to 5 ° C in an ice bath. The crystals which precipitated were collected by filtration, and washed twice with cooling ethanol (2 mL), and then dried under reduced pressure at 60 ° C for 3 hours to give the title compound (2.39 g).

Example 88: (+)-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}(2,4,5-trifluoro Phenyl)methanol

(+)-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) (2,4, obtained in Example 87, The 5-trifluorophenyl)methanol ethanolate (0.40 g) was suspended in water (8 mL). The suspension was heated and stirred at 90 ° C for 1 hour. After cooling to room temperature, the precipitated crystals were collected by filtration. Furthermore, the crystals were washed three times with water, and dried under reduced pressure to give the title compound (0.34 g).

Example 89: (+)-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}(2,4,5-trifluoro Phenyl)methanol

[化61]

(+)-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) (in the same manner as in Example 87) The ethanolate (7.10 g) of 2,4,5-trifluorophenyl)methanol was suspended in water (71 mL). The seed crystal obtained in Example 88 was added, and the mixture was stirred under heating at 90 ° C for 6 hours. After cooling to room temperature, the precipitated crystals were collected by filtration. Furthermore, the crystals were washed three times with water, and dried under reduced pressure to give the title compound (6.08 g).

A diagram of the powder X-ray diffraction pattern is shown in Fig. 1, and its main peaks are shown in the following table. Further, a diagram of the DSC-TGA is shown in FIG. According to the chart of DSC-TGA, no change in weight was observed at the endothermic peak, and therefore it was confirmed to be anhydrate crystal.

Example 90: (+)-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}(2,4,5-trifluoro Phenyl)methanol phosphate

(+)-(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) (2,4, obtained in Example 87) Phosphoric acid (21 μL) was added to a suspension of methanol (0.5 mL) of 5-trifluorophenyl)methanol (100 mg), and stirred at 50 ° C for 1 hour. Further, the mixture was stirred at room temperature for 21 hours, and precipitation of crystals was confirmed. Ethyl acetate (2 mL) was added and stirred for 1.5 h. The precipitated solid was collected by filtration, and the residue was washed three times with ethyl acetate (0.5 mL).

(+)-{4-Methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl} (2,4,5-trifluoro) Phenyl)methanol phosphate (50 mg) was dissolved in methanol, and one half of methanol was added with ethanol and the same amount of isopropanol as ethanol. The solvent was slowly volatilized at room temperature, and coarse needle-like crystals were precipitated, and the crystals were collected by filtration to carry out X-ray crystal analysis.

The analysis results are shown in the following five tables. Further, based on the analysis results, it was confirmed that the absolute structure of the present compound is (S)-body. The three-dimensional structure is shown in FIG.

Also, since the present compound is known (Example 90: (+)-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl} ( The absolute structure of 2,4,5-trifluorophenyl)methanol phosphate) is (S)-form, thus determining the corresponding compound of Example 4 and Example 89 ((+)-(4-methyl-6) -((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol), and the compound of Example 87 ((+ -{4-Methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}(2,4,5-trifluorophenyl)methanol The compounds are also (S)-body, respectively.

Example 91: (+)-{4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl} (2,3,4-trifluoro Crystallization of phenyl)methanol and powder X-ray crystal analysis

(+)-{4-Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl} (2,3, obtained in Example 32, 4-Trifluorophenyl)methanol (1.33 g) was added with hexane/chloroform = 1/1 (4 mL), and stirred for 1 day. The crystals were collected by filtration, washed with hexane/chloroform = 1/1, and dried. White crystals (1.29 g) were obtained.

A diagram of the powder X-ray diffraction pattern is shown in Figure 4, and its main peak is shown below. In the table. Further, a diagram of the DSC-TGA is shown in FIG. According to the chart of DSC-TGA, no change in weight was observed at the endothermic peak, and therefore it was confirmed to be anhydrate crystal.

Pharmacological test

Hereinafter, the pharmacological test methods and the results of the representative compounds of the present invention are disclosed, but the present invention is not limited to the test examples.

Test Example 1: Cell proliferation inhibition experiment

NCI-H23 cells were obtained from ATCC (American Type Culture Collection). NCI-H23 was cultured in RPMI1640 medium containing 10% FCS (Fetal Calf Serum, fetal calf serum) and 1% penicillin/streptomycin at 37 ° C in the presence of 5% CO ₂ . HCT116 was at 37 ° C. The culture was carried out in DMEM medium containing 10% FCS, 1% penicillin/streptomycin in the presence of 5% CO ₂ .

The cells were seeded in a 96-well plate at 500 to 3000 cells/well, and the test substance was added in such a manner that the final concentration of DMSO was 0.1%, and cultured for 4 to 7 days. Thereafter, the number of viable cells was measured using a Presto blue (Life Technologies), and a concentration (Cytotoxicity IC ₅₀ value; μM) which inhibited 50% of cell proliferation of each test substance was calculated, and it was confirmed that the compound of the present invention has cancer cells. Proliferative inhibition.

Test Example 2: Cytotoxicity test using rat hepatocytes

Rat liver parenchymal cells were isolated from Crl:CD (SD) male rats at 6 weeks of age. The number of viable cells and dead cells in the suspension was counted by trypan blue staining, and viability (survival rate) was calculated to prepare 1.0 × 10 ⁴ cells/100 μL of hepatocyte suspension. The suspension was added to a Type 1 collagen-coated 384-well plate (Corning) at 60 μL/well, and cultured overnight at 37 ° C in the presence of 5% CO ₂ . The medium was removed from the 384 well cell culture plate, and the culture solution containing the test substance (n = 4) was added at 50 μL/well. After the end of the addition, the cultivation was continued in this order at 37 ° C in the presence of 5% CO ₂ . After 2 days, at 5μL / well WST-8 reagent was added (Cell Counting Lit-8, Dojindo Laboratories) and stirred at 37 ℃, 5% CO incubated for about 3 hours in the presence of _2. After the incubation, 0.1 N HCl was added at 15 μL/well to stop color development, and the absorbance was measured at a wavelength of 450 nm, and the number of viable cells was measured to calculate a concentration (Cytotoxicity IC ₅₀ value; μM) which inhibited 50% of cell proliferation of each test substance. It was confirmed that the compound of the present invention is less toxic to hepatocytes.

Test Example 3: Metabolic stability test of compounds

0.4 ml of human liver microsomes (manufactured by Xenotech Co., Ltd., about 20 mg protein/ml) was added to 39.6 ml of 25 mM Kpi (pH 7.4) to prepare a microsomal solution. A 10 mM solution of 1 mM of the test compound in DMSO was diluted 100-fold with acetonitrile. Cofactor prepared by dissolving 300 mg of NADPH (nicotinamide adenine dinucleotide phosphate) (6.5 mM) in 55.2 ml of 125 mM Kpi (pH 7.4) was added to 5 μl of the solution. An intermediate dilution was prepared by 250 μl of a (cofactor) solution. On a 96-well plate, use a screening machine made by Tecan For each person, 50 μl of the intermediate dilution solution was placed in 2 wells, and 50 μl of the mixed microsome solution was added thereto, and the mixture was shaken at 37 ° C for 30 minutes while maintaining the reaction sample. Separately, 50 μl of the intermediate dilution solution was placed in 2 wells, and the microparticle solution was not added and the same was carried out to prepare an unreacted sample. After the completion of the incubation, 400 μl of methanol was added to each of the reaction sample and the unreacted sample. Further, after adding methanol to the pores of the unreacted sample, 50 μl of the mixed microsome solution was added to prepare. After standing at -20 ° C for 30 minutes, centrifugation was carried out, and 10 μl of the supernatant was injected into an LC-MS/MS system (HPLC manufactured by Shimadzu Corporation, API 4000 manufactured by AB Sciex Co., Ltd.), and 2 wells of the reaction sample were measured. The unreacted sample 2 wells totaled 4 wells, and the average value of the chromatographic peak area values of each was calculated. Using this value, the clearance rate of the compound was determined according to the following formula using the natural logarithm (LN).

Compound clearance = -LN{(reaction sample average) ÷ (average of unreacted sample)}/30/0.1

From the results, it was confirmed that the stability of the microparticles of the compound of the present invention was improved.

Test Example 4: hERG inhibition test

The test substance was added to the cells of the CHO (Chinese Hamster Ovary) cell strain stably expressing the hERG gene in a manner such that the final concentration of DMSO was 0.0135 to 0.5%. The hERG current was measured using QPatch HT (Sophion), and the concentration of each of the test substances to suppress 50% of the hERG current (IC ₅₀ value; μM) was calculated, and it was confirmed that the hERG inhibitory activity of the compound of the present invention was weak.

The test shown in Test Example 1 to Test Example 4 was carried out for the compound obtained in the examples. The results are shown in the following table.

Test Example 5: Kinase inhibition assay

Will use assay buffer (20 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid, 4-(2-hydroxyethyl)-1-piperidine) 5 μL of 4-fold concentration test substance solution prepared by ethanesulfonic acid), 0.01% Triton X-100, 2 mM DTT (Dithiothreitol, dithiothreitol), pH 7.5), 4 μl concentration of substance/ATP of 5 μL (Adenosine Triphosphate, adenosine triphosphate)/metal solution and 10 μL of a 2-fold concentration kinase solution were mixed in a well of a 384-well plate made of polypropylene, and allowed to react at room temperature for 1 hour. The reaction was stopped by adding 60 μL of Termination Buffer (QuickScout Screening Assist MSA; Carna Biosciences). The substrate and the phosphorylated peptide in the reaction solution were separated and quantified using a LabChip system (Perkin Elmer). The kinase reaction was evaluated by the product ratio (P/(P+S)) calculated from the peak height (S) of the peptide and the peak height (P) of the phosphorylated peptide. Moreover, in the data analysis, the average signal of the control well was set to 0% inhibition, and the average signal of the background hole (without added enzyme) was set to 100% inhibition, and the inhibition rate was calculated from the average signal of each subject substance hole. . From the results, it was confirmed that the compound of the present invention has kinase inhibitory activity.

For the compound obtained in the examples, the test shown in Test Example 5 was carried out. The test results are shown in the following table.

Test Example 6: Tumor proliferation inhibition experiment in mice with HCT-116 human colon adenocarcinoma cells

HCT-116 cells (ATCC) were suspended in HBSS (Hank's Balanced Salt Solution) to the ventral side of 5-week-old female BALB/cAnNCrj-nu/nu mice (Charles River, Japan) Subcutaneous transplantation of 3 × 10 ⁶ . After 7 days from the transplantation, the test substance suspended in a 0.5% methylcellulose solution (Wako Pure Chemicals) was orally administered for 13 to 15 days twice a day, and the test substance was administered to the group. The vehicle was administered in a similar manner to a 0.5% methylcellulose solution. The number of each group is set to 7-8. After starting the administration, the tumor diameter and body weight were measured 1 to 3 times a week. The tumor volume was calculated according to the following formula.

Tumor volume (mm ³ ) = long diameter (mm) × short diameter (mm) × short diameter (mm) × 1/2

Using the average tumor volume of each administered group, the tumor growth inhibition rate was calculated according to the following formula.

Tumor proliferation inhibition rate (%) = 100-100 × (T-T0) / (C-C0)

T: mean tumor volume after administration of the test substance at the end of administration

T0: mean tumor volume at the start of administration of the test substance

C: mean tumor volume after administration of the vehicle

C0: mean tumor volume at the start of vehicle administration

Using the average body weight of each administered group, the body weight change rate was calculated according to the following formula.

Weight change rate (%) = 100 × (T / T0) / (C / C0)

T: average body weight after the end of the test substance administration

T0: average body weight at the start of administration of the test substance

C: average body weight after the end of the administration of the vehicle

C0: average body weight at the start of the administration of the vehicle

For the compound obtained in the examples, the test shown in Test Example 6 was carried out. The results are shown in the following table.

Test Example 7: Tumor proliferation inhibition experiment in mice with HCC1806 human breast cancer cells

HCC1806 cells (ATCC) were suspended in HBSS, and 3×10 ⁶ were subcutaneously transplanted into the ventral side of 5-week-old female BALB/cAnNCrj-nu/nu mice (Charles River, Japan). After 7 days from the transplantation, the test substance (200 mg/kg, twice a day, orally administered) suspended in 0.5% methylcellulose solution (Wako Pure Chemical) was suspended in physiological saline (Otsuka Pharmaceutical Co., Ltd.) In the case of European paclitaxel (5 mg/kg, 3 times a week, tail vein administration), or the compound obtained in Example 4 (150 mg/kg, twice a day, oral administration) and Europe Paclitaxel (5 mg/kg, 3 times a week, and tail vein administration) was administered for 15 days. The vehicle was administered to the group twice a day for 15 days with a 0.5% methylcellulose solution. The number of each group is set to 5~8. The tumor diameter and body weight of all individuals were measured 1 to 3 times a week during the 15 days of the administration period. Further, in the 35 days after the end of the administration without the administration of the drug, the docetaxel administration group and the tumor diameter and body weight of the combination of the test substance and the European paclitaxel were measured.

The tumor volume was calculated according to the following formula.

Tumor volume (mm ³ ) = long diameter (mm) × short diameter (mm) × short diameter (mm) × 1/2

The measurement result of the tumor diameter of the test shown in Test Example 7 of the compound obtained in Example 4 is shown in Fig. 6. On the final day of drug administration, European paclitaxel was administered The tumor volume of the group, and the tumor-administered group of the test substance and the combination of the paclitaxel and the paclitaxel group was significantly inhibited relative to the tumor-administered group (ρ<0.05, Dunnett's assay). Further, after the administration of the drug, the administration of the paclitaxel group in Europe confirmed that the tumor volume was increased, but the tumor volume of the test substance and the combination of the paclitaxel and the paclitaxel continued to be suppressed and completely disappeared. Further, no recurrence of the tumor was observed in all cases during the observation period.

The measurement results of the body weight of the test shown in Test Example 7 of the compound obtained in Example 4 are shown in Fig. 7. The body weight of the docetaxel administration group (19 days and 22 days) was significantly inhibited relative to the body weight of the vehicle administration group (ρ<0.05, Student's t-test). On the other hand, the weight of the test substance and the combination of the paclitaxel and the paclitaxel group was significantly changed from the weight of the vehicle administration group on any measurement day.

Test Example 8: Tumor proliferation inhibition experiment using cancer cells of FaDu human pharyngeal carcinoma cells

FaDu cells (ATCC) were suspended in HBSS, and 1×10 ⁶ were subcutaneously transplanted into the ventral side of 5-week-old female BALB/cAnNCrj-nu/nu mice (Charles River, Japan). The test substance (50, 100, or 200 mg/kg, twice a day, orally administered) suspended in a 0.5% methylcellulose solution (Wako Pure Chemical) was administered to the patient 15 days after the transplantation. day. The vehicle was administered to the group twice a day for 15 days with a 0.5% methylcellulose solution. The number of each group is set to 10. The tumor diameter and body weight of all individuals were measured 1 to 3 times a week during the 15 days of the administration period.

The tumor volume was calculated according to the following formula.

Tumor volume (mm ³ ) = long diameter (mm) × short diameter (mm) × short diameter (mm) × 1/2

The mean and standard error are shown in Figures 8 and 9.

The measurement result of the tumor diameter of the test shown in Test Example 8 of the compound obtained in Example 4 is shown in Fig. 8. On the final day of the assay, the tumor volume of the test substance-administered group was significantly inhibited in a dose-dependent manner relative to the tumor volume of the vehicle-administered group (ρ < 0.025, Williams assay).

The compound obtained in Example 4 was subjected to the test body shown in Test Example 8. The results of the measurement are shown in Fig. 9. On the final day of the assay, the body weight of the test substance-administered group was significantly increased in a dose-dependent manner relative to the dose of the vehicle-administered group (ρ < 0.025, Williams test). Further, regarding the weight gain effect, no abnormal cause such as edema was observed.

Test Example 9: Adenosine A3 antagonistic activity test

Coelenterazine h (125 nM) was loaded into CHO cells expressing adenosine A3 gene, luminescent protein, and Gα16. Thereafter, the test substance was added, and after 2 minutes, a ligand (adenosine 1 μM) was added, and the luminescence of the luminescent protein was measured by FDSS 7000 (Hamamatsu Photonics), and the inhibition rate was calculated according to the following formula.

Inhibition rate = (luminous intensity when no test substance is added - luminous intensity when the test substance is added) / luminous intensity of the test substance not added * 100

From the results, it was confirmed that the compound of the present invention does not have adenosine A3 antagonistic activity at 1 μM.

The test obtained in Test Example 9 was carried out on the compound obtained in Example 4. The test results are shown in the following table.

Test Example 10: Solubility measurement

15 μL of the test substance (10 mM DMSO solution) was dispensed into a U-shaped tube on a 96-well sample introduction tank, placed in a centrifugal evaporator, and evaporated to dryness. After adding 3 μL of DMSO and re-dissolving, 300 μL of each of pH 7.4 and 1.2 buffer was added thereto, and the mixture was shaken at 110 rpm for 90 minutes at 25° C., and then allowed to stand for 16 to 20 hours. The insoluble matter was separated by centrifugation at 2000 G for 15 minutes, and 100 μL of the supernatant was collected and placed in a 96-well plate. In addition, to 96 holes 2 μL of the test substance (10 mM DMSO solution) was dispensed into the plate, and diluted with 198 μL of 50% acetonitrile to prepare a 100 μM standard solution. Further, 100 μM of the standard solution was diluted 10-fold with 50% acetonitrile to prepare a 10 μM standard solution. The solubility measurement sample and the standard solution were analyzed by liquid chromatography, and the solubility was calculated from the area ratio of the standard solution.

The test shown in Test Example 10 was carried out on the compound obtained in the examples. The test results are shown in the following table.

Test Example 11: Block proliferation inhibition test

HCC1806 cells were obtained from ATCC. The HCC1806 cell line was cultured in RPMI1640 medium containing 10% fetal calf serum, 1% penicillin/streptomycin at 37 ° C in the presence of 5% CO ₂ . The cells were seeded at 1,000 to 3,000 cells/well in a 96-well plate, and the test substance was added thereto at a DMSO concentration of 0.1%, and cultured for 5 days. Thereafter, the number of viable cells was measured using a Presto blue (Life Technologies), and the concentration (IC ₅₀ : μM) at which 50% of the cells of each test substance were inhibited from proliferation was calculated.

Test Example 12: Cancer cell ball formation inhibition experiment

HCC1806 cells were obtained from ATCC. Contains B27 Supplement (GIBCO), 20 ng/mL epithelial cell proliferation factor (EGF) (peprotech), 20 ng/mL basic fibroblast growth factor (bFGF) (peprotech), 5 μg/mL insulin (GIBCO) and 1% A In the DMEM/F12 medium of Nacalai Tesque, the cells were seeded at 1,000 to 3,000 cells/well and inoculated into a Corning 96-well transparent round-bottom ultra-low adsorption surface microplate (Corning, #7007). The test substance was added so that the DMSO concentration became 0.1%, and culture was carried out for 10 days. Thereafter, the number of spheres was measured, and the concentration (IC ₅₀ : μM) at which 50% of the cell proliferation of each test substance was suppressed was calculated.

The test results shown in Test Example 11 and Test Example 12 were carried out on the compounds obtained in the examples. The test results are shown in the table below.

Test Example 13: Nanog performance inhibition experiment using the test substance

HCC1806 cells were obtained from ATCC. The cells were subcultured in RPMI medium containing 10% fetal calf serum, 1% penicillin/streptomycin at 37 ° C in the presence of 5% CO ₂ . On the day before the test substance was added, 2 × 10 ⁵ cells were seeded into a 6-well plate and cultured overnight. The test substance was added, and after culturing for 24 hours, the supernatant was removed. The cells were washed with an ice bath cooled PBS (Phosphate Buffered Saline, phosphate buffer), and an ice bath cooled RIPA containing a protease (phosphine hatchase inhibitor cocktail) (Cell signaling technology, #5872S) was added. Radio Immunoprecipitation Assay, Cell Signaling Technology (#9806S), cells were recovered using a cell scraper. After ultrasonic treatment, it was allowed to stand on ice for 10 minutes. After centrifugation (15,000 rpm, 10 minutes), the supernatant was recovered to quantify the protein concentration. The solution containing the RIPA buffer and SDS (Sodium Dodecyl Sulfonate) sample buffer (Nacalai Tesque, #09499-14) adjusted to a certain concentration of cellular protein was heated at 100 ° C for 5 minutes. The protein is separated by electrophoresis. After transferring the protein to a PVDF (Polyvinylidene fluoride) membrane, use 5% Skim milk/TBST (Tris Buffered Saline with Tween, Tween-added Tris buffer solution) The solution was added with anti-Nanog antibody (Cell signaling technology, #4903S), or anti-β-actin antibody (Cell signaling technology, #5125S), and incubated at 4 ° C overnight. After washing the PVDF membrane to which the antibody was hybridized with the TBST solution, the antibody (HRP (Horse Radish Peroxidase)-labeled anti-rabbit IgG) was added twice, and the mixture was incubated at room temperature for 1 hour. After washing with the TBST solution, a color developing reagent (ECL Prime Western Point Detection Reagent, GE healthcare, #RPN2232) was added, and the luminescence was detected by a detector.

Using the compound obtained in Example 4 as a test substance, Test Example 13 was carried out on Pabsini (selective CDK4/6 inhibitor; purchased from Selleck Chemicals) and European paclitaxel (purchased from Sanofi Aventis) as a control compound. The test shown in . Further, the compound obtained in Example 72 was subjected to the same test as a test substance. The results are shown in Figure 10 (the compound of Example 4) and Figure 11 (the compound of Example 72). The compounds of Example 4 and Example 72 reduced the performance level of Nanog in a concentration-dependent manner. On the other hand, Pabsini, and European paclitaxel did not affect the performance level of Nanog. Furthermore, none of the tested substances affected the performance level of β-actin.

The Nanog performance inhibitory effect was also confirmed in the same manner for the other example compounds. Further, the effect of the compound of the present invention on the functions of other stem cell genes (Sox2, β-chain protein, Oct4, etc.) can be confirmed in the same manner. The compound of Example 4 also showed an inhibitory effect on the performance of Sox2 and β-chain protein.

[Industrial availability]

The compound of the present invention is useful as a multi-kinase inhibitor for the prevention and/or treatment of diseases such as cancer which are likely to be affected by cell proliferation.

Claims (34)

A compound or a pharmacologically acceptable salt thereof, which is represented by the following formula (1), [In the formula (1), X represents a nitrogen atom or CR ⁵ ; Y represents a hydrogen atom, a C _1-6 alkyl group (the group may also be selected from a halogen atom, a hydroxyl group, a C _1-6 alkoxy group, and C _{3 - a} 1 to 3 substituent in the _10- cycloalkyl group, or a C _3-10 cycloalkyl group (the group may also be selected from a halogen atom, a hydroxyl group, a C _1-6 alkyl group, and a C _1-6 alkane group). a saturated heterocyclic ring of the same or different 1-4 in the oxy group) or a member of 3 to 8 members (the group may also be selected from a halogen atom, a hydroxyl group, a C _1-6 alkyl group, and a C _1-6 alkane) 1 to 4 substituents which are the same or different in the oxy group; R ^1a , R ^1b , R ^1c , R ^1d and R ^{1e are the} same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, C _{a 1-6} alkyl group (the group may also be substituted by the same or different one to three groups selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group), a C _1-6 alkoxy group (the group is also Substituted by the same or different 1 to 3 groups selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group, an amine group, a C _1-6 alkylamino group (the group may also be selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group of 1 to 3 identical or different substituents), C _2-12 dialkylamino group (the group may also be selected by a halogen atom, a hydroxyl And a C _1-6 alkoxy group of 1 to 6 identical or different substituents), the 3 to 6-membered cyclic amino group (the group may also be selected by a halogen atom, a hydroxyl group, C _1-6 alkyl And the same or different 1 to 4 substituents in the C _1-6 alkoxy group) or a C _1-6 alkylcarbonyl group (the group may also be selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group) 1 or 3 substituents which are the same or different); R ⁴ represents a hydrogen atom, a cyano group, a hydroxyl group, a C _1-6 alkyl group (the group may also be selected from a halogen atom, a hydroxyl group and a C _1-6 alkoxy group). The same or different 1-3 substituents or C _3-10 cycloalkyl groups (the group may also be the same or different from the halogen atom, the hydroxyl group and the C _1-6 alkoxy group) R ² , R ³ and R ^{5 are the} same or different and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C _1-6 alkyl group (the group may also be selected from a halogen atom, a hydroxyl group) , C _1-6 alkoxy and C _3-10 cycloalkyl, the same or different 1-3 substituents, C _1-6 alkoxy (this group may also be the same or different 1~3 halogen atoms), are the same or different amino, C _1-6 alkyl group (the group may also be selected by a halogen atom, a hydroxyl group and the C _1-6 alkoxy group 1 to 3 substituents), C _2-12 dialkylamino group (the group may also be selected by a halogen atom, a hydroxyl group and a C _1-6 alkoxy group in the same or different 1 to 6 substituents) a cyclic amine group of 3 to 6 members (the group may also be substituted by the same or different 1 to 4 groups selected from the group consisting of a halogen atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group) , C _1-6 alkylcarbonyl (the group may also be substituted by the same or different 1-3 halogen atoms), C _3-10 cycloalkyl (this group may also be selected from a halogen atom, a hydroxyl group, C _{1- a} saturated heterocyclic ring of 3 to 8 members, which may be the same or different from the _6- alkyl group and the C _1-6 alkoxy group (the group may also be selected from a halogen atom, a hydroxyl group, C _{1- a 1-6} alkyl group which is the same or different in a ₆ alkyl group and a C _1-6 alkoxy group), a C _6-10 aryl group (the group may also be selected from a halogen atom, a C _1-6 alkyl group and a C group) a monocyclic or polycyclic heteroaryl group of the same or different _1-4 alkoxy groups) or a 5- to 10-membered heteroaryl group (the group may also be selected from a halogen atom, C _{1 1-6} alkyl and C _1-6 alkoxy in the same or different 1 to 4 substituents); Ar represents the C _6-10 monocyclic or polycyclic aromatic group of five or ten of ~ Single or multi-ring Yl]. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein Ar is a phenyl group or a pyridyl group. A compound according to claim 1 or 2, wherein R is a phenyl group, or a pharmacologically acceptable salt thereof. The compound of any one of claims 1 to 3, wherein X is CR ⁵ ; R ⁵ is a hydrogen atom, a halogen atom or a C _1-6 alkyl group (the group may also be subjected to 1), or a pharmacologically acceptable salt thereof. ~3 fluorine atoms are substituted). The compound of any one of claims 1 to 3, wherein X is a nitrogen atom, or a pharmacologically acceptable salt thereof. The compound of any one of claims 1 to 5, wherein Y is a hydrogen atom or a C _1-6 alkyl group (the group may also be substituted with 1 to 3 fluorine atoms), or a pharmacologically acceptable salt thereof. The compound of any one of claims 1 to 6 or a pharmacologically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, a C _1-6 alkyl group (the group may also be substituted with 1 to 3 fluorine atoms) or C _3-10 cycloalkyl (this group may also be substituted with 1 to 4 fluorine atoms). The compound of any one of claims 1 to 7 or a pharmacologically acceptable salt thereof, wherein R ⁴ is a hydrogen atom, a C _1-6 alkyl group (the group may also be substituted with 1 to 3 fluorine atoms) or C _3-4 cycloalkyl group (the group may also be substituted with 1 to 4 fluorine atoms). The compound of any one of claims 1 to 8 or a pharmacologically acceptable salt thereof, wherein R ² and R ^{3 are the} same or different and are a hydrogen atom, a halogen atom or a C _1-6 alkyl group (the group may also be Replaced by 1 to 3 fluorine atoms). The compound of any one of claims 1 to 9 or a pharmacologically acceptable salt thereof, wherein R ^1a , R ^1b , R ^1c , R ^1d and R ^{1e are the} same or different and are a hydrogen atom, a halogen atom, C _{1 a -6} alkyl group (the group may also be substituted by the same or different 1-3 groups selected from a fluorine atom and a C _1-6 alkoxy group) or a C _1-6 alkoxy group (the group may also be subjected to 1) ~3 fluorine atoms are substituted). The compound of any one of claims 1 to 10, wherein R ^1a , R ^1b , R ^1c , R ^1d and R ^{1e are the} same or different and are a hydrogen atom, a halogen atom or C ₁ , or a pharmacologically acceptable salt thereof. _-6 alkyl (this group may also be substituted by 1 to 3 fluorine atoms). The requested item 1 to 11 may be permitted by the compound or a pharmacologically acceptable salt thereof, wherein R ⁴ is a C _1-6 alkyl group (the group may be substituted with 1 to 3 fluorine atoms) or cyclopropyl . A compound according to claim 1 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: (4-methyl-6-((5-methyl-1H-pyrazole-3-) (amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol, (4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2 -(), (2,4,5-trifluorophenyl)methanol, (4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) (2,3, 4-trifluorophenyl)methanol, (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,4-tri Fluorophenyl)methanol, (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl) Methanol, (4-(((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol, (3,4 -difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (3,4-difluorophenyl)(4-A -6-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (4-methyl-6-((5-methyl-1H-pyrazole) -3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol, (4-((5-methyl-1H-pyrazol-3-yl)amino) Pyrimidin-2-yl)(2,3,5-trifluorophenyl) A Alcohol, (2,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (2,4-difluorobenzene (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (4-methyl-6-((5-A) -1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,6-trifluorophenyl)methanol, (4-((5-methyl-1H-pyrazole-3) -amino)pyrimidin-2-yl)(2,4,6-trifluorophenyl)methanol, (2,3-difluorophenyl)(4-((5-methyl-1H-pyrazole) 3-yl)amino)pyrimidin-2-yl)methanol, (2,3-difluorophenyl)(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)) Amino)pyrimidin-2-yl)methanol, (4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(pentafluorophenyl)methanol, (4- Methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(pentafluorophenyl)methanol, (3,4-difluorophenyl)(5 -Fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (3,4-difluorophenyl)(5-fluoro-4-methyl -6-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (5-fluoro-4-methyl-6-((5-methyl-) 1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol, (5-fluoro-4-((5-methyl-1H-pyrazole) -3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl) Alcohol, (5-fluoro-4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) (2,3,5-trifluorophenyl) Methanol, (5-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol, (5-chloro 4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol, (5-chloro-4-methyl) 5-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol, 1-(3,4- Difluorophenyl)-1-(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)ethane-1-ol, 1-(3,4- Difluorophenyl)-1-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)ethane-1-ol, (4 -((3-ethyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol, (4-((3-cyclopropyl) -1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol, (4-((3-cyclopropyl-1H-pyrazole-5) -amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol, 1-(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino) Pyrimidine-2-yl)-1-(2,4,5-trifluorophenyl)ethane-1-ol, (4-((3-cyclopropyl-1H-pyrazol-5-yl))amine (4-pyrimidin-2-yl)(4-fluoro-3-methylphenyl)methanol, (4-chloro-3-fluorophenyl)(4-((3-cyclopropyl-1H-pyrazole-5) -amino)pyrimidin-2-yl)methanol, 1-(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidine-2 -yl)-1-(4-fluoro-3-methylphenyl)ethane-1-ol, and 1-(4-chloro-3-fluorophenyl)-1-(4-((3-ring) Propyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)ethane-1-ol. A compound according to claim 1 or a pharmacologically acceptable salt thereof, which is selected from the group consisting of: (4-methyl-6-((5-methyl-1H-pyrazole-3-) (amino)pyrimidin-2-yl)(2,4,5-trifluorophenyl)methanol, (4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine-2 -(), (2,4,5-trifluorophenyl)methanol, (4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl) (2,3, 4-trifluorophenyl)methanol, (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,3,4-tri Fluorophenyl)methanol, (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl) Methanol, (4-(((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(3,4,5-trifluorophenyl)methanol, (3,4 -difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (3,4-difluorophenyl)(4-A -6-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (4-methyl-6-((5-methyl-1H-pyrazole) -3-yl)amino)pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol, (4-((5-methyl-1H-pyrazol-3-yl)amino) Pyrimidin-2-yl)(2,3,5-trifluorophenyl)methanol, (2,4-difluorophenyl)(4-((5-methyl-1H-pyrazol-3-yl)amine base) Pyridin-2-yl)methanol, (2,4-difluorophenyl)(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl Methanol, (4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,6-trifluorophenyl)methanol, (4- ((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)(2,4,6-trifluorophenyl)methanol, (2,3-difluorophenyl) ( 4-((5-Methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, (2,3-difluorophenyl)(4-methyl-6-((5) -methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)methanol, 1-(3,4-difluorophenyl)-1-(4-methyl-6-(5 -methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)ethane-1-ol, (4-((3-ethyl-1H-pyrazol-5-yl))) Pyrimidine-2-yl)(3,4,5-trifluorophenyl)methanol, (4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl) (3,4,5-trifluorophenyl)methanol, (4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(2,4,5- Trifluorophenyl)methanol, 1-(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)-1-(2,4,5-trifluoro Phenyl)ethane-1-ol, (4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)(4-fluoro-3-methylphenyl) Methanol, (4-chloro-3-fluorophenyl)(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)methanol, 1-(4- ((3-Cyclopropyl-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)-1-(4-fluoro-3-A Phenyl)ethane-1-ol, and 1-(4-chloro-3-fluorophenyl)-1-(4-((3-cyclopropyl-1H-pyrazol-5-yl)amino) Pyrimidin-2-yl)ethane-1-ol. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt thereof. A kinase inhibitor comprising the compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt thereof as an active ingredient. An anticancer agent containing the compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt thereof as an active ingredient. The anticancer agent according to claim 17, wherein the cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer, pancreatic cancer, stomach cancer, flesh Tumor, myeloma, or blood cancer. A method for the treatment and/or prevention of cancer comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt thereof to a patient in need of treatment. The method for treating and/or preventing according to claim 19, wherein the cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer, Pancreatic cancer, gastric cancer, osteosarcoma, myeloma, or blood cancer. A use of a compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt thereof, for the manufacture of a therapeutic and/or prophylactic agent for cancer. The use of claim 21, wherein the cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer, pancreatic cancer, gastric cancer, osteosarcoma, Myeloma, or blood cancer. A compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt thereof, for use in the treatment and/or prevention of cancer. The compound of claim 23, or a pharmacologically acceptable salt thereof, wherein the cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor, endometrial cancer , pancreatic cancer, stomach cancer, osteosarcoma, bone marrow Tumor, or blood cancer. The anticancer agent according to claim 17 or 18, which has an inhibitory effect on the expression of a stem cell gene. The anticancer agent according to claim 25, wherein the stem cell gene is any one selected from the group consisting of Nanog, Sox2, β-chain protein, and Oct4. The anticancer agent according to claim 25, wherein the stem cell gene is Nanog. An expression inhibitor of a stem cell gene, which comprises the compound of any one of claims 1 to 14 or a pharmacologically acceptable salt thereof as an active ingredient. An anticancer agent containing a compound which inhibits three or more kinases. The anticancer agent according to claim 29, wherein the kinase system is selected from the group consisting of CDK2, CDK5, JAK2, AURKA, AURKB and CDK1. An anticancer agent comprising a compound which blocks two or more kinases selected from the group consisting of CDK2, CDK5 and JAK2. A method of treating cancer comprising inhibiting three or more kinases. A method of treating cancer comprising inhibiting the performance of a stem cell gene. A method for inhibiting the expression of a stem cell gene, which comprises blocking CDK5.