WO2016195083A1

WO2016195083A1 - Novel heteroarylamino-3-pyrazole derivatives and pharmacologically acceptable salts thereof

Info

Publication number: WO2016195083A1
Application number: PCT/JP2016/066617
Authority: WO
Inventors: 誠治堀; 太志長谷川; 慎也戸▲崎▼; 雄介今▲崎▼; 智哉柄澤; 博之上野; 裕太松村; チャンチアリー
Original assignee: 大日本住友製薬株式会社
Priority date: 2015-06-05
Filing date: 2016-06-03
Publication date: 2016-12-08
Also published as: TW201704227A; JP2018135268A

Abstract

Provided are highly safe compounds having reduced side effects including compounds represented by formula (1): [in formula (1), X indicates a nitrogen atom or CR⁵, Y indicates a hydrogen atom, C_1-6 alkyl, or the like, Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄ, and R^1e are the same or different and indicate a hydrogen atom, halogen atom, hydroxy, or the like, R⁴ indicates a hydrogen atom, cyano, C_1-6 alkyl, or the like, R², R³, and R⁵ are the same or different and indicate a hydrogen atom, halogen atom, hydroxy, C_1-6 alkyl, or the like, Ar indicates a C_6-10 monocyclic or polycyclic aryl or 5-membered to 10-membered monocyclic or polycyclic heteroaryl] or a pharmacologically acceptable salt thereof that actualize an antitumor effect by inhibiting multiple kinases and signals such as ＣＤＫ１、ＣＤＫ２、ＣＤＫ５、ＡＵＲＫＡ、ＡＵＲＫＢ、and ＪＡＫ２ necessary for the cell cycle, cell proliferation, or survival of cancer stem cells.

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, the present invention relates to a heteroarylamino-3-pyrazole derivative and a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the derivative or a salt thereof, and a therapeutic agent for a pathological condition involving a kinase containing the composition. .

In the process of normal somatic cells becoming cancerous, abnormal cell division control is known as one of the fundamental features. Cell division is divided into four cycles, which are G1 phase, S phase, G2 phase, and mitosis (M) phase, and different proteins are involved in the control of that phase.

Many of the currently used anticancer agents involved in the control of cell division inhibit the activity of proteins involved in one or more of these cell cycles, and their clinical effectiveness varies. Proven by research. On the other hand, it is reported that many of the current anticancer agents related to cell division control exhibit various side effects whose cause is not clear in addition to side effects derived from the inhibition mechanism. Therefore, anticancer drugs cannot be administered sufficiently, and there are cases where treatment limits have occurred. For these reasons, creation of an anticancer agent having an excellent therapeutic effect and few side effects is desired.

In cell cycle control, cyclin-dependent kinase (CDK) synchronizes with its regulatory subunit, cyclin, and progresses through the four stages of G1, S, G2, and M phases. To control. At least 13 types of CDK are known in mammalian cells, and among these, CDK1 (CDC2), CDK2, CDK3, CDK4 and CDK6 have been shown to be involved in cell cycle progression. In addition, although all CDKs are involved in the transition from G1 phase to S phase, CDK1 and CDK2 form a complex with cyclin E or cyclin A, respectively, and the transition from G1 phase to S phase or from S phase, respectively. It plays an essential role in the transition to G2.
In mitosis, it has been shown that in addition to CDK1, a small number of specific kinases control a complex series of mitosis. Serine and threonine kinases have been shown to play an important role as a small number of specific kinases (Non-Patent Document 1). Among them, Aurora kinase is a chromosome with high fidelity. Is known to be controlled so as to be distributed to daughter cells (Non-patent Document 2). Three types of Aurora kinases are known in mammalian cells, and of these, at least AURKA (Aurora kinase-A) and AURKB (Aurora kinase-B) are known to be involved in chromosome separation and cytoplasm separation. ing.
There is a report that CDK5 plays an important role in the development of nerves and the formation of brain functions (Non-patent Document 3). In addition, there are reports that CDK5 is related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Non-patent document 4), and a report that suggests an association with cancer (Non-patent document 5).

It has been reported that inhibition of the functions of CDK and Aurora kinase promotes suppression of cell cycle progression, suppression of cell proliferation, apoptosis, differentiation and aging, and exhibits antitumor action. In addition, CDK1, cyclin A, cyclin E, AURKA and AURKB are overexpressed in many human solid cancers and blood cancers, and their expression and activity are reported to correlate with poor prognosis (non-patent) Therefore, it is considered that the utility value of a low molecular weight compound targeting CDK or Aurora as an anti-cancer agent is high because of Reference 6, Non-Patent Document 7, Non-Patent Document 8, Non-Patent Document 9, and Non-Patent Document 10).

On the other hand, the presence of cancer stem cells has been reported in some cancers such as blood cancer, brain tumor, colon cancer, and breast cancer. Cancer stem cells are defined as a small number of cancer cells constituting cancer that have stem cell-like properties and high tumor-forming ability. Moreover, it may be called Tumor (Cancer) -Initiating Cell from a viewpoint of the main cause of malignant transformation of cancer. In recent years, the role of specific kinase signals in cancer stem cells has been elucidated (Non-patent Document 11). For example, the JAK2 / STAT3 signal is necessary for the survival of cancer stem cells in breast cancer and prostate cancer (Non-patent Document 12), and the TGF-beta signal is activated in cancer stem cells of breast cancer that are resistant to chemotherapy. (Non-Patent Document 13).
In addition, Myc, known as a proto-oncogene, is considered to be one of the main causes of cancer malignancy, and it is known that the prognosis of breast cancer patients whose Myc signal is activated is extremely poor. Furthermore, from the search for target molecules that induce synthetic lethality using cancer cell lines in which the Myc signal is constitutive, CDK1, CDK2, AURKA and AURKB inhibitors are used to suppress the growth of cancer cells that depend on the Myc signal and to selectively It is considered effective in inducing cell death (Non-Patent Document 14).

So far, as the arylaminopyrazole derivatives, for example, the following compounds have been disclosed in Patent Document 1.

[Wherein Z ¹ or Z ² represents a nitrogen atom, Q is —S— or the like, R ^x and R ^y are —T—R ³ , —L—Z—R ³ , and R ¹ Is —T— (D ring) [D ring is a 5- to 7-membered monocycle, etc.], T is a valence bond, etc., Z is a C _1-4 alkylidene chain, etc. L is —O—, R ² and R ^{2 ′} are —R, —T—W—R ^{6 and the} like, R ³ is —R, etc., R is a hydrogen atom, etc. W is —C (R ⁶ ) ₂ O— or the like, and R ⁶ is a hydrogen atom or the like. ]

Further, for example, the following compound is disclosed in Patent Document 2.

[Wherein, K is NH, O, S or the like, A is aryl or the like, m is 0 or the like, X is O or S, and R ¹ is a hydrogen atom or the like] , R ² is amino or the like, R ³ is aryloxy or the like, and R ⁴ is alkyl or the like. ]

Further, for example, the following compounds are disclosed in Patent Document 3.

[Wherein R ¹ is a hydrogen atom, R ² is a hydroxyl group, R ³ is an alkyl, R ⁴ is a hydrogen atom, etc., and R ⁵ is a hydrogen atom, etc. , R ⁶ is halogen or the like, R ⁷ is halogen or the like, n is 0 to 4, and p is 0 to 5. ]

Further, for example, the following compound is disclosed in Patent Document 4.

However,

Patent Documents

1, 2, 3 and 4 do not disclose any compounds represented by the formula (1) of the present invention.

International Publication No. 2002/066641 International Publication No. 2013/033862 International Publication No. 2010/099379 International Publication No. 2013/130600

The problem to be solved by the present invention is to inhibit a plurality of kinases and signals selected from CDK1, CDK2, AURKA, AURKB, JAK2, CDK5 and the like necessary for cell cycle, cell proliferation or cancer stem cell survival as described above. Thus, it is to provide a highly safe compound that exhibits an anticancer effect and has reduced side effects. Another object of the present invention is to provide a highly safe compound that exerts cancer stem cell control action by inhibiting kinase and has reduced side effects.

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 sometimes referred to as “the compound of the present invention”) is CDK1, CDK2. , AURKA, AURKB, JAK2, CDK5, etc., have high inhibitory action on kinases selected from ARKKA, AURKB, JAK2, CDK5, etc. . In addition, among the preferred compounds of the present invention, it is confirmed that the compound has a PK profile based on suitable solubility and metabolic stability and / or weak cardiotoxicity and weak toxicity to normal cells. It came to complete.

That is, the present invention is as follows.

[Claim 1]
Formula (1):

[In Formula (1),
X represents a nitrogen atom or CR ⁵ ;
Y is a hydrogen atom, C _1-6 alkyl (the group is substituted with the same or different 1 to 3 groups selected from a halogen atom, hydroxy, C _1-6 alkoxy and C _3-10 cycloalkyl) C _3-10 cycloalkyl (which is substituted with 1 to 4 groups identical or different selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy). Or a 3- to 8-membered saturated heterocyclic ring (the group is substituted with the same or different 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) May be)
R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are the same or different and each represents a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, C _1-6 alkyl (the group is a halogen atom, hydroxy and C ₁ Optionally substituted with 1 to 3 identical or different groups selected from _-6 alkoxy), C _1-6 alkoxy (the same selected from halogen atom, hydroxy and C _1-6 alkoxy) Or optionally substituted with 1 to 3 different groups), amino, C _1-6 alkylamino (the group is the same or different 1 to 3 selected from halogen atom, hydroxy and C _1-6 alkoxy) ), C _2-12 dialkylamino (which is selected from halogen atoms, hydroxy and C _1-6 alkoxy) 3 to 6-membered cyclic amino (which is selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy), which may be substituted with the same or different 1-6 groups. Or a C _1-6 alkylcarbonyl (the group may be the same or different 1-3 selected from halogen atom, hydroxy and C _1-6 alkoxy). Which may be substituted with
R ⁴ represents a hydrogen atom, cyano, hydroxy, C _1-6 alkyl (the group may be substituted with the same or different 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy) Or a C _3-10 cycloalkyl, which group may be substituted with 1 to 4 groups identical or different selected from a halogen atom, hydroxy and C _1-6 alkoxy;
R ² , R ³ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, C _1-6 alkyl (the group is a halogen atom, hydroxy, C _1-6 alkoxy and C _{3 -10} may be substituted with the same or different 1 to 3 groups selected from cycloalkyl), C _1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms which are the same or different May be substituted with the same or different 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy), amino, C _1-6 alkylamino, C _2-12 dialkylamino (in which the halogen atom, optionally substituted by the same or different 1-6 groups selected from hydroxy and C _1-6 alkoxy ), 3 cyclic amino (base to 6-membered, halogen atom, hydroxy, optionally substituted by the same or different 1 to 4 groups selected from C _1-6 alkyl and C _1-6 alkoxy ), C _1-6 alkylcarbonyl (the group may be substituted with the same or different 1 to 3 halogen atoms), C _3-10 cycloalkyl (the group is a halogen atom, hydroxy, C ₁ 3 to 8 membered saturated heterocyclic ring (which may be substituted with the same or different 1 to 4 groups selected from _-6 alkyl and C _1-6 alkoxy), which is a halogen atom, hydroxy, Optionally substituted with 1 to 4 identical or different groups selected from C _1-6 alkyl and C _1-6 alkoxy), C _6-10 aryl (the group is a halogen atom, C _1-6 Archi And the same or different one to four monocyclic or heteroaryl (substrate polycyclic which may also be) or a 5- to 10-membered optionally substituted with a group selected from C _1-6 alkoxy, halogen And optionally substituted with 1-4 identical or different groups selected from atoms, C _1-6 alkyl and C _1-6 alkoxy;
Ar represents C _6-10 monocyclic or polycyclic aryl or 5- to 10-membered monocyclic or polycyclic heteroaryl]
Or a pharmacologically acceptable salt thereof.

[Section 2]
Item 2. The compound according to Item 1 or a pharmacologically acceptable salt thereof, wherein Ar is phenyl or pyridyl.

[Section 3]
Item 3. The compound or pharmacologically acceptable salt thereof according to

Item

1 or 2, wherein Ar is phenyl.

[Claim 4]
X is CR ⁵ ;
Item 4. The compound according to any one of Items 1 to 3, wherein R ⁵ is a hydrogen atom, a halogen atom, or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or Its pharmacologically acceptable salt.

[Section 5]
Item 4. The compound or a pharmacologically acceptable salt thereof according to any one of Items 1 to 3, wherein X is a nitrogen atom.

[Claim 6]
Item 6. The compound according to any one of Items 1 to 5, wherein Y is a hydrogen atom or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or a pharmacologically thereof Acceptable salt.

[Claim 7]
R ⁴ is a hydrogen atom, C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or C _3-10 cycloalkyl (the group is substituted with 1 to 4 fluorine atoms). Item 7. The compound or a pharmacologically acceptable salt thereof according to any one of Items 1 to 6, which may be substituted with an atom.
[Section 8]
R ⁴ is a hydrogen atom, C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or C _3-4 cycloalkyl (the group is substituted with 1 to 4 fluorine atoms). Item 8. The compound or a pharmacologically acceptable salt thereof according to any one of Items 1 to 7, which may be substituted with an atom.

[Claim 9]
R ² and R ³ are the same or different and are a hydrogen atom, a halogen atom or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms), The compound according to any one of the above or a pharmacologically acceptable salt thereof.

[Section 10]
R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are the same or different and are each a hydrogen atom, a halogen atom or C _1-6 alkyl (the same group selected from a fluorine atom and C _1-6 alkoxy) Or any one of items 1 to 9 which may be substituted with 1 to 3 different groups) or C _1-6 alkoxy (the group may be substituted with 1 to 3 fluorine atoms) Or a pharmacologically acceptable salt thereof.

[Section 11]
R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are the same or different and each represents a hydrogen atom, a halogen atom or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) The compound according to any one of Items 1 to 10 or a pharmacologically acceptable salt thereof.

[Claim 12]
Item 12. The compound or drug according to any one of Items 1 to 11, wherein R ⁴ is C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or cyclopropyl. A scientifically acceptable salt.

[Claim 13]
Item 13. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 12, wherein at least one of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e is a halogen atom.

[Section 14]
Item 14. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 13, wherein at least two of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are halogen atoms.

[Section 15]
Item 15. The compound or a pharmacologically acceptable salt thereof according to any one of Items 1 to 14, wherein at least two of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are fluorine atoms.

[Section 16]
The following compound groups:
(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl) 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 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-pyrazol-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) 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-methyl-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) amino) pyrimidin-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) 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 [Examples] 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) ethan-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 2. The compound according to Item 1, which is a compound selected from: or a pharmacologically acceptable salt thereof.

[Section 17]
The following compound groups:
(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl) 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 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-pyrazol-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) amino) pyrimidin-2-yl) methanol [Example 35],
(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) 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 [Examples] 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) ethan-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 2. The compound according to Item 1, which is a compound selected from: or a pharmacologically acceptable salt thereof.

[Section 18]
Item 53. A pharmaceutical composition comprising the compound according to any one of Items 1 to 17 or Item 52 or a pharmaceutically acceptable salt thereof.

[Section 19]
53. A kinase inhibitor comprising the compound according to any one of Items 1 to 17 or 52 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Section 20]
Item 53. An anticancer agent comprising the compound according to any one of Items 1 to 17 or Item 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[Claim 21]
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. The anticancer agent as described in.

[Item 22]
Treating and / or treating cancer comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of Items 1-17 or 52 or a pharmaceutically acceptable salt thereof. Or a way to prevent.

[Section 23]
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, pancreatic cancer, gastric cancer, osteosarcoma, myeloma, or blood cancer. A method for the treatment and / or prevention according to 1.

[Claim 24]
Item 53. Use of the compound according to any one of Items 1 to 17 or Item 52 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for cancer.

[Claim 25]
Item 24. The cancer is breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain cancer, endometrial cancer, pancreatic cancer, gastric cancer, osteosarcoma, myeloma, or blood cancer. Use as described in.

[Claim 26]
53. The compound or a pharmacologically acceptable salt thereof according to any one of Items 1 to 17 or Item 52 for use in the treatment and / or prevention of cancer.

[Section 27]
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 26. A pharmacologically acceptable salt thereof.

[Claim 28]
Item 20. The anticancer agent according to Item 20, wherein the cancer is blood cancer, myeloma, liver cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma, colon cancer, breast cancer, skin cancer or epithelial cell cancer, 27. A method for preventing, a use according to Item 24, or a compound according to Item 26 or a pharmacologically acceptable salt thereof.

[Item 29]
Item 53. A cell cycle arrester comprising the compound according to any one of Items 1 to 17 or Item 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[Section 30]
Item 53. A cancer stem cell growth inhibitor comprising the compound according to any one of Items 1 to 17 or Item 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[Claim 31]
Item 22. The anticancer agent according to Item 20 or Item 21, which has a stemness gene expression inhibitory action.

[Section 32]
Item 32. The anticancer agent according to Item 31, wherein the stemness gene is any one selected from the group consisting of Nanog, Sox2, b-catenin and Oct4.

[Section 33]
Item 32. The anticancer agent according to Item 31, wherein the stemness gene is Nanog.

[Section 34]
Item 53. A stemness gene expression inhibitor comprising the compound according to any one of Items 1 to 17 or Item 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[Claim 35]
An anticancer agent comprising a compound that inhibits three or more kinases.

[Claim 36]
Item 36. The anticancer agent according to Item 35, wherein the kinase is selected from the group consisting of CDK2, CDK5, JAK2, AURKA, AURKB, and CDK1.

[Section 37]
An anticancer agent comprising a compound that inhibits two or more kinases selected from the group consisting of CDK2, CDK5 and JAK2.

[Section 38]
An anticancer agent comprising a compound that inhibits all of CDK2, CDK5, and JAK2.

[Section 39]
A method of treating cancer comprising inhibiting three or more kinases.

[Claim 40]
40. The method according to Item 39, wherein the kinase is selected from the group consisting of CDK2, CDK5, JAK2, AURKA, AURKB, and CDK1.

[Section 41]
A method for treating cancer, comprising inhibiting two or more kinases selected from the group consisting of CDK2, CDK5 and JAK2.

[Section 42]
A method for treating cancer, comprising inhibiting all of CDK2, CDK5 and JAK2.

[Section 43]
A method for treating cancer, comprising suppressing the expression of a stemness gene.

[Item 44]
A method for suppressing the expression of a stemness gene, comprising inhibiting CDK5.

[Section 45]
Item 51. A therapeutic agent for cancer having resistance to treatment with a chemotherapeutic agent, comprising the compound according to any one of Items 1 to 17 or Item 52 or a pharmacologically acceptable salt thereof as an active ingredient.

[Claim 46]
Item 46. The therapeutic agent according to Item 45, wherein the chemotherapeutic agent is a taxane anticancer agent.

[Section 47]
Item 22. The anticancer agent according to Item 20 or Item 21, which has a cell cycle arresting action.

[Section 48]
Item 48. The anticancer agent according to any one of Item 20, Item 21, or Item 47, which has an effect of inhibiting the growth of cancer stem cells.

[Item 49]
Item 49. The anticancer agent according to any one of Items 20 to 21 or 47 to 48, which also has an effect of preventing cancer recurrence.

[Section 50]
Item 52. The anticancer agent according to any one of Items 20 to 21 or 47 to 49, which also has a cancer metastasis suppressing effect.

[Section 51]
A method for suppressing the expression of a stemness gene, comprising inhibiting two or more kinases selected from the group consisting of CDK2, CDK5 and JAK2.

[Section 52]
The following compound groups:
(−)-(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-pyrazol-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) methanol [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-yl} (2,3,4-trifluorophenyl) methanol [Examples] 31]
Item 2. The compound according to Item 1, which is a compound selected from: or a pharmacologically acceptable salt thereof.

[Section 53]
Item 1-17 or Item 52 or a pharmacologically acceptable salt thereof, and (1) a hormonal therapeutic agent, (2) a chemotherapeutic agent, (3) an immunotherapeutic agent, and ( 4) A pharmaceutical composition comprising one or more drugs selected from the group consisting of cell growth factors or drugs that inhibit cell growth factor receptor action.

[Section 54]
(1) a hormonal therapeutic agent, (2) a chemotherapeutic agent, (3) an immunizing 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 A therapeutic agent, and (4) an anticancer agent for use in combination with one or more drugs selected from the group consisting of cell growth factors or drugs that inhibit cell growth factor receptor action.

[Section 55]
A therapeutically effective amount of the compound according to any one of Items 1 to 17 or Item 52 or a pharmacologically acceptable salt thereof, and (1) a hormonal therapeutic agent, and (2) Cancer, comprising administering both a chemotherapeutic agent, (3) an immunotherapeutic agent, and (4) a cell growth factor or one or more agents selected from the group consisting of agents that inhibit the receptor action of cell growth factor For the treatment and / or prevention.

The compound represented by the formula (1), or a pharmacologically acceptable salt thereof (sometimes referred to as the compound of the present invention) may be combined with CDK1, CDK2, CDK5, JAK2, AURKA or AURKB, or other kinases. By having an excellent inhibitory effect on the interaction, it can be applied to the prevention and treatment of various symptoms involving kinases such as cancer diseases. In addition, since cardiotoxicity and toxicity to normal cells are weak, it can be applied to the prevention and treatment of various diseases involving kinases as an anticancer agent having particularly excellent therapeutic effects and few side effects.

2 is a chart of a powder X-ray diffraction pattern of the compound of Example 89. 2 is a DSC-TGA chart of the compound of Example 89. 6 is a three-dimensional structure diagram obtained by X-ray crystal analysis of the crystal obtained in Example 90. FIG. 2 is a chart of a powder X-ray diffraction pattern of the compound of Example 91. 2 is a DSC-TGA chart of the compound of Example 91. About the compound obtained in Example 4, the measurement result of the tumor diameter which performed the test shown in Test example 7 is represented. The vertical axis shows the change in tumor volume. The horizontal axis shows the number of days after tumor transplantation. The plot and error bar show the mean and standard error of the tumor volume, respectively. # Indicates the result of a significant difference test (p <0.05, Dunnett's test). About the compound obtained in Example 4, the measurement result of the body weight which performed the test shown in Test example 7 is represented. The vertical axis shows the change in body weight. The horizontal axis shows the number of days after tumor transplantation. The plot and error bar show the mean weight value and standard error, respectively. # Indicates the result of a significant difference test (p <0.05, Students t-test). About the compound obtained in Example 4, the measurement result of the tumor diameter which performed the test shown in Test example 8 is represented. The vertical axis shows the change in tumor volume. The horizontal axis shows the number of days after tumor transplantation. The plot and error bar show the mean and standard error of the tumor volume, respectively. # Indicates the result of a significant difference test (p <0.025, Williams' test). About the compound obtained in Example 4, the measurement result of the body weight which performed the test shown in Test example 8 is represented. The vertical axis shows the change in body weight. The horizontal axis shows the number of days after tumor transplantation. The plot and error bar show the mean weight value and standard error, respectively. # Indicates the result of a significant difference test (p <0.025, Williams' test). About the compound obtained in Example 4, the result of the Nanog expression level which performed the test shown in Test example 13 is shown. In addition, the results of the control compounds Palbociclib and Docetaxel are also shown. About the compound obtained in Example 72, the result of the Nanog expression level which performed the test shown in Test example 13 is shown.

The present invention is described in further detail below.
In the present specification, a group defined as “optionally substituted” is an unsubstituted or substituted group, and the number of substituents in the group is the number of substituents unless otherwise specified. There is no restriction | limiting in particular and it is one or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably they are a fluorine atom or a chlorine atom, More preferably, it is a fluorine atom.

“C _1-6 alkyl” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Specific examples include, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, 3-methylbutyl, 2-methylbutyl, 2,2 -Dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl and the like. Preferable “C _1-6 alkyl” includes C _1-4 alkyl and the like, more preferably C _1-3 alkyl.
Specific examples of “C _1-4 alkyl” include methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl having 1 to 4 carbon atoms in the specific example of “C _1-6 alkyl”. , 1-methylpropyl, 1,1-dimethylethyl and the like. Specific examples of “C _1-3 alkyl” include methyl, ethyl, propyl, 1-methylethyl and the like having 1 to 3 carbon atoms in the specific example of “C _1-6 alkyl”.
In this document, for example, C _1-6 has 1 to 6 carbon atoms, C _1-4 has 1 to 4 carbon atoms, and C _1-3 has 1 to 3 carbon atoms. Yes, or C ₆ represents 6 carbon atoms. The same applies to other numbers.

“C _3-10 cycloalkyl” means a cyclic alkyl having 3 to 10 carbon atoms, and includes a partially crosslinked structure. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl and the like. Preferred “C _3-10 cycloalkyl” includes C _3-8 cycloalkyl, more preferably C _3-6 cycloalkyl.
“C _3-8 cycloalkyl” means a cyclic alkyl of 3 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl having 3 to 8 carbon atoms in the specific example of “C _3-10 cycloalkyl”.
“C _3-6 cycloalkyl” means a cyclic alkyl of 3 to 6 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like having 3 to 6 carbon atoms in the specific example of “C _3-10 cycloalkyl”.

“C _1-6 alkoxy” means “C _1-6 alkyloxy”, and the “C _1-6 alkyl” moiety is as defined above for “C _1-6 alkyl”. Specific examples include, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy, 1,1-dimethylethoxy, pentyloxy group, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1,1-dimethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethyl Examples include butoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy and the like. Preferred “C _1-6 alkoxy” includes C _1-4 alkoxy.
Specific examples of “C _1-4 alkoxy” include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy having 1 to 4 carbon atoms in the specific example of “C _1-6 alkoxy”.

_{"C 1-6} alkyl" moiety in _{"C 1-6} alkylcarbonyl" is synonymous with _{"C 1-6} alkyl" of the. Specific examples of “C _1-6 alkylcarbonyl” include, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 2-methylpropylcarbonyl, 1-methylpropylcarbonyl, 1,1- And dimethylethylcarbonyl. Preferred “C _1-6 alkylcarbonyl” includes C _1-4 alkylcarbonyl.
Specific examples of “C _1-4 alkylcarbonyl” include, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 2-methylpropylcarbonyl and the like.

_{"C 1-6} alkyl" moiety in _{"C 1-6} alkylamino" is the same as defined in the _{"C 1-6} alkyl". Specific examples of “C _1-6 alkylamino” include, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino and the like. Preferred “C _1-6 alkylamino” includes “C _1-4 alkylamino”.
Specific examples of the "C _1-4 alkylamino", "C _1-6 alkylamino" methylamino carbon atoms is of 1 to 4 in the specific example of, ethylamino, propylamino, isopropylamino, butylamino, etc. Is mentioned.

“C _2-12 dialkylamino” means “amino in which two identical or different C _1-6 alkyls are bonded”, and the C _1-6 alkyl is as defined above. Specific examples of “C _2-12 alkylamino” include, for example, dimethylamino, diethylamino, ethylmethylamino, methylpropylamino, ethylpropylamino, dipropylamino, isopropylmethylamino, isopropylethylamino, diisopropylamino, methylbutyl Examples include amino, ethylbutylamino, dibutylamino, diisobutylamino, ditert-butylamino, dipentylamino, dihexylamino and the like. Preferred “C _2-12 dialkylamino” includes “C _2-8 dialkylamino”.
Specific examples of “C _2-8 dialkylamino” include, for example, dimethylamino, diethylamino, ethylmethylamino, methylpropylamino, ethylpropylamino, dipropylamino, isopropylmethylamino, isopropylethylamino, diisopropylamino, methylbutyl Amino, ethylbutylamino, dibutylamino, diisobutylamino, ditert-butylamino and the like can be mentioned.

“3- to 6-membered cyclic amino” includes 3- to 6-membered monocyclic cyclic amino containing at least one nitrogen atom. The “3- to 6-membered cyclic amino” may further have one same or different heteroatom selected from a nitrogen atom, an oxygen atom or a sulfur atom. The bond of the group is a nitrogen atom constituting the ring in “3- to 6-membered cyclic amino”. The group also includes a cyclic amino in which a part of the ring contains an unsaturated bond. Specific examples of the “3- to 6-membered cyclic amino” include aziridino, azetidino, pyrrolidino, imidazolidino, oxazolidino, thiazolidino, piperazino, piperidino, morpholino, thiomorpholino, tetrahydropyridino and the like. Preferable “3- to 6-membered cyclic amino” includes “5- to 6-membered cyclic amino”.
Specific examples of “5-membered cyclic amino” include pyrrolidino, imidazolidino, oxazolidino, thiazolidino, piperazino, piperidino, morpholino, thiomorpholino, tetrahydropyridino and the like.

“3- to 6-membered cyclic amino” and “5- or 6-membered cyclic amino” form a fused ring with C _3-6 cycloalkyl, 6-membered aryl or 5- or 6-membered heteroaryl. Also good. Specific examples of the condensed ring include “group” represented by the following.

“3- to 8-membered saturated heterocyclic ring” means 3 to 8 atoms including 1 to 2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. It means a monocyclic or bicyclic saturated heterocyclic ring. The group may be partially crosslinked or spirolated. The group may be condensed with C _6-10 aryl or C _5-10 heteroaryl. In this group, the nitrogen atom constituting the ring is not a bond of the “group”. That is, the group does not include concepts such as 1-pyrrolidino. Specific examples include azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran group and the like. Preferable “3- to 8-membered saturated heterocycle” includes monocyclic 5- to 6-membered saturated heterocyclic groups (“5- to 6-membered monocyclic saturated heterocycle”).
Specific examples of “5- to 6-membered monocyclic saturated heterocycle” include pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, which are monocyclic 5- to 6-membered in the specific example of “3- to 8-membered saturated heterocycle” , Tetrahydropyran and the like.

“C _6-10 monocyclic or polycyclic aryl” means an aromatic hydrocarbon having 6 to 10 carbon atoms. Specific examples include phenyl, 1-naphthyl, 2-naphthyl group and the like. Preferably, phenyl is used.
The group may be C _4-6 cycloalkyl, or a 5- to 6-membered heterocyclic group having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom. . The bond of the group is a carbon atom constituting the ring in “C _6-10 monocyclic or polycyclic aryl”. Specific examples include groups represented by the following.

The term “5- to 10-membered monocyclic or polycyclic heteroaryl” refers to monocyclic 5 containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Means a 6-membered aromatic heterocyclic group or a bicyclic 8- to 10-membered aromatic heterocyclic group. Specific examples include, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, indrylyl, , Quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, or 6,11-dihydrodibenzo [b, e] thiepinyl Is mentioned. Preferable “5- to 10-membered monocyclic or polycyclic heteroaryl” includes 5- to 6-membered monocyclic heteroaryl.
Specific examples of the 5- to 6-membered monocyclic heteroaryl include monocyclic examples in the specific examples of “5- to 10-membered monocyclic or polycyclic heteroaryl”.
More preferably, a 5- to 6-membered monocyclic aromatic heterocyclic ring having one or more nitrogen atoms in the ring is used. Specific examples include pyridyl, pyrimidinyl and the like, and more preferably pyridyl.

The compounds of the present invention may have some or all atoms of isotopes (eg, D, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ³⁵ S, ¹⁸ F, ¹²⁵ I Etc.), and these compounds are also included in the compounds of the present invention.

The preferred embodiment of the present invention will be further described.

Preferred R ^1a , R ^1b , R ^1c , R ^1d , R ^1e , R ² , R ³ , R ⁴ , R ⁵ , X, Y and Ar in the compound represented by the formula (1) are shown below. The technical scope of the invention is not limited thereto.

The pyrazole moiety of the compound represented by the formula (1) can take tautomers such as the following formulas (1a) and (1b), and all tautomers are included in the compound of the present invention. .

“X” is preferably a nitrogen atom or CR ⁵ . More preferably, a nitrogen atom is mentioned.

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

“R ^1a ”, “R ^1b ”, “R ^1c ”, “R ^1d ” or “R ^1e ” are preferably the same or different and each represents a hydrogen atom, a halogen atom, C _1-6 alkyl (the group is fluorine Optionally substituted with the same or different 1 to 3 groups selected from an atom and C _1-6 alkoxy) or C _1-6 alkoxy (the group is substituted with 1 to 3 fluorine atoms) May be included). More preferably, they are the same or different and include a hydrogen atom, a halogen atom or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms). Even more preferably, a hydrogen atom or a halogen atom is the same or different.

“R ² ” and “R ³ ” are preferably the same or different and each represents a hydrogen atom, a halogen atom or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms). Can be mentioned.

“R ⁴ ” is preferably a hydrogen atom, C _1-6 alkyl (optionally substituted with 1 to 3 fluorine atoms) or C _3-10 cycloalkyl (substituted with 1 to 4 fluorine atoms). May be included). More preferable examples include C _1-6 alkyl (which may be substituted with 1 to 3 fluorine atoms) and C _3-6 cycloalkyl (which may be substituted with 1 to 4 fluorine atoms). It is done. Even more preferred are C _1-3 alkyl ( _optionally substituted with 1 to 3 fluorine atoms) and cyclopropyl.

“R ⁵ ” is preferably a hydrogen atom, a halogen atom, or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms or C _1-6 alkoxy). More preferable examples include a hydrogen atom and C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms). Even more preferred is a hydrogen atom.

“Ar” is preferably phenyl or pyridyl. More preferably, phenyl is mentioned.

“Pharmaceutically acceptable salts” include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, acetate, formic acid Salt, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and other organic acid salts. Inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, or organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, diisopropylammonium salt, and the like, and arginine And amino acid salts such as basic or acidic amino acids such as aspartic acid and glutamic acid.

When it is desired to obtain the compound of the present invention as a salt, it can be purified as it is when the compound of the present invention is obtained in a salt form. When the compound of the present invention is obtained in a free form, an appropriate organic solvent can be used. It may be dissolved or suspended in the solution, and an acid or base may be added to form a salt by a conventional method.
The compound of the present invention may exist in the form of an adduct (hydrate, solvate) with water or various solvents, and these adducts are also included in the present invention. Furthermore, the present invention also includes all tautomers of the compounds of the present invention and crystal forms of all embodiments.

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

In the present specification, the term “prodrug of the compound represented by formula (1)” is a compound that is converted into a compound represented by formula (1) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo. For example, it means a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. and converted to a compound represented by formula (1).

The compound of the present invention includes compounds having one or more asymmetric carbon atoms in the molecule. Accordingly, the compound of the present invention includes optical isomers, racemates, diastereomers and the like. The compounds of the present invention also include cis-trans isomers, isomers resulting from axial asymmetry, and the like. As described above, the compound of the present invention includes all isomers and mixtures thereof.

Examples of the kinase in which the compound of the present invention exhibits inhibitory activity include various tyrosine kinases, various serine kinases, and various threonine kinases. CDK1, CDK2, CDK5, AURKA, AURKB, JAK2 and the like are preferable.

Hereinafter, the method for producing the compound represented by the formula (1) or a pharmacologically acceptable salt thereof will be described by way of example, but the present invention is not limited thereto.

The compound of the present invention can be produced from a known compound by appropriately combining, for example, the following production method and a method analogous thereto, or a synthesis method well known to those skilled in the art.

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

[Wherein LG and LG ′ are the same or different and each represents a leaving group such as a halogen atom, methanesulfonyloxy, p-toluenesulfonic acid oxy or trifluoromethanesulfonic acid oxy, phenoxy, trifluorophenoxy, Tetrafluorophenoxy, pentafluorophenoxy, nitrophenoxy and the like can be mentioned. The other definitions are the same as those described in item 1. ]

Production method 1 of compound represented by formula (A-3)
Step 1:
Step 1-1:
Synthesizing a compound of formula (A-3) by reacting a compound of formula (A-2) wherein X is a nitrogen atom with a compound of formula (A-1) in the presence of a base, if necessary. Can do. The base is not particularly limited. For example, triethylamine, diisopropylethylamine, tributylamine, 1.5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4. 0] Organic bases such as undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM), or sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, hydroxide Examples include inorganic bases such as sodium and potassium hydroxide.
The solvent should just be a solvent which does not react on the reaction conditions of this process. Specifically, for example, alcohol solvents such as methanol, ethanol, 2-propanol (isopropyl alcohol), t-butanol, such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane and the like. Ether solvents, aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene and xylene, ester solvents such as ethyl acetate and methyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2 An aprotic solvent such as pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, water, or a mixture thereof.
The reaction temperature is from −80 ° C. under heating under reflux, and is usually from 25 ° C. to 90 ° C. The reaction time is usually 30 minutes to 12 hours.

Step 1-2:
A compound of the formula (A-2) in which X is a carbon atom is optionally combined with a compound of the formula (A-1) in Ulman type conditions (for example, in an aprotic solvent such as DMF, in the presence of a metal catalyst, Using a metal catalyst such as copper (II) acetate, or refluxing under Buchwald type conditions (for example, BINAP, Pd ₂ (dba) ₃ or Pd (OAc) ₂ under a carbonate base such as cesium carbonate) The compound of the formula (A-3) is reacted by reacting using a palladium catalyst and a ligand such as dppf, Xantphos, etc. under reaction conditions such as heating and refluxing in an inert solvent such as toluene. Can be synthesized.
As a solvent, what is necessary is just a solvent which does not react on the reaction conditions of this process. Specific examples include ether solvents such as tetrahydrofuran and 1,4-dioxane.
The reaction temperature is from −80 ° C. to heating under reflux, usually from 25 ° C. to 150 ° C. The reaction time is usually 30 minutes to 12 hours.

Production method 2 of compound represented by formula (A-3)
Step 2 (Production method of the compound represented by the formula (A-5)):
Synthesizing a compound of formula (A-5) by reacting a compound of formula (A-4) wherein X is a nitrogen atom with a compound of formula (A-1) in the presence of a base, if necessary. Can do. The base is not particularly limited. For example, triethylamine, diisopropylethylamine, tributylamine, 1.5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4. 0] Organic bases such as undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM), or sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, hydroxide Examples include inorganic bases such as sodium and potassium hydroxide.
The solvent should just be a solvent which does not react on the reaction conditions of this process. Specifically, alcohol solvents such as methanol, ethanol, 2-propanol and t-butanol, for example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole and 1,4-dioxane, Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene and xylene, ester solvents such as ethyl acetate and methyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, aprotic solvents such as dimethyl sulfoxide, water, or a mixture thereof.
The reaction temperature is from −80 ° C. under heating under reflux, and is usually from 25 ° C. to 90 ° C. The reaction time is usually 30 minutes to 12 hours.

Step 3 (Production method of compound represented by formula (A-3)):
A compound of the formula (A-3) can be synthesized by reacting a compound of the formula (A-5) in which X is a nitrogen atom with a cyanide ion in the presence of a base, if necessary.
The base is not particularly limited. For example, triethylamine, diisopropylethylamine, tributylamine, 1.5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2. 2] Organic bases such as octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, dimethylaminopyridine, picoline, N-methylmorpholine (NMM) It is done.
The solvent should just be a solvent which does not react on the reaction conditions of this process. Specifically, alcohol solvents such as methanol, ethanol, 2-propanol and t-butanol, for example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole and 1,4-dioxane, Aromatic hydrocarbon solvents such as benzene, toluene, chlorobenzene and xylene, ester solvents such as ethyl acetate and methyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1 , 3-dimethyl-2-imidazolidinone, aprotic solvents such as dimethyl sulfoxide, water, or a mixture thereof.
The reaction temperature is usually from 25 ° C to 150 ° C. The reaction time is usually 30 minutes to 12 hours.

Method for producing compound represented by formula (A-6)
Step 4:
Synthesizing a compound of the formula (A-6) by reacting a compound of the formula (A-3) in which X is a carbon atom or a nitrogen atom with an organometallic species such as a substituted aryl Grignard reagent in an inert solvent. Can do.
The inert solvent should just be a solvent which does not react on the reaction conditions of this process. Specific examples include ether solvents such as tetrahydrofuran and diethyl ether.
The reaction temperature is from −80 ° C. to heating under reflux, usually from −10 ° C. to 25 ° C. The reaction time is usually 30 minutes to 24 hours.

Method for producing compound represented by formula (1)
Step 5:
Step 5-1
A compound represented by the formula (1) can be synthesized by reacting a compound of the formula (A-6) in which X is a carbon atom or a nitrogen atom with a reducing agent, an alkyl Grignard reagent, an alkylating reagent or the like.
Examples of the reducing agent include sodium borohydride, lithium aluminum hydride, diisobutylaluminum hydride and the like. Examples of the alkyl Grignard reagent include methyl magnesium bromide and isopropyl magnesium bromide. Examples of the alkylating reagent include trifluoromethyltrimethylsilane.
The solvent should just be a solvent which does not react on the reaction conditions of this process. Specifically, for example, an alcohol solvent such as methanol or ethanol is used when a reducing agent is used, an ether solvent such as tetrahydrofuran or diethyl ether is used when an alkyl Grignard reagent is used, and dimethyl is used when an alkylating reagent is used. Examples include aprotic solvents such as acetamide and N-methyl-2-pyrrolidinone.
The reaction temperature is usually from −10 ° C. to 50 ° C. under heating to reflux from −80 ° C. The reaction time is usually 10 minutes to 48 hours.

Step 5-2:
A compound of the formula (A-6) in which X is a carbon atom or a nitrogen atom is reacted with hydrogen in the presence of a catalyst, in the presence or absence of a ligand, in the presence or absence of a base, to give a compound of the formula (1) Can be synthesized.
Catalysts include metals such as palladium and nickel, salts of transition metals such as ruthenium chloride and palladium acetate, complexes such as the BINAP complex of ruthenium acetate, (R) -RUCY ^TM -Xylbinap, (S) -RUCY ^TM -Xylbinap, etc. And illegal catalysts.
As the ligand, in addition to a phosphorus-based ligand such as diphenylphosphinoethane, an asymmetric ligand such as BIAP can also be used.
Examples of the base include tert-butoxy potassium, tert-butoxy sodium, sodium ethoxide, sodium methoxide and the like.
Examples of the hydrogen source include ammonium formate in addition to hydrogen gas.
As a solvent, what is necessary is just a solvent which does not react on the reaction conditions of this process. Specific examples include alcohol solvents such as isopropyl alcohol, methanol and ethanol, and ether solvents such as tetrahydrofuran and diethyl ether.
The reaction temperature is usually from −10 ° C. to 50 ° C. under heating to reflux from −80 ° C. The reaction time is usually 10 minutes to 48 hours.

In each reaction of the production method described above, any functional group other than the reactive site changes under the described reaction conditions, even when the use of a protecting group is not specifically stated, or the described method When it is inappropriate to carry out, the compound other than the reaction point is protected as necessary, and the target compound can be obtained by deprotection after completion of the reaction or after a series of reactions.
As the protecting group, an ordinary protecting group described in literature (for example, Protective Groups in Organic Synthesis, 3rd ed., TWGreene, John Wiley & Sons Inc. (1999)) can be used. Specifically, examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like, and examples of the hydroxy protecting group include trialkylsilyl such as trimethylsilyl, tert-butyldimethylsilyl, Acetyl or benzyl can be mentioned respectively.
Introduction and elimination of protecting groups can be performed by methods commonly used in organic synthetic chemistry (see, for example, the above-mentioned Protective Groups in Organic Synthesis) or methods based thereon.

Throughout this specification, protecting groups, condensing agents and the like may be represented by abbreviations by IUPAC-IUB (Biochemical Nomenclature Board) commonly used in this technical field.
Suitable and pharmaceutically acceptable salts of the starting and target compounds are conventional non-toxic salts, such as organic acid salts (eg acetate, trifluoroacetate, maleate, fumarate) Citrate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.) and inorganic acid salts (eg hydrochloride, hydrobromide, hydroiodide, sulfate) Acid addition salts such as nitrates, phosphates, etc., salts with amino acids (eg arginine, aspartic acid, glutamic acid etc.), alkali metal salts (eg sodium salts, potassium salts etc.), alkaline earth metal salts (eg calcium Metal salts such as salts and magnesium salts), ammonium salts, organic base salts (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dioxygen salt) Black hexylamine salt, N, N'- dibenzylethylenediamine salt, etc.) and the like.

The intermediate or final product in the above production method may be converted as appropriate by its functional group (for example, protecting and deprotecting the functional group as necessary to establish an amino group, hydroxyl group, carbonyl group, halogen group, etc.) Can be converted into other compounds included in the present invention. The functional group can be converted by a commonly used general method (for example, see Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999)).

The intermediates and target compounds in each of the above production methods are isolated and purified by purification methods commonly used in synthetic organic chemistry such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do. In addition, the intermediate can be subjected to the next reaction without any particular purification.

Among the compounds (1) of the present invention, there are optical isomers based on optically active centers, atropisomers based on axial or planar chirality generated by restraining intramolecular rotation, other stereoisomers, tautomerism Isomers, geometric isomers and the like may exist, but all possible isomers and mixtures thereof are included in the scope of the present invention.

In particular, optical isomers and atropisomers can be obtained as racemates, or can be obtained as optically active substances using optically active starting materials and intermediates. Further, at an appropriate stage of the production method, the corresponding raw material, intermediate or final racemate is physically or chemically separated by a known separation method such as a method using an optically active column or a fractional crystallization method. Can be divided into their optical enantiomers. For example, a racemate can be reacted with an optically active resolving agent to synthesize two diastereomers, which can be separated by a method such as fractional crystallization utilizing the different physical properties (diastereomeric method). .

When it is desired to obtain a pharmacologically acceptable salt of the compound of the present invention, if the compound represented by the formula (1) is obtained in the form of a pharmacologically acceptable salt, it may be purified as it is, When it is obtained in a free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or base may be added to form a salt by a conventional method.

Among the raw materials and intermediates in each of the production methods described above, those that have not been described in particular are commercially available compounds, or methods known to those skilled in the art from commercially available compounds, or equivalents thereto. It can be synthesized by the method.

The compound of the present invention is provided as, for example, an anticancer agent, and the cancer type to which it is applied is not limited, but specific examples include, for example, breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, prostate cancer, brain tumor And endometrial cancer, pancreatic cancer, gastric cancer, osteosarcoma, myeloma, or hematological cancer. Among these, preferable 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 preferable cancer types are , Breast cancer, ovarian cancer, head and neck cancer, lung cancer, colon cancer, skin cancer, liver cancer, or prostate cancer.
In another preferred embodiment when the compound of the present invention is applied as an anticancer agent, the cancer types to be applied are blood cancer, myeloma, liver cancer, osteosarcoma, skin cancer, epithelial cell carcinoma, breast cancer, lung cancer. Ovarian cancer, uterine cancer, colon cancer, prostate cancer or pharyngeal cancer. Among these, preferable cancer types include blood cancer, myeloma, liver cancer, breast cancer, lung cancer, ovarian cancer, uterine cancer, colon cancer, prostate cancer or pharyngeal cancer, and more preferable cancer types include breast cancer, Mention may be made of lung cancer, ovarian cancer, uterine cancer, colon cancer, prostate cancer or pharyngeal cancer.
In the present invention, “blood cancer” is a concept including lymphoma and leukemia.
In the present invention, the “anticancer agent” has an effect of reducing or eliminating a carcinoma or not increasing the tumor when administered for the purpose of preventing and / or treating cancer.
In the present invention, “prevention” is an act of administering the active ingredient of the present invention to a healthy person who has not developed a disease, and is intended to prevent, for example, the onset of the disease. “Treatment” is the act of administering the active ingredient of the present invention to a person (patient) diagnosed as having developed a disease by a doctor. For example, alleviating a disease or symptom, It is intended not to increase or to return to the state before the onset of the disease. In addition, the therapeutic purpose also includes cases where the purpose of administration is prevention of worsening of diseases and symptoms or prevention of increase in carcinoma.

The compounds of the present invention are used orally or parenterally (for example, intravenous, subcutaneous or intramuscular injection, topical, rectal, transdermal or nasal) as pharmaceutical compositions when used for treatment. Can be administered. Examples of the composition for oral administration include tablets, capsules, pills, granules, powders, liquids, suspensions and the like. These preparations are prepared using conventionally known techniques, and can contain non-toxic and inert carriers or excipients usually used in the field of preparation.

When the compound of the present invention is administered, the amount to be used varies depending on symptoms, age, administration method, etc. For example, in the case of oral administration, the lower limit is 0.01 mg per day for adults (preferably 1 mg), and as an upper limit, 5000 mg (preferably 500 mg) is desirably administered once or several times according to symptoms. In the case of intravenous injection, for adults, 0.01 mg (preferably 0.1 mg) as the lower limit and 1000 mg (preferably 30 mg) as the upper limit per day, divided into one or several times, The effect is expected by administering according to the symptoms. In addition, intermittent administration is also preferable in oral and intravenous injection depending on the patient's symptoms.

The compound of the present invention can be used in combination with other drugs for the purpose of enhancing its effect and / or reducing side effects. Specifically, the compound of the present invention can be used in combination with a drug such as a hormonal therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, a cell growth factor or a drug that inhibits cell growth factor receptor action. Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.

Examples of hormone therapeutic agents include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, Olmeroxifene, levormeloxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, buserelin, Leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (eg, fadrozole hydrochloride, anastrozo) , Letrozole, exemestane, borozole, formestane, etc.), antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (eg, For example, abiraterone etc.), retinoids and drugs that delay the metabolism of retinoids (eg riarosol etc.) and the like.

As the chemotherapeutic agent, for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like are used. A typical example is described below.

Examples of the alkylating agent include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, melphalan, Dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozidine, pipobrommann, etoglucid, carboplatin, cisplatin, dibrospium hydrochloride, fotemustine, prednimustine, pumitepa, ribomuthine, temozolomide, treosorphan, Trophosphamide, dinostatin stimamarer, adzeresin, systemustin, vizeresin and their D S formulation, and the like.

Examples of the antimetabolite include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine okphosphat, ancitabine hydrochloride, 5-FU drugs (for example, fluorouracil, tegafur, UFT, Doxyfluridine, carmofur, galocitabine, emiteful, capecitabine, etc.), aminopterin, nerzarabine, leucoporin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarpamide treptostatine, pentostatin , Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and those DDS formulation, and the like.

Anticancer antibiotics include, for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neo Examples include cartinostatin, myramicin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations.

Examples of plant-derived anticancer agents include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and their DDS preparations.

Examples of immunotherapeutic agents include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum, levamisole , Polysaccharide K, procodazole, anti-CTLA4 antibody, PD-1 antibody, Toll-like Receptors agonist (for example, TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.).

The cell growth factor in the drug that inhibits the action of the cell growth factor and the receptor for the cell growth factor may be any substance as long as it is a substance that promotes cell growth, and usually has a molecular weight of 20,000 or less. Thus, a factor that exerts its action at a low concentration by binding to a receptor can be mentioned. Specifically, EGF (epidermal grow factor) or a substance having substantially the same activity (for example, TGFalpha), insulin or a substance having substantially the same activity (for example, insulin, IGF (insulin-insulin- like growth factor) -1, IGF-2, etc.), FGF (fibroblast growth factor) or a substance having substantially the same assay as it (for example, acidic FGF, basic FGF, KGK (keratinocyte growth factor), FGF-10) And other cell growth factors (for example, CSF (colony （stimukating factor), EPO (erythropoietin), IL-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), heregulin, angiopoietin, etc.).

The administration period of the compound of the present invention and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention. In addition, for the purpose of suppressing the side effects, it can be used in combination with drugs such as antiemetics, sleep inducers, anticonvulsants and the like (these are also included in the concomitant drugs).

The compound of the present invention has a high inhibitory action on a kinase selected from CDK1, CDK2, AURKA, AURKB, JAK2, CDK5, etc., as shown in the test examples and the like in this specification, and various kinases involved. It can be applied to the prevention and treatment of symptoms such as cancer diseases. In particular, among the compounds of the present invention, preferred compounds exhibit a stemness gene expression suppressing action by inhibiting CDK5 (the stemness gene will be described later). By using a substance that inhibits CDK5 other than the compound of the present invention (for example, siRNA of CDK5 that can directly inhibit CDK5), the suppressive action of stemness gene expression by the CDK5 inhibitor can be confirmed. Further, by confirming the expression of the stemness gene in cells (CDK5 knockdown, CDK5 dominant negative, etc.) in which the expression of CDK5 is eliminated or suppressed, the relationship between CDK5 inhibition and stemness gene expression suppression is also confirmed. Can be confirmed.

A stemness gene is a gene that can induce self-replication and / or differentiation into different cells. Examples of stemness genes include Nanog, Sox2, β-catenin, Oct4, and the like. Among the compounds of the present invention, a preferred compound has an action of suppressing the expression of stemness gene (Test Example 11). Among the compounds of the present invention, preferred compounds exhibit a sphere formation inhibitory action, and therefore can be expected to suppress the growth of cancer stem cells.
Due to these effects, the preferred compounds of the present invention can be expected to be useful as anticancer agents having an effect of preventing cancer recurrence.
Among the compounds of the present invention, preferred compounds are also useful as therapeutic agents for cancer having resistance to treatment with chemotherapeutic agents. Preferable chemotherapeutic agents here include, for example, taxane anticancer agents. Examples of the taxane anticancer agent in the present specification include an anticancer agent having a taxane skeleton, and examples thereof include paclitaxel and docetaxel.

In recent years, the relationship between GPCR and tumorigenesis has been clarified (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-29 cell 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. See Sorrentino R, Pinto A, Morello S. Oncoimmunology. 2013 Jan 1; 2 (1): e22448).
The compound of the present invention is a compound that is weak in agonistic and antagonistic properties to GPCR, and is considered to have little influence on GPCR and on tumor formation via GPCR.

Hereinafter, the present invention will be described more specifically with reference examples, examples and test examples. However, the present invention is not limited to these examples. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.

In this specification, the following abbreviations may be used.
THF: Tetrahydrofuran TFA: Trifluoroacetic acid NaBH (OAc) ₃ : Sodium triacetoxyborohydride DMAP: N, N-dimethyl-4-aminopyridine (Boc) ₂ O: Di-tert-butyldicarbonate 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-pyrrolidinone Boc: tert-butoxycarbo Nyl Cbz or Z: benzyloxycarbonyl (R) -RUCY ^™ -XylBINAP: RuCl [(R) -daipena] [(R) -xylbinap], CAS number: 1384974-38-2
(S) -RUCY ^™ -XylBINAP: RuCl [(S) -daipena] [(S) -xylbinap], CAS number: 1312713-39-5
N: Normal (for example, 2N HCl indicates 2N hydrochloric acid)
M: Molar concentration (mol / L) (2M methylamine as an example indicates a 2 mol / L methylamine solution)
t _R : Retention time obs MS [M + 1]: Observed molecular mass

Reversed phase HPLC preparative purification was performed as follows.
Purification was performed using a Gilson HPLC System. The column used was a YMC CombiPrep ODS-A column (5 μm, 50 × 20 mm ID), and the solvent was a mixed solvent system of CH ₃ CN (containing 0.035% TFA) and water (containing 0.05% TFA). UV detection was performed at wavelengths of 210 nm, 220 nm, and 254 nm.
The elution conditions are as follows.
Preparative equipment: Gilson HPLC System
Column: YMC CombiPrep ODS-A 5μm, 50 × 20 mm ID
Solvent: CH ₃ CN (containing 0.035% TFA), water (containing 0.05% TFA)
Flow rate: 35 mL / min
Gradient: linear gradient from 1:99 (v / v) CH ₃ CN / water to 95: 5 (v / v) CH ₃ CN / water within 13 min at 35 mL / min

The powder X-ray diffraction measurement was performed under the following conditions.
・ Device: X'pert-MPD (Spectris)
· _{X-ray: Cu Kα 1/45 kV /} 40 mA
-Incident slit: 15 mm (automatic) / Divergence prevention slit: 15 mm (automatic)
・ Sample plate: Non-reflective Si plate ・ Step size: 0.017 °
・ Scanning range: 4-40 ° (2θ)
Accumulation time: 100 seconds / step Note that the diffraction peak value at the diffraction angle 2θ (°) described in this specification may cause some measurement error depending on the measurement equipment or measurement conditions. Specifically, the measurement error may be within a range of ± 0.2, preferably ± 0.1.

Differential scanning calorimetry (DSC) measurement was performed under the following conditions.
・ Equipment: DSCQ1000 (TA Instruments)
・ Measurement temperature range: 10-250 ℃
・ Temperature increase rate: 10 ℃ / min ・ Vessel: Aluminum hermetic pan (Pin hole)
・ Atmospheric gas flow: Dry nitrogen, approx. 50 mL / min

Thermogravimetry (TGA) was performed under the following conditions.
・ Device: TGAQ500 (TA Instruments)
・ Measurement temperature range: Room temperature to 250 ℃
・ Temperature increase rate: 10 ℃ / min ・ Vessel: Platinum pan ・ Atmospheric gas flow rate: Dry nitrogen, sample flow rate approx. 60 mL / min, balance flow rate approx. 40 mL / min

X-ray diffraction measurement was performed under the following conditions.
-X-ray diffractometer: 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 analysis conditions for compound identification are as follows.
LC / MS measurement method:
Detector: 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: A solution: 0.06% formic acid / H ₂ O, B solution: 0.06% formic acid / MeCN
Gradient condition: 0.0-1.3 min Linear gradient from B 2% to 96%
Flow rate: 0.8 mL / min
UV: 220 nm and 254 nm

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

To a solution of 5-methyl-pyrazol-3-amine (18.0 g) in ethanol (500 mL) was added 2,4-dichloropyrimidine (25.0 g) and N-ethyl-diisopropylamine (30.6 mL), and the mixture was heated to 70 ° C. And stirred for 9 hours. After allowing 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 (300 MHz, DMSO-d ₆ ) δ12.1 (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 obtained in Reference Example 1 (4.8 g) in DMSO (100 mL) was added sodium cyanide (2.24 g) and 1,4-diazabicyclo [2.2.2] octane (1.28 g). Stir for 3 hours at ° C. After cooling to room temperature, water was added to the reaction solution, and insoluble matters were removed by filtration. Ethyl acetate was added to the obtained filtrate, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (3.67 g).
¹ H-NMR (300 MHz, 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 Reference Example 2 in THF (170 mL) was added 1.0 M THF solution (68 mL) of 3-methoxyphenylmagnesium bromide, and the mixture was stirred at room temperature for 1 hour. 2N Hydrochloric acid (70 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hr. 6N aqueous sodium hydroxide solution (12 mL) was added, and THF was evaporated under reduced pressure. The precipitated solid was collected by filtration, washed with water and ethyl acetate, and then dried under reduced pressure to obtain the title compound (4.5 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ12.07 (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) was added 3,4-difluorophenylmagnesium bromide in 0.5 M THF (3 mL) under ice cooling, and the mixture was stirred for 45 minutes under ice cooling. After 2N hydrochloric acid (1 mL) was added, the mixture was warmed to room temperature and stirred for 45 minutes. A 6N aqueous sodium hydroxide solution (0.5 mL) and water were added to the reaction mixture, and ethyl acetate was further added to extract the desired product into the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Hexane / ethyl acetate (1/1, 3 mL) was added to the residue obtained by concentrating the organic layer under reduced pressure, and the mixture was passed through an ultrasonic cleaner, and the precipitated solid was collected by filtration and filtered with hexane / ethyl acetate (1/1). Washing (1 mL × 4) gave the title compound (91 mg).
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ12.10 (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 Reference Example 2 in THF (120 mL) was added 3,5-dimethoxyphenylmagnesium bromide in 1M THF (80 mL), and the mixture was stirred for 2 hours and 20 minutes. 2N Hydrochloric acid (80 mL) was added, and the mixture was stirred at room temperature for 13 hr. A 6N aqueous sodium hydroxide solution (15 mL) and water were added to the reaction solution, and ethyl acetate was further added to extract the desired product into an 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 passed through an ultrasonic cleaner, and the precipitated solid was collected by filtration and filtered with hexane / ethyl acetate (1/1). Washing (10 mL × 2) gave the title compound (4.73 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ12.08 (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: tert-butyl 5-amino-3-methyl-1H-pyrazole-1-carboxylate

Boc ₂ O (15.26 g) was added to a chloroform solution (200 mL) of 3-methyl-1H-pyrazol-5-amine (6.79 g) at room temperature. 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 collected by filtration to obtain the title compound (12.3 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 6.24 (br-s, 2H), 5.13 (s, 1H), 1.99 (s, 3H), 1.53 (s, 9H).

Reference Example 7: tert-butyl 3- (6-cyanopyridin-2-ylamino) -5-methyl-1H-pyrazole-1-carboxylate

The compound (3.94 g) obtained in Reference Example 6, 2-chloro-6-cyanopyridine (2.76 g), Pd (OAc) ₂ (448 mg), Xantphos (1.15 g), cesium carbonate (16.25 g) And dioxane (100 mL) were mixed and heated to reflux for 3 hours. The mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.54 g).
¹ H-NMR (300 MHz, 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: tert-butyl 3-((6- (3,4-difluorobenzoyl) pyridin-2-yl) amino) -5-methyl-1H-pyrazole-1-carboxylate

To a THF (20 mL) solution of the compound obtained in Reference Example 7 (1.8 g), a 1.5 M THF solution (12 mL) of 3,4-difluorophenylmagnesium bromide was added under ice cooling. The mixture was stirred at room temperature for 2 hours, and 10% aqueous potassium hydrogen sulfate solution (30 mL) was added. After stirring at room temperature for 1 hour, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and ethyl acetate was added to the reaction mixture. The target product was extracted into the 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 under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.70 g).
¹ H-NMR (300 MHz, 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

Dichloromethane (0.5 mL) and trifluoroacetic acid (0.2 mL) were added to the compound (19 mg) obtained in Reference Example 8, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the resulting residue, and the desired product was extracted into the 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 resulting crude product was washed with diethyl ether to obtain the title compound (8.0 mg).
¹ H-NMR (300 MHz, 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 THF (8 mL) solution of the compound (250 mg) obtained in Reference Example 7 was added a 1M THF solution (2.5 mL) of 4-ethoxyphenylmagnesium bromide under ice-cooling, and the mixture was stirred for 10 minutes under ice-cooling. Stir for 18.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. 2N Hydrochloric acid (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. After that, saturated aqueous sodium hydrogen carbonate was added. Ethyl acetate was added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Dichloromethane (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 hours and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the resulting residue, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine, and then 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 resulting residue. The mixture was subjected to an ultrasonic cleaner, and the precipitated solid was collected by filtration, and further hexane / ethyl acetate (3/1). (2 mL × 2) to give the title compound (187 mg).
LC / MS, t _R 0.77 min, 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) was added a solution of 3,4,5-trifluorophenylmagnesium bromide in 0.3 M THF (8.4 mL) under ice cooling, and the mixture was cooled under ice cooling. The mixture was stirred for 10 minutes and stirred at room temperature for 18.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. 2N Hydrochloric acid (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate was added. Ethyl acetate was added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Dichloromethane (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, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the resulting residue, the target product was extracted into the organic layer, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (250 mg).
LC / MS, t _R 0.87 min, obs MS [M + 1] 333.1.

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

To a THF (8 mL) solution of the compound (250 mg) obtained in Reference Example 7 was added a 0.5 M THF solution (5 mL) of 3-fluoro-4-chlorophenylmagnesium bromide under ice cooling, and the mixture was stirred for 10 minutes under ice cooling. And stirred at room temperature for 18.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. 2N Hydrochloric acid (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and saturated aqueous sodium hydrogen carbonate was added. Ethyl acetate was added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Dichloromethane (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 and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the resulting residue, and the target product was extracted into the organic layer, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (250 mg).
LC / MS, t _R 0.87 min, obs MS [M + 1] 331.1.

Reference Example 13: tert-butyl 3-((6- (3,5-dimethoxybenzoyl) pyridin-2-yl) amino) -5-methyl-1H-pyrazole-1-carboxylate

To a THF (6.7 mL) solution of the compound (500 mg) obtained in Reference Example 7 was added a 0.5 M THF solution (16 mL) of 3,5-dimethoxyphenylmagnesium bromide under ice cooling, and the mixture was stirred for 10 minutes under ice cooling. And stirred at room temperature for 18.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours, and saturated aqueous sodium hydrogen carbonate was further added. Ethyl acetate was added to the reaction mixture, and the target product 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 resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (450 mg).
LC / MS, t _R 1.07 min, obs MS [M + 1] 439.6.

Reference Example 14: tert-butyl 3-((6- (3-methoxybenzoyl) pyridin-2-yl) amino) -5-methyl-1H-pyrazole-1-carboxylate

The title compound (466 mg) was obtained in the same manner as in Reference Example 8 using the compound (500 mg) obtained in Reference Example 7 and a 0.5 M THF solution of 3-methoxyphenylmagnesium bromide.
LC / MS, t _R 1.08 min, 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) was slowly added a 0.5 M THF solution (200 mL) of 3,4,5-trifluorophenylmagnesium bromide under ice cooling. . After stirring at room temperature for 2 hours, 2N hydrochloric acid (200 mL) was added under ice cooling, and the mixture was warmed to room temperature and stirred for 14 hours. A 6N aqueous sodium hydroxide solution (55 mL) was added, and the reaction mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with water (40 mL × 2), ethyl acetate (40 mL × 3), and THF (10 mL × 3) and then dried under reduced pressure to obtain the title compound (6.50 g).
¹ H-NMR (300 MHz, 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) pyrimidin-4-amine

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 allowing to cool to room temperature, water and ethyl acetate were added to the reaction solution, and the target product 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 obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.24 g).
¹ H-NMR (400 MHz, 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 obtained in Reference Example 16 (1.24 g) in DMSO (100 mL) / isopropyl alcohol (3 mL), sodium cyanide (0.31 g) and 1,4-diazabicyclo [2.2.2] octane (0. 32 g) was added and stirred at 90 ° C. for 5 hours. After cooling to room temperature, water was added and insolubles were removed by filtration. Ethyl acetate was added to the obtained filtrate, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (0.66 g).
¹ H-NMR (400 MHz, 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) methanone

To a THF (4 mL) solution of the compound (0.2 g) obtained in Reference Example 17, a 1.0 M THF solution (5.6 mL) of 3,4,5-trifluorophenylmagnesium bromide was slowly added under ice cooling. . After stirring at room temperature for 3 hours, 10% aqueous potassium hydrogen sulfate solution (30 mL) was added under ice cooling, and the mixture was warmed to room temperature and stirred for 16 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the precipitated solid was collected by filtration. The product was further washed with chloroform and hexane and dried under reduced pressure to obtain the title compound (0.22 g).
¹ H-NMR (400 MHz, 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) obtained in Reference Example 17 in THF (5 mL) was slowly added a 0.5 M THF solution (7.5 mL) of 3,4-difluorophenylmagnesium bromide under ice cooling, and the mixture was stirred at room temperature. Stir for hours. 2N Hydrochloric acid (3.1 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 50 min. A saturated aqueous sodium carbonate solution and ethyl acetate were added to the reaction solution, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with hexane and ethyl acetate, and then dried under reduced pressure to obtain the title compound (0.28 g).
LC / MS, t _R 0.75 min, obs MS [M + 1] 330.6.

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

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

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

To a THF (30 mL) solution of the compound (4.2 g) obtained in Reference Example 2, 2,4,5-trifluorophenylmagnesium bromide (120 mL of 1M THF solution) obtained in Reference Example 20 was slowly added under ice cooling. The mixture was stirred at room temperature for 2 hours and 50 minutes. 2N Hydrochloric acid (7 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium carbonate solution and ethyl acetate were added to the reaction solution, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine, and then 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 obtain the title compound (2.49 g).
LC / MS, t _R 0.74 min, 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) methanone

To a THF (15 mL) solution of the compound (0.5 g) obtained in Reference Example 17, 2,4,5-trifluorophenylmagnesium bromide (1 M THF solution 10 mL) obtained in Reference Example 20 was slowly added under ice cooling. The mixture was stirred at room temperature for 2 hours and 50 minutes. 2N Hydrochloric acid (7 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. A saturated aqueous sodium carbonate solution and ethyl acetate were added to the reaction mixture, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the precipitated solid was collected by filtration, washed with hexane and ethyl acetate, and then dried under reduced pressure to obtain the title compound (0.62 g).
LC / MS, t _R 0.74 min, obs MS [M + 1] 349.2.

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

Sodium borohydride (113 mg) was added to a solution of the compound obtained in Reference Example 8 (1.00 g) in methanol (6 mL) and THF (6 mL), and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution, and the target product was extracted into an 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 (hexane / ethyl acetate) to obtain the title compound (0.950 g).
LC / MS, t _R 0.84 min, obs MS [M + 1] 417.3.

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

2,4-Dichloropyrimidine (1.21 g) and N-ethyl-diisopropylamine (1.49 mL) were added to a solution of 5-cyclopropyl-pyrazol-3-amine (1.10 g) in ethanol (30 mL) at 70 ° C. For 11 hours. After allowing to cool to room temperature, water was added, and the mixture was extracted 3 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 silica gel column chromatography to obtain the title compound (1.04 g).
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 obtained in Reference Example 24 (364 mg) in DMSO (1.4 mL) / isopropyl alcohol (0.70 mL), sodium cyanide (106 mg) and 1,4-diazabicyclo [2.2.2] octane ( 87 mg), and the mixture was stirred at 90 ° C. for 6 hours. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated with an evaporator. The residue was diluted with ethyl acetate and then diluted 10-fold with hexane. The resulting solid was collected by filtration and dried to obtain the title compound (0.309 g).
¹ H-NMR (400 MHz, 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

To a solution of 5-cyclopropyl-pyrazol-3-amine (1.11 g) in ethanol (30 mL) was added 2,4-dichloro-6-methylpyrimidine (1.34 g) and N-ethyl-diisopropylamine (1.50 mL). In addition, the mixture was stirred at 70 ° C. for 5 hours. After allowing to cool to room temperature, water was added, and the mixture was extracted 3 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 silica gel column chromatography to obtain the title compound (0.96 g).
¹ H-NMR (400 MHz, 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 0.70 min, 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 obtained in Reference Example 26 (0.32 g) in DMSO (1.4 mL) / isopropyl alcohol (0.70 mL), sodium cyanide (75 mg) and 1,4-diazabicyclo [2.2.2] octane ( 72 mg) and stirred at 90 ° C. for 6 hours. After cooling to room temperature, water was added to the reaction solution and filtered. The obtained residue was washed 3 times with water and twice with ethyl acetate / hexane = 1/10 solvent, and dried under reduced pressure to give the title compound (0.24 g).
¹ H-NMR (400 MHz, 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 0.72 min, obs MS [M + 1] 241.1.

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

2,4-Dichloropyrimidine (0.405 g) and N-ethyl-diisopropylamine (0.497 mL) were added to a solution of 5-ethyl-pyrazol-3-amine (0.332 g) in ethanol (10 mL), and the mixture was heated to 70 ° C. And stirred for 6 hours. The mixture was allowed to cool to room temperature, concentrated, and the residue was purified by silica gel column chromatography to give the title compound (171 mg).
¹ H-NMR (400 MHz, 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 = 7.2Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H).
LC / MS, t _R 0.65 min, obs MS [M + 1] 224.1.

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

To a suspension of the compound obtained in Reference Example 28 (171 mg) 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 added and the mixture was stirred at 90 ° C. for 6 hours. After cooling to room temperature, water was added to the reaction solution and diluted with ethyl acetate / hexane = 1/1. This mixture was extracted twice with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated by an evaporator. The obtained residue was suspended in ethyl acetate / hexane = 1/10 and filtered. 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 0.66 min, 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 THF (10 mL) solution of the compound (87 mg) obtained in Reference Example 25, a 0.5 M THF solution (3.2 mL) of 3,4,5-trifluorophenylmagnesium bromide was slowly added under ice cooling. After stirring at room temperature for 2 hours, 2M hydrochloric acid (200 mL) was added under ice cooling, 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. The mixture was extracted 3 times with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated with an evaporator. The residue was purified by silica gel column chromatography to obtain the title compound (45 mg).
¹ H-NMR (400 MHz, 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 0.90 min, 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 obtained in Reference Example 29 (62 mg) in THF (4 mL) was slowly added a 0.5 M THF solution (2.4 mL) of 3,4,5-trifluorophenylmagnesium bromide under ice cooling. . After stirring at room temperature for 2 hours, 2M hydrochloric acid (200 mL) was added under ice cooling, 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. The mixture was extracted 3 times with ethyl acetate, and the organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated with an evaporator. The residue was purified by silica gel column chromatography to obtain the title compound (43 mg).
¹ H-NMR (400 MHz, 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 0.90 min, obs MS [M + 1] 348.2.

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

Lawesson's reagent (22.3 g) was added to a solution of 6-methylpyrimidine-2,4 (1H, 3H) -dione (12.6 g) in pyridine (100 mL), and the mixture was stirred at 140 ° C. for 2 hours. After cooling 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 allowing 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 1M aqueous sodium hydroxide solution (287 mL), cooled to 0 ° C., iodomethane (6.0 mL) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hours. did. The mixture was further stirred at room temperature for 2.5 hours, cooled to 0 ° C., acetic acid (130 mL) was added, and the mixture was concentrated under reduced pressure. Water was added to the obtained solid and dissolved by heating to 100 ° C., then cooled to room temperature and recrystallized. The precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain 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 phosphoryl chloride (4 mL) and stirred at 100 ° C. for 1.5 hours. The mixture was allowed to cool to room temperature, and concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (490 mg).
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) was added sodium cyanide (165 mg) and 1,4-diazabicyclo [2.2.2] octane (157 mg). And stirred at room temperature for 23 hours. Saturated aqueous sodium hydrogen carbonate, 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, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (436 mg).
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

A solution of the compound obtained in Reference Example 35 (165 mg) in acetonitrile (10 mL) was cooled to 0 ° C., and sulfuryl chloride (0.4 mL) was added dropwise thereto, followed by stirring at 0 ° C. for 25 minutes. A saturated aqueous sodium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (159 mg).
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 obtained in Reference Example 36 (154 mg) in DMSO (4 mL), 5-methyl-pyrazol-3-amine (146 mg) and N-ethyl-diisopropylamine (0.26 mL) were added and stirred at room temperature for 67 hours. did. Water was added, and the precipitated solid was filtered, washed with water, and then dried under reduced pressure to obtain 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 injected 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 the internal temperature was cooled to 0 ° C. Water (320 g), triethylamine (248 g) and 37.5% aqueous potassium carbonate solution (640 g) were successively added dropwise at an internal temperature of 5 ° C. or lower, and the organic layer was separated. The aqueous layer was extracted twice with isopropyl acetate (200 g), combined with the first organic layer, and concentrated to a content of 148 g. Isopropyl alcohol (148 g) was added, and concentration was repeated twice until the internal volume reached 148 g. Isopropyl alcohol (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 cooled isopropyl alcohol / water (30 g / 120 g), and dried under reduced pressure at 40 ° C. to obtain 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) pyrimidin-4-amine

To a solution of 2,4-dibromo-6-methyl-pyrimidine (40 g) and 5-methyl-pyrazol-3-amine (22 g) obtained in Reference Example 38 in 2-pyrrolidone (120 g), water (280 g) and hydrogen carbonate Sodium (16 g) was added and stirred at 60 ° C. for 16 hours. The mixture was cooled to 0 ° C. over 6 hours, stirred at 0 ° C. overnight, filtered, and the crystals obtained were washed with chilled acetonitrile (80 g) and dried under reduced pressure at 40-50 ° C. to give the title compound (36 g). .
LC / MS, t _R 0.635 min, 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 added to DMF (240 g) / isopropyl alcohol (30 g). The mixture was suspended, sodium cyanide (7.4 g) was added, and the temperature was raised to 70 ° C. 1,4-diazabicyclo [2.2.2] octane (4 g) was added, the temperature was raised to 90 ° C., and the mixture was stirred for 11 hours. Water (900g) was added after cooling to 50 degreeC, and it cooled to 0 degreeC. The crystals were filtered, washed with water (60 g), cooled acetonitrile (30 g), and dried under reduced pressure at 50 ° C. to give the title compound (16 g).
¹ H-NMR (400 MHz, 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)
Sodium borohydride (3.6 mg) was added to a solution of the compound (30 mg) obtained in Reference Example 4 in methanol (2 mL), and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, and the target product was extracted into the 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 resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (22 mg).
¹ H-NMR (400 MHz, 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
Example 3: (+)-(3,4-Difluorophenyl) (4-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) methanol (Synthesis Method B)
The racemic (3,4-difluorophenyl) (4-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) methanol (20 mg) obtained in Example 1 was added to hexane: isopropyl. Dissolve in alcohol: methanol = 7: 3: 5 (1.5 mL) and divide into 2 steps using HPLC system consisting of Shimadzu CR-6A CHROMATOPAC, HITACHI L-6000PUMP, Shimadzu SPD-6A and column Daicel Chiral PAK AD -H, 20 mmφ × 25 cm, solvent was hexane: isopropyl alcohol = 70: 30, flow rate was 10 mL / min, and optical resolution was carried out. Example 2 (10.9 mg) and Example 3 (10.7 mg) Each compound was obtained.
Example 2: Retention time 19.9 min, [α] _D ²⁰ = −22.8 (c = 0.50, MeOH)
Example 3: Retention 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-trifluorophenyl) methanol

(Synthesis Method C)
(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) (2,4,5-trifluorophenyl) methanone obtained in the same manner as in Reference Example 22. To a solution of (2.0 g) in isopropyl alcohol (10 mL) was added 0.01 M t-butoxypotassium isopropyl alcohol solution (30 mL) and (R) -RUCY ^™ -Xylbinap (0.2 g) under a nitrogen atmosphere. The reaction mixture was stirred at 40 ° C. for 3 hours under a hydrogen stream (5 atm). After replacing hydrogen in the reaction vessel with nitrogen, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (1.45 g).
¹ H-NMR (400 MHz, 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, 4.6 mmφ × 25 cm, hexane: isopropyl alcohol: 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-trifluorophenyl) methanol ( Synthesis method D)
(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidine-2-) was used in the same manner as in Example 4 using (S) -RUCY ^™ -Xylbinap as the catalyst. Yl) (2,4,5-trifluorophenyl) methanone (100 mg) gave the title compound (54 mg).
_{LC / MS, t R 0.58min,} obs MS [M + 1] 351.3.
LC analysis (column Daicel Chiral PAK AD-H, 4.6 mmφ × 25 cm, hexane: isopropyl alcohol: 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

To a solution of the compound (200 mg) obtained in Reference Example 11 in methanol (5 mL), sodium borohydride (23 mg) was added and stirred at room temperature for 3 hours and 20 minutes. Water and ethyl acetate were added to the reaction solution, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by amino silica gel column chromatography (ethyl acetate / methanol) to obtain racemic (6-((5-methyl-1H-pyrazol-3-yl) amino) Pyridin-2-yl) (3,4,5-trifluorophenyl) methanol (130 mg) was obtained.
_{LC / MS, t R 0.63 min} , MS [M + 1] 334.9.
The racemic (6-((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) (3,4,5-trifluorophenyl) methanol (28.7 g) was obtained in the same manner. ) Were optically resolved by DAICEL to obtain the compounds of Example 6 (10.3 g) and Example 7 (9.6 g).
The compounds of Example 6 and Example 7 were analyzed by column Daicel Chiral PAK OJ-H, 4.6 mmφ × 25 cm, the solvent was hexane: ethanol: methanol: ethylenediamine = 40: 40: 20: 0.1, and the flow rate was 1.0 mL / min. The retention times obtained are shown below.
Example 6: 3.69 min
Example 7: 5.90 min

Examples 8-44
The compounds of Examples 8 to 44 shown in the following table were obtained in the same manner as in Example 1, 2, 3, 4 or 5 (Synthesis methods A, C and D) using the corresponding starting compounds. LC analysis using a chiral column is performed under the following conditions, and the retention time is shown.
Column Daicel Chiral PAK AD-H, 4.6 mmφ × 25 cm, hexane: isopropyl alcohol: 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 obtained in Reference Example 4 (47 mg) in methanol (0.8 mL) was added sodium deuteride (7.4 mg), and the mixture was stirred at room temperature for 2 hours. 3N HCl and 5N NaOH were added to the reaction solution to adjust the pH of the reaction solution to 8, and then concentrated under reduced pressure. Water was added to the residue, and the precipitated solid was collected by filtration, washed with water and hexane, and then dried under reduced pressure to obtain the title compound (44 mg).
¹ H-NMR (400 MHz, 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-ol

Methyl magnesium bromide (0.98M, 0.2 mL) was added to a THF (1 mL) solution of the compound (20 mg) obtained in Reference Example 3, and the mixture was stirred at room temperature for 20 hours. Thereafter, methylmagnesium bromide (0.98M, 1.5 mL) was added, and the mixture was stirred at room temperature for 20 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the target product was extracted into an organic layer. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (7.8 mg).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ12.10 (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 table were obtained in the same manner as in Example 46 using the corresponding starting compounds.

Examples 53-70
The compounds of Examples 53 to 70 shown in the following table were obtained in the same manner as in Example 1 (Synthesis Method A) using the corresponding starting compounds.

Examples 71-86
The compounds of Examples 71 to 86 shown in the following table were obtained in the same manner as in Example 46 using the corresponding starting compounds.

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

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

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

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

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

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

A chart of the powder X-ray diffraction pattern is shown in FIG. 1, and its main peak is shown in the table below. A DSC-TGA chart is shown in FIG. From the DSC-TGA chart, since no weight change was observed at the endothermic peak, it was confirmed to be an anhydrous crystal.

Example 90: (+)-{4-Methyl-6-[(5-methyl-1H-pyrazol-3-yl) amino] pyrimidin-2-yl} (2,4,5-trifluorophenyl) methanol phosphorus Acid salt

(+)-(4-Methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) (2,4,5-trifluorophenyl) obtained in Example 87 Phosphoric acid (21 μL) was added to a methanol (0.5 mL) suspension of methanol-ethanol product (100 mg), and the mixture was stirred at 50 ° C. for 1 hour. Further, the mixture was stirred at room temperature for 21 hours to confirm crystal precipitation. Ethyl acetate (2 mL) was added and stirred for 1.5 hours. The precipitated solid was collected by filtration, and the residue was washed three times with ethyl acetate (0.5 mL) and dried under reduced pressure at 50 ° C. to obtain the title compound (111 mg).

The obtained (+)-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl) amino] pyrimidin-2-yl} (2,4,5-trifluorophenyl) methanol phosphoric acid The salt (50 mg) was dissolved in methanol, and half of ethanol in methanol and isopropyl alcohol in the same amount as ethanol were added. The solvent was volatilized slowly at room temperature, and when thick needle-like crystals were precipitated, the crystals were collected by filtration and subjected to X-ray crystal analysis.
The analysis results are shown in the following five tables. From the analysis results, the absolute structure of this compound was determined to be (S) -isomer. The three-dimensional structure is shown in FIG.

In addition, this compound (Example 90: (+)-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl) amino] pyrimidin-2-yl} (2,4,5-tri Since the absolute structure of (fluorophenyl) methanol phosphate) was found to be the (S) -form, the corresponding compounds ((+)-(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 ethanolate) was also determined to be the (S) -isomer, respectively. .

Example 91: (+)-{4-Methyl-6-((5-methyl-1H-pyrazol-3-yl) amino] pyrimidin-2-yl} (2,3,4-trifluorophenyl) methanol Crystallization and powder X-ray crystallography

(+)-{4-Methyl-6-((5-methyl-1H-pyrazol-3-yl) amino] pyrimidin-2-yl} (2,3,4-trifluorophenyl) obtained in Example 32 Hexane / chloroform = 1/1 (4 mL) was added to methanol (1.33 g), and the mixture was stirred for 1 day.The crystals were collected by filtration, washed with hexane / chloroform = 1/1, dried and dried to give white crystals (1 .29 g) was obtained.

A chart of the powder X-ray diffraction pattern is shown in FIG. A DSC-TGA chart is shown in FIG. From the DSC-TGA chart, since no weight change was observed at the endothermic peak, it was confirmed to be an anhydrous crystal.

Pharmacological test Although the pharmacological test method and the results of the representative compounds of the present invention are shown below, the present invention is not limited to these test examples.

Test Example 1: Cell Growth Inhibition Experiment NCI-H23 cells were obtained from ATCC (American Cultured Cell Line Storage Organization). NCI-H23 was cultured in RPMI 1640 medium containing 10% FCS and 1% penicillin / streptomycin, and HCT116 was cultured in DMEM medium containing 10% FCS and 1% penicillin / streptomycin in the presence of 37 ° C. and 5% CO ₂ .
Cells were seeded on a 96-well plate at 500-3000 cells / well, the test substance was added so that the final DMSO concentration was 0.1%, and the cells were cultured for 4-7 days. Thereafter, the number of viable cells was measured using Presto Blue (Life Technologies), and the concentration (Cytotoxicity IC ₅₀ value; μM) of each test substance that inhibits cell growth was calculated. It was confirmed to have a growth inhibitory action.

Test Example 2: Cytotoxicity test using rat liver parenchymal cells Rat liver parenchymal cells were isolated from 6-week-old Crl: CD (SD) male rats. The number of viable cells and dead cells in the suspension was counted by trypan blue staining and viability was calculated, and then a 1.0 × 10 ⁴ cell / 100 μL hepatocyte suspension was prepared. This 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 50 μL / well of a test substance-containing culture solution was added (n = 4). After completion of the addition, the culture was continued successively in the presence of 37 ° C. and 5% CO ₂ . Two days later, 5 μL / well of WST-8 reagent (Cell Counting Lit-8, Dojindo Laboratories) was added and stirred, and incubated at 37 ° C. in the presence of 5% CO ₂ for about 3 hours. After incubation, 0.1N HCl was added at 15 μL / well to stop color development, the absorbance was measured at a wavelength of 450 nm, the number of viable cells was counted, and the concentration at which each test substance inhibits 50% cell growth (Cytotoxicity IC ₅₀ value; μM) was calculated. It was confirmed that the toxicity of the compound of the present invention to hepatocytes was weak.

Test Example 3: Metabolic stability test of compound To 39.6 ml of 25 mM Kpi (pH 7.4), 0.4 ml of human liver microsome (Xenotech, approximately 20 mg protein / ml) was added to prepare a microsome solution. 10 μl of 1 mM test compound in DMSO was diluted 100-fold with acetonitrile. An intermediate diluted solution was prepared by adding 250 μl of Cofactor solution prepared by dissolving (6.5 mM) NADPH 300 mg in 55.2 ml of 125 mM Kpi (pH 7.4) to 5 μl of this solution. Using a Tecan screening robot on a 96-well plate, take 50 μl of the intermediate dilution in 2 wells, add 50 μl of the microsomal solution to each well, and incubate with shaking at 37 ° C. for 30 minutes. Was prepared. Separately, 50 μl of the intermediate dilution was taken in 2 wells and incubated in the same manner without adding the microsome solution to prepare an unreacted sample. After incubation, 400 μl of methanol was added to each well of the reaction sample and unreacted sample. Furthermore, for the wells of the unreacted sample, 50 μl of microsome solution was added and mixed after methanol addition. Centrifuge for 30 minutes at -20 ° C, centrifuge, and inject 10 µl of the supernatant into an LC-MS / MS system (Shimadzu HPLC, AB Sciex API 4000). 2 reaction samples and 2 unreacted samples A total of 4 wells were measured, and the average value of each chromatographic peak area value was calculated. Using this value, the clearance of the compound was determined by the following equation using the natural logarithm (LN).
Compound clearance = −LN {(average value of reaction sample) ÷ (average value of unreacted sample)} / 30 / 0.1
From this result, it was confirmed that the stability of the compound of the present invention in microsomes was improved.

Test Example 4: hERG inhibition test A test substance was added to the cultured hERG gene stably expressing CHO cell line so that the final DMSO concentration was 0.0135 to 0.5%. The hERG current was measured using QPatch HT (Sophion), the concentration at which each test substance suppresses 50% hERG current (IC ₅₀ value; μM) was calculated, and the hERG inhibitory activity of the compound of the present invention was weak. confirmed.

Tests shown in Test Examples 1 to 4 were performed on the compounds obtained in the examples. The results are shown in the following table.

Test Example 5: Kinase inhibition experiment assay buffer (20 mM HEPES, 0.01% Triton X-100, 2 mM DTT, pH 7.5) 5 μL of 4-fold concentration test substance solution, 5 μL of 4-fold concentration substrate / ATP / The metal solution and 10 μL of the double concentration kinase solution were mixed in the wells of a polypropylene 384-well plate and reacted at room temperature for 1 hour. The reaction was stopped by adding 60 μL Termination Buffer (QuickScout Screening Assist MSA; Carna Biosciences). The substrate peptide and phosphorylated peptide in the reaction solution were separated and quantified by LabChip system (Perkin Elmer). The kinase reaction was evaluated by the product ratio (P / (P + S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P). In the data analysis, the average signal of the control well was 0% inhibition, the average signal of the background well (no enzyme added) was 100% inhibition, and the inhibition rate was calculated from the average signal of each test substance well. From the results, it was confirmed that the compound of the present invention has kinase inhibitory activity.

Tests shown in Test Example 5 were performed on the compounds obtained in the examples. The test results are shown in the following table.

Test Example 6: Tumor Growth Suppression Experiment in HCT-116 Human Colon Adenocarcinoma Cell Carrying Mice HCT-116 cells (ATCC) were suspended in HBSS and 5-week-old female BALB / cAnNCrj-nu / nu mice (Charles Japan) 3 × 10 ⁶ cells were transplanted subcutaneously on the ventral part of the river. From 7 days after transplantation, the test substance suspended in a 0.5% methylcellulose solution (Wako Pure Chemical Industries) was orally administered twice a day for 13 to 15 days to obtain a test substance administration group. A 0.5% methylcellulose solution was similarly administered to the vehicle administration group. The number of animals in each group was 7-8. Tumor diameter and body weight were measured 1-3 times a week after the start of administration. Tumor volume was calculated from the following equation.
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) x 1/2
The tumor growth inhibition rate was calculated from the following formula using the average tumor volume of each administration group.
Tumor growth inhibition rate (%) = 100-100 × (T-T0) / (C-C0)
T: Average tumor volume after administration of test substance
T0: Average tumor volume at the start of test substance administration
C: Average tumor volume after vehicle administration
C0: Average tumor volume at the start of vehicle administration The weight change rate was calculated from the following formula using the average body weight of each administration group.
Weight change rate (%) = 100 x (T / T0) / (C / C0)
T: Average body weight after administration of test substance
T0: Average body weight at the start of test substance administration
C: Average body weight after vehicle administration
C0: Average body weight at the start of vehicle administration

Tests shown in Test Example 6 were performed on the compounds obtained in the examples. The results are shown in the following table.

Test Example 7: Tumor growth suppression experiment in HCC1806 human breast cancer cell-bearing mice HCC1806 cells (ATCC) were suspended in HBSS, and the ventral part of 5-week-old female BALB / cAnNCrj-nu / nu mice (Charles River Japan) 3 × 10 ⁶ cells were transplanted subcutaneously. 7 days after transplantation, test substance suspended in 0.5% methylcellulose solution (Wako Pure Chemical Industries) (200 mg / kg, twice a day, oral administration), docetaxel suspended in physiological saline (Otsuka Pharmaceutical) (5 mg / kg, once a week for 3 times, tail vein administration) or the compound obtained in Example 4 (150 mg / kg, twice a day, oral administration) and docetaxel (5 mg / kg, 1 time per week) 3 times, tail vein administration) was administered for 15 days. In the vehicle administration group, 0.5% methylcellulose solution was administered twice a day for 15 days. The number of animals in each group was 5-8. During the administration period of 15 days, the tumor diameter and body weight of all individuals were measured 1 to 3 times a week. In addition, the tumor diameter and body weight of the docetaxel administration group and the combination group of the test substance and docetaxel were measured for 35 days after the end of administration without drug administration.
Tumor volume was calculated from the following equation.
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) x 1/2

FIG. 6 shows the measurement results of the tumor diameter of the compound obtained in Example 4 in which the test shown in Test Example 7 was performed. On the last day of drug administration, the tumor volume in the docetaxel administration group and the test substance and docetaxel combination administration group was significantly suppressed compared to that in the vehicle administration group (p <0.05, Dunnett's test). Furthermore, after the drug administration was completed, the tumor volume increased in the docetaxel administration group, but the tumor volume in the combination administration group of the test substance and docetaxel continued to be suppressed and disappeared completely. Furthermore, no tumor recurrence was observed in all cases within the observation period.

FIG. 7 shows the measurement results of body weight of the compound obtained in Example 4 in which the test shown in Test Example 7 was performed. The body weight (19th and 22nd days) of the docetaxel administration group was significantly suppressed compared with that of the vehicle administration group (p <0.05, Student's ＜ t-test). On the other hand, the weight of the test substance and docetaxel combined administration group was not significantly changed from that of the vehicle administration group on any measurement day.

Test Example 8: Tumor growth inhibition experiment in tumor-bearing mice using FaDu human pharyngeal carcinoma cells FaDu cells (ATCC) were suspended in HBSS, and 5-week-old female BALB / cAnNCrj-nu / nu mice (Charles River Japan) 1 × 10 ⁶ cells were transplanted subcutaneously in the ventral region of each other. From 7 days after transplantation, a test substance (50, 100, or 200 mg / kg, orally administered twice a day) suspended in a 0.5% methylcellulose solution (Wako Pure Chemical Industries) was administered for 15 days. In the vehicle administration group, 0.5% methylcellulose solution was administered twice a day for 15 days. The number of animals in each group was 10. During the administration period of 15 days, the tumor diameter and body weight of all individuals were measured 1 to 3 times a week.
Tumor volume was calculated from the following equation.
Tumor volume (mm ³ ) = major axis (mm) x minor axis (mm) x minor axis (mm) x 1/2
8 and 9 show average values and standard errors.

FIG. 8 shows the measurement results of the tumor diameter of the compound obtained in Example 4 in which the test shown in Test Example 8 was performed. On the last day of measurement, the tumor volume of the test substance-administered group was significantly suppressed in a dose-dependent manner compared to that of the vehicle-administered group (p <0.025, Williams' test).

FIG. 9 shows the measurement results of the body weight of the compound obtained in Example 4 in which the test shown in Test Example 8 was performed. On the last day of measurement, the body weight of the test substance-administered group significantly increased in a dose-dependent manner compared with that of the vehicle-administered group (p <0.025, Williams' test). In this weight gain action, no abnormal cause such as edema was observed.

Test Example 9: Adenosine A3 antagonist activity test Coelenterazine h (125 nM) was loaded into CHO cells expressing adenosine A3 gene, aequorin and Gα16. Thereafter, a test substance was added, and 2 minutes later, a ligand (adenosine 1 μM) was added, aequorin luminescence was measured with FDSS 7000 (Hamamatsu Photonics), and the inhibition rate was calculated from the following formula.
Inhibition rate = (luminescence intensity when no test substance is added-luminescence intensity when test substance is added)
/ Luminescence intensity with no test substance added * 100
From the results, it was confirmed that the compound of the present invention had no adenosine A3 antagonist activity at 1 μM.

For the compound obtained in Example 4, the test shown in Test Example 9 was conducted. The test results are shown in the following table.

Test Example 10: Solubility Measurement A test substance (10 mM DMSO solution) was dispensed by 15 μL each into a Utube on a 96-well rack, set in a centrifugal evaporator, and evaporated to dryness. After 3 μL of DMSO was added and redissolved, 300 μL each of pH 7.4 and 1.2 buffers were added, and the mixture was shaken at 110 rpm for 90 minutes at 25 ° C. and then allowed to stand for 16 to 20 hours. Insoluble matters were separated by centrifugation at 2000 G for 15 minutes, and 100 μL of the supernatant was collected in a 96-well plate. Separately, 2 μL of a test substance (10 mM DMSO solution) was dispensed into a 96-well plate and diluted with 198 μL of 50% acetonitrile to prepare a 100 μM standard solution. Further, a 100 μM standard solution was diluted 10-fold with 50% acetonitrile to obtain a 10 μM standard solution. The solubility measurement sample and two standard solutions were analyzed by liquid chromatography, and the solubility was calculated from the area ratio with the standard solution.
Tests shown in Test Example 10 were performed on the compounds obtained in the examples. The test results are shown in the following table.

Test Example 11: Bulk growth inhibition test HCC1806 cells were obtained from ATCC. HCC1806 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin in the presence of 37% at 5% CO ₂ . Cells were seeded in a 96-well plate at 1,000 to 3,000 cells / well, a test substance was added so that the DMSO concentration was 0.1%, and the cells were cultured for 5 days. Thereafter, the number of viable cells was counted using Presto Blue (Life Technologies), and the concentration (IC ₅₀ ; μM) at which 50% cell growth of each test substance was suppressed was calculated.

Test Example 12: Cancer cell sphere formation inhibition experiment HCC1806 cells were obtained from ATCC. Cells were B27 Supplement (GIBCO), 20 ng / mL epidermal growth factor (EGF) (peprotech), 20 ng / mL basic fibroblast growth factor (bFGF) (peprotech), 5 μg / mL insulin (GIBCO) and 1 Cells were seeded at 1,000-3,000 cells / well in DMEM / F12 medium containing% methylcellulose (Nacalai Tesque) and seeded on Corning 96-well clear round bottom ultra-low attachment microplates (Corning, # 7007). A test substance was added so that the DMSO concentration was 0.1%, and the cells were cultured for 10 days. Thereafter, the number of spheres was counted, and the concentration (IC ₅₀ : μM) at which 50% cell growth of each test substance was suppressed was calculated.

The compounds shown in Examples were subjected to the tests shown in Test Example 11 and Test Example 12. The test results are shown in the table below.

Test Example 13 Nanog Expression Inhibition Experiment with Test Substance HCC1806 cells were obtained from ATCC. The cells were subcultured in RPMI medium containing 10% fetal bovine serum and 1% penicillin / streptomycin in the presence of 5% CO ₂ at 37 ° C. On the day before the addition of the test substance, the cells were seeded in 2 × 10 ⁵ cells in a 6-well plate and cultured overnight. After adding a test substance and culturing for 24 hours, the supernatant was removed. The cells were washed with ice-cold PBS, ice-cold RIPA buffer (Cell signaling technology, # 9806S) containing Proteinase / Phosphatase inhibitor cocktail (Cell signaling technology, # 5872S) was added, and the cells were collected using a cell scraper. After sonication, it was left on ice for 10 minutes. After centrifugation (15,000 rpm, 10 minutes), the supernatant was recovered and the protein concentration was quantified. A solution containing cell proteins adjusted to a constant concentration with RIPA buffer and SDS sample buffer (Nacalai Tesque, # 09499-14) was heated at 100 ° C. for 5 minutes, and then the proteins were separated by electrophoresis. After the protein is transferred to the PVDF membrane, an anti-Nanog antibody (Cell signaling technology, # 4903S) or an anti-β-actin antibody (Cell signaling technology, # 5125S) is added using a 5% skim milk / TBST solution. Incubate overnight at 4 ° C. After washing the antibody-hybridized PVDF membrane with a TBST solution, a secondary antibody (HRP-labeled anti-rabbit IgG) was added and incubated at room temperature for 1 hour. After washing with TBST solution, a coloring reagent (ECL Prime western blotting detection reagent, GE healthcare, # RPN2232) was added, and luminescence was detected with a detector.

Using the compound obtained in Example 4 as a test substance, Palbociclib (selective CDK4 / 6 inhibitor; purchased from Selleck Chemicals) and Docetaxel (purchased from Sanofi Aventis) as control compounds were subjected to the test shown in Test Example 13. It was. A similar test was conducted using the compound obtained in Example 72 as a test substance. The results are shown in FIG. 10 (the compound of Example 4) and FIG. 11 (the compound of Example 72). The compounds in Example 4 and Example 72 decreased the expression level of Nanog in a concentration-dependent manner. On the other hand, Palbociclib and Docetaxel did not affect the expression level of Nanog. None of the test substances affected the expression level of β-actin.
Similarly, the Nanog expression inhibitory effect can be confirmed also about other Example compounds. Similarly, the effect of the compound of the present invention on the functions of other stemness genes (Sox2, β-catenin, Oct4, etc.) can be confirmed. The compound of Example 4 also showed an expression inhibitory effect on Sox2 and β-catenin.

The compound of the present invention is useful as a multikinase inhibitor for the prevention and / or treatment of diseases that may be affected by cell proliferation, for example, diseases such as cancer.

Claims

Formula (1):

[In Formula (1),
X represents a nitrogen atom or CR 5 ;
Y is a hydrogen atom, C 1-6 alkyl (the group is substituted with the same or different 1 to 3 groups selected from a halogen atom, hydroxy, C 1-6 alkoxy and C 3-10 cycloalkyl) C 3-10 cycloalkyl (which is substituted with 1 to 4 groups identical or different selected from a halogen atom, hydroxy, C 1-6 alkyl and C 1-6 alkoxy). Or a 3- to 8-membered saturated heterocyclic ring (the group is substituted with the same or different 1 to 4 groups selected from a halogen atom, hydroxy, C 1-6 alkyl and C 1-6 alkoxy) May be)
R 1a , R 1b , R 1c , R 1d and R 1e are the same or different and each represents a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, C 1-6 alkyl (the group is a halogen atom, hydroxy and C 1 Optionally substituted with 1 to 3 identical or different groups selected from -6 alkoxy), C 1-6 alkoxy (the same selected from halogen atom, hydroxy and C 1-6 alkoxy) Or optionally substituted with 1 to 3 different groups), amino, C 1-6 alkylamino (the group is the same or different 1 to 3 selected from halogen atom, hydroxy and C 1-6 alkoxy) ), C 2-12 dialkylamino (which is selected from halogen atoms, hydroxy and C 1-6 alkoxy) 3 to 6-membered cyclic amino (which is selected from a halogen atom, hydroxy, C 1-6 alkyl and C 1-6 alkoxy), which may be substituted with the same or different 1-6 groups. Or a C 1-6 alkylcarbonyl (the group may be the same or different 1-3 selected from halogen atom, hydroxy and C 1-6 alkoxy). Which may be substituted with
R 4 represents a hydrogen atom, cyano, hydroxy, C 1-6 alkyl (the group may be substituted with the same or different 1 to 3 groups selected from a halogen atom, hydroxy and C 1-6 alkoxy) Or a C 3-10 cycloalkyl, which group may be substituted with 1 to 4 groups identical or different selected from a halogen atom, hydroxy and C 1-6 alkoxy;
R 2 , R 3 and R 5 are the same or different and each represents a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, C 1-6 alkyl (the group is a halogen atom, hydroxy, C 1-6 alkoxy and C 3 -10 may be substituted with the same or different 1 to 3 groups selected from cycloalkyl), C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms which are the same or different May be substituted with the same or different 1 to 3 groups selected from a halogen atom, hydroxy and C 1-6 alkoxy), amino, C 1-6 alkylamino, C 2-12 dialkylamino (in which the halogen atom, optionally substituted by the same or different 1-6 groups selected from hydroxy and C 1-6 alkoxy ), 3 cyclic amino (base to 6-membered, halogen atom, hydroxy, optionally substituted by the same or different 1 to 4 groups selected from C 1-6 alkyl and C 1-6 alkoxy ), C 1-6 alkylcarbonyl (the group may be substituted with the same or different 1 to 3 halogen atoms), C 3-10 cycloalkyl (the group is a halogen atom, hydroxy, C 1 3 to 8 membered saturated heterocyclic ring (which may be substituted with the same or different 1 to 4 groups selected from -6 alkyl and C 1-6 alkoxy), which is a halogen atom, hydroxy, Optionally substituted with 1 to 4 identical or different groups selected from C 1-6 alkyl and C 1-6 alkoxy), C 6-10 aryl (the group is a halogen atom, C 1-6 Archi And the same or different one to four monocyclic or heteroaryl (substrate polycyclic which may also be) or a 5- to 10-membered optionally substituted with a group selected from C 1-6 alkoxy, halogen And optionally substituted with 1-4 identical or different groups selected from atoms, C 1-6 alkyl and C 1-6 alkoxy;
Ar represents C 6-10 monocyclic or polycyclic aryl or 5- to 10-membered monocyclic or polycyclic heteroaryl]
Or a pharmacologically acceptable salt thereof.
Ar is phenyl or pyridyl, The compound or its pharmacologically acceptable salt of Claim 1 characterized by the above-mentioned.
Ar is phenyl, The compound of Claim 1 or Claim 2, or its pharmacologically acceptable salt.
X is CR 5 ;
The compound according to any one of claims 1 to 3, wherein R 5 is a hydrogen atom, a halogen atom or C 1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms). Or a pharmacologically acceptable salt thereof.
The compound according to any one of claims 1 to 3, or a pharmacologically acceptable salt thereof, wherein X is a nitrogen atom.
The compound or pharmacology thereof according to any one of claims 1 to 5, wherein Y is a hydrogen atom or C 1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms). Top acceptable salt.
R 4 is a hydrogen atom, C 1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or C 3-10 cycloalkyl (the group is substituted with 1 to 4 fluorine atoms). The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6, which may be substituted with an atom.
R 4 is a hydrogen atom, C 1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or C 3-4 cycloalkyl (the group is substituted with 1 to 4 fluorine atoms). The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, which may be substituted with an atom.
R 2 and R 3 are the same or different and each is a hydrogen atom, a halogen atom or C 1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms). Or a pharmacologically acceptable salt thereof.
R 1a , R 1b , R 1c , R 1d and R 1e are the same or different and are each a hydrogen atom, a halogen atom or C 1-6 alkyl (the same group selected from a fluorine atom and C 1-6 alkoxy) Or a C 1-6 alkoxy (which may be substituted with 1 to 3 fluorine atoms) or a C 1-6 alkoxy (which may be substituted with 1 to 3 different groups). The compound according to any one of the above or a pharmacologically acceptable salt thereof.
R 1a , R 1b , R 1c , R 1d and R 1e are the same or different and each represents a hydrogen atom, a halogen atom or C 1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) The compound according to any one of claims 1 to 10 or a pharmacologically acceptable salt thereof.
The compound according to any one of claims 1 to 11, wherein R 4 is C 1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or cyclopropyl. Pharmacologically acceptable salt.
The following compound groups:
(4-methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) (2,4,5-trifluorophenyl) methanol,
(4-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) (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-trifluorophenyl) 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-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) (2,3,5-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) amino) pyrimidin-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,
(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-pyrazol-3-yl) amino) pyrimidin-2-yl) (2,4,5-trifluorophenyl) methanol,
(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-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) 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-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-trifluorophenyl) 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-methylphenyl) ethan-1-ol, and 1- A compound selected from (4-chloro-3-fluorophenyl) -1- (4-((3-cyclopropyl-1H-pyrazol-5-yl) amino) pyrimidin-2-yl) ethane-1-ol The compound according to claim 1 or a pharmacologically acceptable salt thereof.
The following compound groups:
(4-methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) (2,4,5-trifluorophenyl) methanol,
(4-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) (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-trifluorophenyl) 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-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) (2,3,5-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) amino) pyrimidin-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) 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-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-trifluorophenyl) 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-methylphenyl) ethan-1-ol and 1- ( 4-chloro-3-fluorophenyl) -1- (4-((3-cyclopropyl-1H-pyrazol-5-yl) amino) pyrimidin-2-yl) ethan-1-ol The compound according to claim 1 or a pharmacologically acceptable salt thereof.
A pharmaceutical composition comprising the 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 comprising the compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt thereof as an active ingredient.
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 18. The anticancer agent according to 17.
Treatment and / or prevention of cancer comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of claims 1-14 or a pharmacologically acceptable salt thereof. How to do.
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 20. The method for treatment and / or prevention according to 19.
Use of the compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt thereof for producing a therapeutic and / or preventive agent for cancer.
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 21. Use according to 21.
The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 14, for use in the treatment and / or prevention of cancer.
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 hematological cancer Item 24 or a pharmacologically acceptable salt thereof.
The anticancer agent according to claim 17 or 18, which has an action of suppressing expression of a stemness gene.
26. The anticancer agent according to claim 25, wherein the stemness gene is any one selected from the group consisting of Nanog, Sox2, β-catenin and Oct4.
The anticancer agent according to claim 25, wherein the stemness gene is Nanog.
A stemness gene expression 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 a compound that inhibits three or more kinases.
30. The anticancer agent according to claim 29, wherein the kinase is selected from the group consisting of CDK2, CDK5, JAK2, AURKA, AURKB, and CDK1.
An anticancer agent comprising a compound that inhibits 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 for treating cancer comprising suppressing the expression of a stemness gene.
A method for suppressing the expression of a stemness gene, comprising inhibiting CDK5.