JP2018135268A - Novel heteroaryl amino-3-pyrazole derivative and pharmacologically acceptable salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound that inhibits kinases and signals required for cell cycle, cell proliferation or cancer stem cell survival to exhibit antitumor action, and reduce side effects, resulting in improved safety.SOLUTION: The present invention provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof [X is N or CR; Y is H, Calkyl or the like; R-Rindependently represent H, a halogen atom, hydroxy or the like; Ris H, cyano, Calkyl or the like; R, Rand Rindependently represent H, a halogen atom, OH, Calkyl or the like; Ar is Cmonocyclic or polycyclic aryl or 5-10 membered monocyclic or polycyclic heteroaryl].SELECTED DRAWING: None

Description

  The present invention relates to a novel heteroarylamino-3-pyrazole derivative useful as a pharmaceutical 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, abnormalities in cell division control are known as one of the fundamental characteristics. 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 has been reported that many of the current anticancer agents involved in cell division control exhibit side effects beyond those 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 cell cycle through 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. It has been clarified that serine / threonine kinase plays 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 among these, at least Aurora-A and Aurora-B have been shown to be involved in chromosome separation and cytoplasm separation.

  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. It has also been reported that CDK1, cyclin A, cyclin E, Aurora-A and Aurora-B are overexpressed in many human solid cancers and hematological cancers, and their expression and activity correlate with poor prognosis. (Non-patent document 3, Non-patent document 4, Non-patent document 5, Non-patent document 6, Non-patent document 7) Therefore, it is considered that low molecular weight compounds targeting CDK and Aurora are highly useful as anticancer agents. ing.

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 clarified (Non-Patent Document 8). For example, the JAK2 / STAT3 signal is necessary for the survival of cancer stem cells in breast cancer and prostate cancer (Non-Patent Document 9), and the TGF-beta signal is activated in breast cancer cancer stem cells that are resistant to chemotherapy. (Non-Patent Document 10).
Also, 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, Aurora-A and Aurora-B inhibitors are proliferating in cancer cells that depend on the Myc signal. It is considered effective for suppression and induction of selective cell death (Non-patent Document 11).

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

［式中、Ｚ^１またはＺ^２は窒素原子を意味し、Ｑは−Ｓ−等であり、Ｒ^ｘおよびＲ^ｙは、−Ｔ−Ｒ^３、−Ｌ−Ｚ−Ｒ^３であり、Ｒ^１は、−Ｔ−（Ｄ環）であり［Ｄ環は、５員から７員の単環等であり］、Ｔは、原子価結合等であり、Ｚは、Ｃ_１−４アルキリデン鎖等であり、Ｌは、−Ｏ−等であり、Ｒ^２及びＲ^２’は、−Ｒ、−Ｔ−Ｗ−Ｒ^６等であり、Ｒ^３は、−Ｒ等であり、Ｒは、水素原子等であり、Ｗは、−Ｃ（Ｒ^６）_２Ｏ−等であり、Ｒ^６は、水素原子等である。］

[Wherein, Z ¹ or Z ² means 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. Yes, 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.

［式中、Ｋは、ＮＨ、Ｏ、Ｓ等であり、Ａは、アリール等であり、ｍは、０等であり、Ｘは、ＯまたはＳであり、Ｒ^１は、水素原子等であり、Ｒ^２はアミノ等であり、Ｒ^３は、アリールオキシ等であり、Ｒ^４は、アルキル等である。］

[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.

［式中、Ｒ^１は、水素原子等であり、Ｒ^２は水酸基等であり、Ｒ^３は、アルキル等であり、Ｒ^４は、水素原子等であり、Ｒ^５は、水素原子等であり、Ｒ^６は、ハロゲン等であり、Ｒ^７は、ハロゲン等であり、ｎは、０〜４であり、ｐは、０〜５である。］

[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.

しかしながら、特許文献１、２，３及び４には、本発明の式（１）で表される化合物は、一切開示されない。

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

Lim S, Kaldis P. Development. 140 (15): 3079-93 (2013) Cheung CH, et al., Expert Opin Ther Pat. 24 (9): 1021-38 (2014) Chen X, et al., Med Oral Patol Oral Cir Bucal. 20 (1): e7-e12 (2015) Jansen MP, et al., Breast Cancer Res Treat. 133 (3): 937-47 (2012) Yasmeen A, et al., Expert Rev Mol Diagn. 3 (5): 617-33 (2003) Pacaud R, et al., Theranostics. 5 (1): 12-22 (2015) Fu J, et al., Mol Cancer Res. 5 (1): 1-10 (2007) Pattabiraman DR, Weinberg RA. Nat Rev Drug Discov. 13 (7): 497-512 (2013) Marotta LL, et al., J Clin Invest. 121 (7): 2723-35 (2011) Bhola NE, et al., J Clin Invest. 123 (3): 1348-58 (2013) Horiuchi D, et al., Am Soc Clin Oncol Educ Book.e497-502 (2014)

  The problem to be solved by the present invention is to inhibit a plurality of kinases and signals such as CDK1, CDK2, Aurora-A, Aurora-B, JAK2, which are necessary for cell cycle, cell proliferation or survival of cancer stem cells 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. , Aurora-A, Aurora-B, JAK2 and other kinases have been found to have an excellent antitumor effect by having a high inhibitory effect on kinases. In addition, among the preferred compounds of the present invention, the compound has a PK profile based on metabolic stability, weak cardiotoxicity and weak toxicity to normal cells, and the present invention has been completed. .

  That is, the present invention is as follows.

[Claim 1]
Formula (1):

［式（１）中、
Ｘは、窒素原子またはＣＲ^５を示し；
Ｙは、水素原子、Ｃ_１−６アルキル（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルコキシおよびＣ_３−１０シクロアルキルから選択される１〜３個の基で置換されていてもよい）、Ｃ_３−１０シクロアルキル（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルキルおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）または３員〜８員の飽和複素環（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルキルおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）を示し；
Ｒ^１ａ、Ｒ^１ｂ、Ｒ^１ｃ、Ｒ^１ｄおよびＲ^１ｅは、同一または異なって、水素原子、ハロゲン原子、ヒドロキシ、シアノ、ニトロ、Ｃ_１−６アルキル（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜３個の基で置換されていてもよい）、Ｃ_１−６アルコキシ（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜３個の基で置換されていてもよい）、アミノ、Ｃ_１−６アルキルアミノ（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜３個の基で置換されていてもよい）、Ｃ_２−１２ジアルキルアミノ（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜６個の基で置換されていてもよい）、３〜６員の環状アミノ（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルキルおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）またはＣ_１−６アルキルカルボニル（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜３個の基で置換されていてもよい）を示し；
Ｒ^４は、水素原子、シアノ、ヒドロキシ、Ｃ_１−６アルキル（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜３個の基で置換されていてもよい）またはＣ_３−１０シクロアルキル（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）を示し；
Ｒ^２、Ｒ^３およびＲ^５は、同一または異なって、水素原子、ハロゲン原子、ヒドロキシ、シアノ、ニトロ、Ｃ_１−６アルキル（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルコキシおよびＣ_３−１０シクロアルキルから選択される１〜３個の基で置換されていてもよい）、Ｃ_１−６アルコキシ（該基は、１〜３個のハロゲン原子で置換されていてもよい）、アミノ、Ｃ_１−６アルキルアミノ（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜３個の基で置換されていてもよい）、Ｃ_２−１２ジアルキルアミノ（該基は、ハロゲン原子、ヒドロキシおよびＣ_１−６アルコキシから選択される１〜６個の基で置換されていてもよい）、３〜６員の環状アミノ（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルキルおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）、Ｃ_１−６アルキルカルボニル（該基は、１〜３個のハロゲン原子で置換されていてもよい）、Ｃ_３−１０シクロアルキル（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルキルおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）、３員〜８員の飽和複素環（該基は、ハロゲン原子、ヒドロキシ、Ｃ_１−６アルキルおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）、Ｃ_６−１０アリール（該基は、ハロゲン原子、Ｃ_１−６アルキルおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）または５員〜１０員の単環式もしくは多環式のヘテロアリール（該基は、ハロゲン原子、Ｃ_１−６アルキルおよびＣ_１−６アルコキシから選択される１〜４個の基で置換されていてもよい）を示し；
Ａｒは、Ｃ_６−１０の単環式もしくは多環式のアリールまたは５員〜１０員の単環式もしくは多環式のヘテロアリールを示す]
で表される化合物またはその薬理学上許容される塩。

[In Formula (1),
X represents a nitrogen atom or CR ⁵ ;
Y is a hydrogen atom, C _1-6 alkyl (the group may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy, C _1-6 alkoxy and C _3-10 cycloalkyl). ), C _3-10 cycloalkyl (which group may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) or 3 members Represents a ˜8 membered saturated heterocyclic ring, which group may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy;
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 groups selected from _-6 alkoxy), C _1-6 alkoxy (the group is selected from 1 to 3 groups selected from halogen atom, hydroxy and C _1-6 alkoxy) Or a C _1-6 alkylamino group (which may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy). C _2-12 dialkylamino (the group may be substituted with 1 to 6 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy), 3 to 6 members A cyclic amino group (which may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) or C _1-6 alkylcarbonyl ( The group may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy;
R ⁴ represents a hydrogen atom, cyano, hydroxy, C _1-6 alkyl (the group may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy) or C _3-10 cycloalkyl (the group may be substituted with 1 to 4 groups 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} cycloalkyl optionally substituted with 1 to 3 groups selected from cycloalkyl), C _1-6 alkoxy (this group optionally substituted with 1 to 3 halogen atoms), amino , C _1-6 alkylamino (the group may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy), C _2-12 dialkylamino (the group Is optionally substituted with 1 to 6 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy), 3 to 6 membered cyclic amino (the group is a halogen atom, hydroxy, C Optionally substituted with 1 to 4 groups selected from _1-6 alkyl and C _1-6 alkoxy), C _1-6 alkylcarbonyl (the group is substituted with 1 to 3 halogen atoms) C _3-10 cycloalkyl (the group may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy). ) 3 to 8 membered saturated heterocyclic ring (this group may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) , C _6-10 aryl (the group may be substituted with 1 to 4 groups selected from a halogen atom, C _1-6 alkyl and C _1-6 alkoxy) or 5 to 10 membered Monocyclic or polycyclic hetero ants (The group may be substituted with 1 to 4 groups selected from a halogen atom, 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 ^5. 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). 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]
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 pharmacologically Acceptable salt.

[Claim 7]
R ⁴ represents 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 represented by 1 to 4 fluorine atoms). 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 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.

[Claim 9]
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 is selected from a fluorine atom and C _1-6 alkoxy) Item 1-8, which may be substituted with ˜3 groups) or C _1-6 alkoxy (the group may be substituted with 1 to 3 fluorine atoms). 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 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 9 or a pharmacologically acceptable salt thereof.

[Section 11]
Item 11. The compound or the drug according to any one of Items 1 to 10, 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 12]
Item Y is a hydrogen atom or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms), or a pharmacological compound thereof. 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 according to any one of Items 1 to 13, or a pharmacologically acceptable salt thereof, wherein at least two of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are 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,
(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 and
1- (3,4-difluorophenyl) -1- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) ethan-1-ol The compound according to claim 1 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,
(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 and
Item 2. The item according to Item 1, which is a compound selected from (2,3-difluorophenyl) (4-methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) methanol. A compound or a pharmacologically acceptable salt thereof.

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

[Section 19]
Item 18. A kinase inhibitor comprising the compound according to any one of Items 1 to 17 or a pharmacologically acceptable salt thereof as an active ingredient.

[Section 20]
Item 18. An anticancer agent comprising the compound according to any one of Items 1 to 17 or a pharmacologically acceptable salt thereof as an active ingredient.

[Claim 21]
Item 21. 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.

[Item 22]
Treating and / or preventing cancer, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound according to any one of Items 1 to 17 or a pharmacologically acceptable salt thereof; Way for.

[Section 23]
Item 22. The method for treatment and / or prevention according to Item 22, 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. .

[Claim 24]
Item 18. Use of the compound according to any one of Items 1 to 17 or a pharmacologically acceptable salt thereof for producing a therapeutic and / or prophylactic agent for cancer.

[Claim 25]
Item 25. The use according to Item 24, 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.

[Claim 26]
Item 18. The compound according to any one of Items 1 to 17 or a pharmacologically acceptable salt thereof for use in the treatment and / or prevention of cancer.

[Section 27]
Item 26. The compound according to Item 26 or a pharmacologically acceptable salt thereof, wherein the cancer is hematological cancer, myeloma, liver cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma, colon cancer, breast cancer, skin cancer or epithelial cell cancer. Salt.

  The compound represented by the formula (1), or a pharmacologically acceptable salt thereof (sometimes referred to as a compound of the present invention) is a combination of CDK1, CDK2, JAK2, Aurora A or Aurora B, 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.

FIG. 1 shows the measurement results of tumor diameters obtained by conducting the test shown in Test Example 7 for the compound obtained in Example 4. 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). FIG. 2 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 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's t-test). FIG. 3 shows the measurement results of the tumor diameters obtained by conducting the test shown in Test Example 8 for the compound obtained in Example 4. 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). FIG. 4 shows the measurement results of body weight of the compound obtained in Example 4 in which the test shown in Test Example 8 was performed. 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).

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, including a partially crosslinked structure. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl and the like. Preferable “C _3-10 cycloalkyl” includes C _3-8 cycloalkyl, more preferably C _3-6 cycloalkyl.
“C _3-8 cycloalkyl” means cyclic alkyl having 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 cyclic alkyl having 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 in the above “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. Preferable “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. Preferable “C _1-6 alkylamino” includes “C _1-4 alkylamino”.
Examples of "C _1-4 alkylamino" include methylamino carbon atoms is 1 to 4 of the specific examples of "C _1-6 alkylamino", 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. Amino, ethylbutylamino, dibutylamino, diisobutylamino, ditert-butylamino, dipentylamino, dihexylamino and the like can be mentioned. Preferable “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 a 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 the “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. Preferred “3- to 6-membered cyclic amino” includes “5- to 6-membered cyclic amino”.
Specific examples of “5-membered to 6-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. Further, 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. Preferred “3- to 8-membered saturated heterocyclic rings” include monocyclic 5 to 6-membered saturated heterocyclic groups (“5 to 6-membered monocyclic saturated heterocyclic rings”).
Specific examples of “5- to 6-membered monocyclic saturated heterocyclic ring” include pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, which are monocyclic 5 to 6-membered members in the specific example of “3- to 8-membered saturated heterocyclic ring”. , 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 “5- to 10-membered monocyclic or polycyclic heteroaryl” is a 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.

In the compounds of the present invention, some or all of the atoms are isotopic elements (for example, D, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ³⁵ S, ¹⁸ F, ¹²⁵ I Etc.), and these compounds are also included in the compounds of the present invention.

  A 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 1 to 3 groups selected from an atom and C _1-6 alkoxy) or C _1-6 alkoxy (the group may be substituted with 1 to 3 fluorine atoms) )
Is mentioned. 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 preferably, 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) may be mentioned. It is done. Even more preferred are C _1-3 alkyl (which may be 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.

  Examples of the “pharmacologically acceptable salt” 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 Organic acid salts such as salts, propionates, benzoates, trifluoroacetates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, camphorsulfonates, etc., as base addition salts Inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt and ammonium salt, or organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt and diisopropylammonium salt, etc. 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 also includes a prodrug of the compound represented by 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 compounds of the present invention also include 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 by 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, Aurora-A, Aurora-B, 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 with reference to examples, 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:
A compound of formula (A-3) is synthesized 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 as necessary. Can do. Although there is no limitation in particular as a base, For example, a triethylamine, a diisopropyl ethylamine, a 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 hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, hydroxylated 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 1-2:
A compound of formula (A-2) wherein X is a carbon atom is optionally combined with a compound of formula (A-1) and Ulmann 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 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)):
A compound of formula (A-5) is synthesized 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. Although there is no limitation in particular as a base, For example, a triethylamine, a diisopropyl ethylamine, a 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 hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, hydroxylated The solvent may be any solvent that does not react under the reaction conditions in this step. Specific examples include inorganic bases such as methanothium and potassium hydroxide. Alcohol solvents such as ethanol, ethanol, 2-propanol, t-butanol, for example, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran, methylcyclopentyl ether, anisole, 1,4-dioxane, benzene, toluene, chlorobenzene Aromatic solvents such as xylene, ester solvents such as ethyl acetate and methyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, 1,3-dimethyl- An aprotic solvent such as 2-imidazolidinone and dimethyl sulfoxide, water, or a mixture thereof can be used.
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 as necessary.
Although there is no limitation in particular as a base, For example, a triethylamine, a diisopropyl ethylamine, a 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) and the like. 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.

Process for producing compound represented by formula (A-6) Step 4:
Synthesizing a compound of formula (A-6) by reacting a compound of formula (A-3) wherein 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 −80 ° C. to heating under reflux, and is usually −10 ° C. to 25 ° C. The reaction time is usually 30 minutes to 24 hours.

Process 5 for producing a compound represented by formula (1):
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. Specific examples include alcohol solvents such as methanol and ethanol when using a reducing agent, ether solvents such as tetrahydrofuran and diethyl ether when using an alkyl Grignard reagent, and dimethyl when using an alkylating reagent. 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 formula (1) Can be synthesized.
Examples of the catalyst include metals such as palladium and nickel, salts of transition metals such as ruthenium chloride and palladium acetate, complexes such as a BINAP complex of ruthenium acetate, (R) -RUCY ^™ -Xylbinap, (S) -RUCY ^™ -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, a normal protecting group described in the literature (for example, Protective Groups in Organic Synthesis, 3rd ed., TW Greene, John Wiley & Sons Inc. (1999)) is used. More specifically, examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl. Examples of the hydroxy protecting group include trimethylsilyl and tert-butyldimethylsilyl. Trialkylsilyl, acetyl, benzyl and the like can be mentioned respectively.
Introduction and elimination of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the above-mentioned Protective Groups in Organic Synthesis) or a method according to them.

Throughout this specification, protecting groups, condensing agents, etc. 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, RC 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, for example, as an anticancer agent, and the cancer type to which it is applied is not limited, but specific examples include blood cancer, myeloma, liver cancer, osteosarcoma, skin cancer, epithelial cell carcinoma (midline 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 cancer or not increasing the tumor when administered for the purpose of preventing / 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 the receptor action of the cell growth factor. 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 inhibitor (eg, fadrozol hydrochloride, anastrozo) , Letrozole, exemestane, borozole, formestane, etc.), antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), corticosteroids (eg, dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (eg, , Abiraterone, etc.), retinoids and drugs that delay the metabolism of retinoids (eg, riarosol).

  Examples of the chemotherapeutic agent include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like. 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 styramer, adzeresin, systemustin, vizeresin and their DD Include the formulation and the like.

  Antimetabolites include, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine okphosphatate, 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 their DS 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 the plant-derived anticancer agent include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vincristine sulfate, vindesine, 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 (eg, 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 a peptide having 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 growth 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- (like growth factor) -1, IGF-2, etc.), FGF (fibroblast growth factor) or a substance having substantially the same assay as this (for example, acidic FGF, basic FGF, KGK (keratinocyte growth factor), FGF-10) And other cell growth factors (for example, CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (i tereukin-2), NGF (near growth factor), PDGF (platelet-derived growth factor), TGF-beta (transforming growth factor beta), HGF (hepatocity). 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. Moreover, it can be used in combination with drugs (concomitant drugs) such as antiemetics, sleep inducers, anticonvulsants and the like for the purpose of suppressing the side effects.

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 tumor formation via GPCR.

  Hereinafter, the present invention will be described more specifically with reference examples, examples, and test examples, but the present invention is not limited thereto. 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
(Boc) ₂ O: di-tert-butyl carbonate 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 YMC CombiPrep ODS-A column (5 μm, 50 × 20 min ID), and the solvent was a mixed solvent system of CH ₃ CN (containing 0.035% TFA) and water (containing 0.05% TFA). Using. UV detection was performed at wavelengths of 210 nm, 220 nm, and 254 nm.
The elution conditions are as follows.
Preparative device: Gilson HPLC System
Column: YMC CombiPrep ODS-A 50x20 minI. D.
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 LC / MS analysis conditions for compound identification are as follows.
LC / MS measurement method:
Detection equipment: ACQUITY (registered trademark) SQ deceter (Waters)
HPLC: ACQUITY UPLC (registered trademark) system
Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 um, 2.1 mm × 30 mm)
Solvent: A solution: 0.06% formic acid / H ₂ O, B solution: 0.06% formic acid / MeCN
Gradient condition: 0.0-1.3min Linear gradient from B 2% to 96%
Flow rate: 0.8 mL / min
UV: 220nm and 254nm

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

2,4-Dichloropyrimidine (25.0 g) and N-ethyl-diisopropylamine (30.6 mL) were added to a solution of 5-methyl-pyrazol-3-amine (18.0 g) in ethanol (500 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 (300MHz, 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 at 0 ° C. for 3 hours. 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 solvent 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 THF (170 mL) solution of the compound (3.40 g) obtained in Reference Example 2, a 1.0 M THF solution (68 mL) of 3-methoxyphenylmagnesium bromide was added, 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 ) δ 12.07 (s, 1H), 10.19 (s, 1H), 8.40 (d, 1H), 7.48-7.39 (m, 3H), 7.29-7.25 (m, 1H), 3.80 (s, 3H), 2.16 (s, 3H).

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

To a THF (10 mL) solution of the compound (100 mg) obtained in Reference Example 2 was added a 0.5 M THF solution (3 mL) of 3,4-difluorophenylmagnesium bromide 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 (400MHz, 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 THF (120 mL) solution of the compound (4.0 g) obtained in Reference Example 2, a 1M THF solution (80 mL) of 3,5-dimethoxyphenylmagnesium bromide was added and 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 ) δ 12.08 (s, 1H), 10.19 (s, 1H), 8.39 (d, 1H), 7.00 (s, 2H), 6.83 (s, 1H), 3.77 (s, 6H), 2.16 (s, 3H).

Reference Example 6: 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 (300MHz, DMSO-d ₆ ) δ 10.4 (s, 1H), 7.82 (dd, 1H), 7.45 (d, 1H), 7.42 (d, 1H), 6.57 (s, 1H), 2.47 ( s, 3H), 1.56 (s, 9H).

Reference Example 8: 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 (1.8 g) obtained in Reference Example 7, 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 (300MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.13 (m, 1H), 7.89 (m, 1H), 7.76 (m, 1H), 7.63 (m, 1H), 7.42- 7.33 (m, 2H), 5.94 (s, 1H), 2.11 (s, 3H).

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

To a 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 at room temperature. 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 0.3 M THF solution (8.4 mL) of 3,4,5-trifluorophenylmagnesium bromide 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) -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) -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 (300MHz, DMSO-d ₆ ) δ12.1 (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 was slowly added a 1.0 M THF solution (5.6 mL) of 3,4,5-trifluorophenylmagnesium bromide 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 ) δ12.0 (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 THF (5 mL) solution of the compound (0.2 g) obtained in Reference Example 17 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. A solution of 2,4,5-trifluorophenyl bromide (2.5 g) in THF (6 mL) was slowly added to the reaction mixture under ice cooling. The reaction mixture was warmed to room temperature and stirred for 1 hour to obtain 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 solution of the compound (4.2 g) obtained in Reference Example 2 in THF (30 mL), 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.

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: isol. Dissolve in propyl alcohol: methanol = 7: 3: 5 (1.5 mL) and divide in two steps using a 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 performed. Example 2 (10.9 mg) and Example 3 (10.7 mg ) Respectively.
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-((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 (2.0 g) in isopropanol (10 mL ) To the solution were 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 (400MHz, DMSO-d ₆ ) δ11.89 (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 0.58min,} 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: isopropanol: methanol: triethylamine: acetic acid = 70: 25: 5: 0.1: 0.05, flow rate 1 mL / min) retention time 11. 37 min.

Example 5: (−)-(4-((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- (S) -RUCY ^™ -Xylbinap was used as a catalyst in the same manner as in Example 4. 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: isopropanol: methanol: triethylamine: acetic acid = 70: 25: 5: 0.1: 0.05, flow rate 1 mL / min) Retention time 8. 66 min.

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

Sodium borohydride (23 mg) was added to a solution of the compound (200 mg) obtained in Reference Example 11 in methanol (5 mL), and the mixture was 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 residue obtained by concentrating the organic layer under reduced pressure 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 0.63min,} MS [M + 1] 334.9.
Racemic (6-((5-methyl-1H-pyrazol-3-yl) amino) pyridin-2-yl) (3,4,5-trifluorophenyl) methanol (28.7 g) 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 added to the column Daicel Chiral PAK OJ-H, 4.6 mmφ × 25 cm, the solvent was hexane: ethanol: methanol: ethylenediamine = 40: 40: 20: 0.1, flow rate 1.0 mL / The retention time analyzed in min is 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 by the same method (Synthesis methods A, C, and D) as in Example 1, 2, 3, 4 or 5 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: isopropanol: methanol: triethylamine: acetic acid = 70: 25: 5: 0.1: 0.05, flow rate 1 mL / min

Example 45: (3,4-Difluorophenyl) (4-((5-methyl-1H-pyrazol-3-yl) amino) pyridin-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 (400MHz, DMSO-d ₆ ) δ11.9 (s, 1H), 9.84 (s, 1H), 8.21 (s, 1H), 7.50-7.26 (m, 3H), 5.84 (s, 1H) , 5.53 (d, 1H), 2.18 (s, 3H).

Example 46: 1- (3-Methoxyphenyl) -1- (4-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) ethane-1-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 ) δ 12.10 (s, 1H), 10.00 (s, 1H), 8.29 (s, 1H), 7.12-7.30 (m, 3H), 6.82 (d, 1H) , 5.72 (s, 1H), 3.77 (s, 3H), 2.28 (s, 3H), 1.87 (s, 3H).

Examples 47-52
The compounds of Examples 47 to 52 shown in the following table were obtained in the same manner as in Example 46 using the corresponding starting compounds.

Pharmacological test Although the pharmacological test method and the result of the representative compound 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. NCI-H23 was cultured in RPMI1640 medium containing 10% FCS, 1% penicillin / streptomycin, and HCT116 was cultured in DMEM medium containing 10% FCS, 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, a 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), the concentration (Cytotoxicity IC ₅₀ value; μM) at which 50% cell growth of each test substance was suppressed, and the compound of the present invention against cancer cells 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 are isolated from 6-week-old Crl: CD (SD) male rats. The number of live cells and dead cells in the suspension is counted by trypan blue staining, and viability is calculated, and then a 1.0 × 10 ⁴ cell / 100 μL hepatocyte suspension is prepared. This suspension is 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 is removed from the 384-well cell culture plate, and 50 μL / well of the test substance-containing culture is added (n = 4). After completion of the addition, the culture is 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) is added, stirred, and incubated at 37 ° C. in the presence of 5% CO ₂ for about 3 hours. After incubation, 15 μL / well of 0.1 N HCl was added 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, and 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) is added to prepare a microsome solution. 10 μl of 1 mM test compound in DMSO is diluted 100-fold with acetonitrile. An intermediate dilution is prepared by adding 250 μl of Cofactor solution prepared by dissolving 300 mg of NADPH in 55.2 ml of 125 mM Kpi (pH 7.4) (6.5 mM) 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. make. Separately, 50 μl of the intermediate dilution is taken in 2 wells and incubated in the same manner without adding the microsome solution to prepare an unreacted sample. After completion of the incubation, 400 μl of methanol is added to each well of the reaction sample and unreacted sample. Furthermore, to the well of the unreacted sample, 50 μl of the microsome solution is added and mixed after the addition of methanol. After standing at −20 ° C. for 30 minutes, the mixture was centrifuged, and 10 μl of the supernatant was injected into an LC-MS / MS system (HPLC manufactured by Shimadzu Corporation, API 4000 manufactured by AB Sciex). A total of 4 wells were measured, and the average value of each chromatographic peak area value was calculated. The clearance of the compound was calculated | required by the following formula | equation using a natural logarithm (LN) using this value.
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 is measured using QPatch HT (Sophion), the concentration at which each test substance suppresses 50% hERG current (IC ₅₀ value; μM) is calculated, and the hERG inhibitory activity of the compound of the present invention is weak. confirmed.

  About the compound obtained in the Example, the test shown in Test example 1-Test example 4 was done. 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 × concentration test substance solution, 5 μL of 4 × concentration substrate / ATP / Metal solution and 10 μL of double concentration kinase solution were mixed in wells of a polypropylene 384 well plate and allowed to react 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.

＊塩酸塩のデータ

* Hydrochloride data

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) × minor axis (mm) × minor axis (mm) × 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 completion of test substance administration T0: Average tumor volume at the start of test substance administration C: Average tumor volume after completion of vehicle administration C0: Average tumor volume at the start of vehicle administration Average weight of each administration group is used The weight change rate was calculated from the following formula.
Weight change rate (%) = 100 × (T / T0) / (C / C0)
T: Average body weight after completion of test substance administration T0: Average body weight at start of test substance administration C: Average body weight after completion of vehicle administration C0: Average body weight at 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.

＊＊：ｐ＜０．０５，Ｄｕｎｎｅｔｔ’ｓ ｔｅｓｔ

**: p <0.05, Dunnett's test

Test Example 7: Tumor Growth Inhibition Experiment in HCC-1806 Human Breast Cancer Cell Carrying Mice HCC-1806 cells (ATCC) were suspended in HBSS and 5-week-old female BALB / cAnNCrj-nu / nu mice (Nippon Charles River) 3 × 10 ⁶ were transplanted subcutaneously in the ventral part of each other. 7 days after transplantation, test substance suspended in 0.5% methylcellulose solution (Wako Pure Chemical Industries) (200 mg / kg, orally administered twice a day), 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 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 to 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-administered group and the test substance-docetaxel combination group 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) × minor axis (mm) × minor axis (mm) × 1/2

  About the compound obtained in Example 4, the measurement result of the tumor diameter which performed the test shown in Test Example 7 is shown in FIG. On the last day of drug administration, the tumor volume of the docetaxel administration group and the test substance and docetaxel combination administration group was significantly suppressed compared to that of 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.

  About the compound obtained in Example 4, the measurement result of the body weight which performed the test shown in Test Example 7 is shown in FIG. 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, Students'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 (Nippon Charles River) 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) × minor axis (mm) × minor axis (mm) × 1/2
3 and 4 show average values and standard errors.

  About the compound obtained in Example 4, the measurement result of the tumor diameter which performed the test shown in Test Example 8 is shown in FIG. 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).

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

  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 (24)

Formula (1):

[In Formula (1),
X represents a nitrogen atom or CR ⁵ ;
Y is a hydrogen atom, C _1-6 alkyl (the group may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy, C _1-6 alkoxy and C _3-10 cycloalkyl). ), C _3-10 cycloalkyl (which group may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) or 3 members Represents a ˜8 membered saturated heterocyclic ring, which group may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy;
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 groups selected from _-6 alkoxy), C _1-6 alkoxy (the group is selected from 1 to 3 groups selected from halogen atom, hydroxy and C _1-6 alkoxy) Or a C _1-6 alkylamino group (which may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy). C _2-12 dialkylamino (the group may be substituted with 1 to 6 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy), 3 to 6 members A cyclic amino group (which may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) or C _1-6 alkylcarbonyl ( The group may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy;
R ⁴ represents a hydrogen atom, cyano, hydroxy, C _1-6 alkyl (the group may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy) or C _3-10 cycloalkyl (the group may be substituted with 1 to 4 groups 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} cycloalkyl optionally substituted with 1 to 3 groups selected from cycloalkyl), C _1-6 alkoxy (this group optionally substituted with 1 to 3 halogen atoms), amino , C _1-6 alkylamino (the group may be substituted with 1 to 3 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy), C _2-12 dialkylamino (the group Is optionally substituted with 1 to 6 groups selected from a halogen atom, hydroxy and C _1-6 alkoxy), 3 to 6 membered cyclic amino (the group is a halogen atom, hydroxy, C Optionally substituted with 1 to 4 groups selected from _1-6 alkyl and C _1-6 alkoxy), C _1-6 alkylcarbonyl (the group is substituted with 1 to 3 halogen atoms) C _3-10 cycloalkyl (the group may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy). ) 3 to 8 membered saturated heterocyclic ring (this group may be substituted with 1 to 4 groups selected from a halogen atom, hydroxy, C _1-6 alkyl and C _1-6 alkoxy) , C _6-10 aryl (the group may be substituted with 1 to 4 groups selected from a halogen atom, C _1-6 alkyl and C _1-6 alkoxy) or 5 to 10 membered Monocyclic or polycyclic hetero ants (The group may be substituted with 1 to 4 groups selected from a halogen atom, 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.   The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein Ar is phenyl or pyridyl.   The compound or pharmacologically acceptable salt thereof according to claim 1 or 2, wherein Ar is phenyl. X is CR ⁵ ;
The compound according to claim 1, 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.   X is a nitrogen atom, The compound or its pharmacologically acceptable salt as described in any one of Claims 1-3. Y is a hydrogen atom or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms), or the compound or pharmacology thereof according to any one of claims 1 to 5. Top acceptable salt. R ⁴ represents 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 represented by 1 to 4 fluorine atoms). The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 6, which may be substituted with an atom). R ² and R ³ 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). 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 is selected from a fluorine atom and C _1-6 alkoxy) Or optionally substituted with 1 to 3 groups) or C _1-6 alkoxy (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 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 9, or a pharmacologically acceptable salt thereof. R ⁴ is C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms) or cyclopropyl, or a compound according to any one of claims 1 to 10 or a compound thereof Pharmacologically acceptable salt. Y is a hydrogen atom or C _1-6 alkyl (the group may be substituted with 1 to 3 fluorine atoms), or the compound or pharmacology thereof according to any one of claims 1 to 11. Top 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 and
1- (3,4-difluorophenyl) -1- (4-methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) ethan-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 and
2. (2,3-Difluorophenyl) (4-methyl-6-((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) A compound selected from methanol. Or a pharmacologically acceptable salt thereof.   The pharmaceutical composition containing the compound as described in any one of Claims 1-14, or its pharmacologically acceptable salt.   The kinase inhibitor which contains the compound as described in any one of Claims 1-14, or its pharmacologically acceptable salt as an active ingredient.   The anticancer agent which contains the compound as described in any one of Claims 1-14, or its salt accept | permitted pharmacologically as an active ingredient.   The anticancer agent according to claim 14, 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.   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 to 14 or a pharmacologically acceptable salt thereof. How to do.   The cancer for treatment and / or prevention according to claim 19, 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. Method.   Use of the compound according to any one of claims 1 to 14 or a pharmacologically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for cancer.   The use according to claim 21, 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.   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.   24. The compound according to claim 23 or a pharmacologically acceptable salt thereof, 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. Salt.

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