JPWO2004043936A1 - PLK inhibitor - Google Patents

Abstract

Formula (I) [wherein Ar represents a substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group, Z1 and Z2 are the same or different and represent a nitrogen atom (N) or CH; Represents a hydrogen atom, substituted or unsubstituted lower alkyl, cyano, tetrazolyl and the like. 1) When X represents cyano or tetrazolyl, Y represents a hydrogen atom, R1 represents -OR2 (wherein R2 represents substituted or non-substituted). W represents -NHCR5R6- (wherein R5 and R6 are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl), and the like. 2) X is cyano. And Y represents a hydrogen atom, a substituted or unsubstituted lower alkyl, or the like, and R1 represents —OR2A (wherein R2A represents a substituted or unsubstituted group). W represents -NHCR5BR6B- (wherein R5B and R6B are the same or different and represent a hydrogen atom, halogen, etc.), etc.] or a pharmacologically thereof Polo-like kinase (PLK) inhibitors and the like containing an acceptable salt as an active ingredient are provided.

Description

  The present invention relates to Polo-like kinase (PLK) inhibitors, pyrimidine derivatives having PLK inhibitory activity or antitumor activity, and the like.

In the cell cycle, the mitotic phase (M phase) is an important step for distributing eukaryotic chromosomes and transmitting accurate genetic information to daughter cells and is strictly controlled. It is known that various protein kinases are involved in the progression of M phase. The PLK family is a group of serine threonine kinases that are involved in various stages in eukaryotes from entry to exit of M phase [Jeans & Dev., 12, p. 3777 (1998). Year)]. The isolation of the mammalian (mouse) PLK gene was first reported by Hamanaka et al. In 1994 [Cell Growth & Diff., Volume 5, 249 (1994)]. .
In many cancer tissues, PLK is overexpressed compared to normal cells, and is considered to be involved in canceration and progression of cancer [US 6180380; International Journal of Oncology (Int. J. Oncol). .), 15, 687 (1999)]. In non-small cell lung cancer, head and neck cancer, and ovarian cancer, there is a correlation between high expression of PLK and cancer malignancy and prognosis recurrence [Oncogene, 14, 543 (1997); International • Journal of Cancer (Int. J. Cancer), 89, 535 (2000); Cancer Letters, 169, 41 (2000)].
In an experiment of introducing a PLK function-inhibiting mutant, it has been reported that PLK inhibition induces cell death in cancer cells at a higher rate than normal cells [Cell Growth & Diff.]. 11, 615 (2000)]. It has also been reported that antisense oligonucleotides of PLK show an antitumor effect in the mouse Xenograft model [Biochemical and Biophysical Research Communications (Biochem. Biophys. Res. Comm.), 260, 352 (2000)].
In addition, the expression of PLK is increased in the brains of Alzheimer's disease patients, and the relationship between neurodegenerative diseases and PLK is becoming clear [Neurobiology of Aging (Neurobiol.Aging), Vol. 21, p. 837 ( 2000)]. From this, it is considered that the PLK inhibitor is also useful as a therapeutic agent for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Furthermore, peripheral blood-derived quiescent lymphocytes do not express PLK, but PLK expression is induced by phytohemagglutinin stimulation or IL-2 stimulation (US6180380). From this, it is considered that the PLK inhibitor is also useful as a therapeutic agent for diseases related to activation of the immune system, for example, allergy and rheumatism.
As described above, drugs that inhibit PLK are considered promising as therapeutic agents for diseases associated with abnormal cell signaling such as cancer, neurodegenerative diseases, and allergic diseases.
As a compound showing PLK enzyme inhibitory activity, scytonemin isolated from cyanobacteria has been reported (WO 01/62900).
The following compounds are known as pyrimidine derivatives having a cyano or heterocyclic group at the 5-position.
A pyrimidine derivative in which Z ¹ and Z ² are N, X is cyano, and the group corresponding to W-Ar is aromatic amino is used as a KDR kinase and / or FGFr kinase inhibitor (WO 00 Pyramidine derivatives in which Z ¹ and Z ² are N and R ¹ is a bicyclic aromatic heterocyclic group as a Src kinase inhibitor (WO 01/00213), A pyrimidine derivative in which Z ¹ and Z ² in formula (I) are N, X is cyano, R ¹ is amino, and the group corresponding to W-Ar is aromatic amino is a cyclin-dependent kinase (CDK) inhibitor (WO 01/72717), a derivative in which X is cyano in the following formula (I) is a CD40 function inhibitor (Japanese Patent Laid-Open No. 2001-89452), and in the following formula (I) In Te ^{Z 1} and ^{Z 2} is N, X is cyano, W-Ar pyrimidine derivative corresponding group is an aromatic amino to as a glycogen synthase kinase-3 inhibitors (WO 02/04429), hereinafter the formula (I ) Is a glycogen synthase kinase 3 inhibitor (WO 99/65897, WO 02/20495), and a pyrimidine derivative in which Z ¹ and Z ² are N in the following formula (I) Are known as antiviral agents (WO 99/41253) or antitumor agents (WO 00/39101), respectively.
Further, there is known a compound in which Z ¹ and Z ² are N, R ¹ is amino, and X is tetrazolyl in the formula (I) described later [Chemicker-Zeitung, Vol. 112, page 135] (1988)].

［式中、Ａｒは置換もしくは非置換のアリールまたは置換もしくは非置換の芳香族複素環基を表し、
Ｚ^１及びＺ^２は、同一または異なって窒素原子（Ｎ）またはＣＨを表し、
Ｘは水素原子、ニトロ、カルボキシ、低級アルコキシカルボニル、置換もしくは非置換の低級アルキル、置換もしくは非置換のシクロアルキル、−ＣＯＮＨＲ^７（式中、Ｒ^７は水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアラルキルまたは置換もしくは非置換の複素環アルキルを表す）、シアノまたはテトラゾリルを表し、
１）Ｘがシアノまたはテトラゾリルを表す場合、
Ｙは水素原子を表し、
Ｒ^１は−ＯＲ^２（式中、Ｒ^２は置換もしくは非置換の低級アルキルを表す）または−ＮＲ^３Ｒ^４（式中、Ｒ^３は置換もしくは非置換の低級アルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアラルキルまたは置換もしくは非置換のアリールを表し、Ｒ^４は水素原子または置換もしくは非置換の低級アルキルを表すか、またはＲ^３とＲ^４が隣接する窒素原子と一緒になって置換もしくは非置換の複素環基を形成する）を表し、
Ｗは−ＮＨＣＲ^５Ｒ^６−（式中、Ｒ^５及びＲ^６は同一または異なって水素原子または置換もしくは非置換の低級アルキルを表す）または−ＮＨＣＲ^５Ｒ^６ＣＲ^５ＡＲ^６Ａ−（式中、Ｒ^５及びＲ^６はそれぞれ前記と同義であり、Ｒ^５Ａ及びＲ^６Ａはそれぞれ前記Ｒ^５及びＲ^６と同義である）を表し、
２）Ｘがシアノ及びテトラゾリル以外の基を表す場合、
Ｙは水素原子、ニトロ、カルボキシ、低級アルコキシカルボニル、置換もしくは非置換の低級アルキル、置換もしくは非置換のシクロアルキルまたは−ＣＯＮＨＲ^７Ａ（式中、Ｒ^７Ａは水素原子、置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアラルキルまたは置換もしくは非置換の複素環アルキルを表す）を表し、
Ｒ^１は−ＯＲ^２Ａ（式中、Ｒ^２Ａは置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアラルキル、置換もしくは非置換のアリールまたは置換もしくは非置換の複素環基を表す）、−ＳＲ^２Ｂ（式中、Ｒ^２Ｂは前記Ｒ^２Ａと同義である）または−ＮＲ^３ＡＲ^４Ａ（式中、Ｒ^３Ａは置換もしくは非置換の低級アルキル、置換もしくは非置換の低級アルケニル、置換もしくは非置換の低級アルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアラルキル、置換もしくは非置換のアリールまたは置換もしくは非置換の複素環基を表し、Ｒ^４Ａは水素原子または置換もしくは非置換の低級アルキルを表すか、またはＲ^３ＡとＲ^４Ａが隣接する窒素原子と一緒になって置換もしくは非置換の複素環基を形成する）を表し、
Ｗは−ＮＨＣＲ^５ＢＲ^６Ｂ−（式中、Ｒ^５Ｂ及びＲ^６Ｂは同一または異なって水素原子、ハロゲンまたは置換もしくは非置換の低級アルキルを表す）、−ＮＨＣＲ^５ＢＲ^６ＢＣＲ^５ＣＲ^６Ｃ−（式中、Ｒ^５Ｂ及びＲ^６Ｂはそれぞれ前記と同義であり、Ｒ^５Ｃ及びＲ^６Ｃはそれぞれ前記Ｒ^５Ｂ及びＲ^６Ｂと同義である）または−ＮＨＣＲ^５ＢＲ^６ＢＣＲ^５ＣＲ^６ＣＣＲ^５ＤＲ^６Ｄ−（式中、Ｒ^５Ｂ、Ｒ^６Ｂ、Ｒ^５Ｃ及びＲ^６Ｃはそれぞれ前記と同義であり、Ｒ^５Ｄ及びＲ^６Ｄはそれぞれ前記Ｒ^５Ｂ及びＲ^６Ｂと同義である）を表す］で表される化合物またはその薬理学的に許容される塩を有効成分として含有するＰＬＫ阻害剤。
（２）Ｘがシアノまたはテトラゾリルであり、
Ｒ^１が−ＯＲ^２ａ（式中、Ｒ^２ａは低級アルキル、シクロアルキルアルキルまたは脂環式複素環アルキルを表す）または−ＮＲ^３Ｒ^４（式中、Ｒ^３及びＲ^４はそれぞれ前記と同義である）であり、
Ｚ^１及びＺ^２が窒素原子（Ｎ）である前記（１）記載のＰＬＫ阻害剤。
（３）式（ＩＡ）

［式中、Ａｒ^Ａは置換または非置換の芳香族複素環基を表し、
ｎは０または１を表し、
Ｒ^８は−ＯＲ^１０（式中、Ｒ^１０は低級アルキル、シクロアルキルアルキルまたは脂環式複素環アルキルを表す）または−ＮＲ^１１Ｒ^１２（式中、Ｒ^１１は低級アルキル、シクロアルキルアルキルまたは置換もしくは非置換のアリールを表し、Ｒ^１２は水素原子または低級アルキルを表すか、またはＲ^１１とＲ^１２が隣接する窒素原子と一緒になってテトラヒドロイソキノリン−２−イル、３，５−ジメチルピペリジノまたは２，６−ジメチルモルホリノを形成する）を表し、
Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃ及びＲ^９ｄは、同一または異なって水素原子または低級アルキルを表す］で表されるピリミジン誘導体またはその薬理学的に許容される塩。
（４）Ｒ^８が−ＮＨＲ^１１ａ（式中、Ｒ^１１ａは置換もしくは非置換のアリールを表す）であり、Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃ及びＲ^９ｄが水素原子である前記（３）記載のピリミジン誘導体またはその薬理学的に許容される塩。
（５）式（ＩＢ）

｛式中、ｎ^ａは０または１を表し、
Ｒ^１３は−ＯＲ^１７（式中、Ｒ^１７はシクロアルキルアルキルまたは含酸素脂環式複素環アルキルを表す）または−ＮＲ^１８Ｒ^１９［式中、Ｒ^１８は低級アルキル、シクロアルキルアルキル、置換もしくは非置換のアリールまたは式（ＩＩ）

（式中、ｎ^ｂは１〜３の整数を表す）で表される基を表し、Ｒ^１９は水素原子または低級アルキルを表すか、またはＲ^１８とＲ^１９が隣接する窒素原子と一緒になってテトラヒドロイソキノリン−２−イル、３，５−ジメチルピペリジノまたは２，６−ジメチルモルホリノを形成する］を表し、
Ｒ^１４ａ、Ｒ^１４ｂ、Ｒ^１４ｃ及びＲ^１４ｄは、同一または異なって水素原子または低級アルキルを表し、Ｒ^１５及びＲ^１６は同一または異なって水素原子、ハロゲン、低級アルキルまたは低級アルコキシを表すか、またはＲ^１５とＲ^１６が一緒になって−Ｏ（ＣＨ_２）_ｍＯ−（式中、ｍは１または２を表す）を形成する｝で表されるピリミジン誘導体またはその薬理学的に許容される塩。
（６）ｎ^ａが０であり、Ｒ^１５及びＲ^１６が同一または異なって水素原子または低級アルコキシであるか、またはＲ^１５とＲ^１６が一緒になって−ＯＣＨ_２Ｏ−である前記（５）記載のピリミジン誘導体またはその薬理学的に許容される塩。
（７）前記（１）または（２）に記載の化合物またはその薬理学的に許容される塩を有効成分として含有するＰＬＫが関与する疾患の予防及び／または治療剤。
（８）ＰＬＫ阻害剤の製造のための、前記（１）または（２）に記載の化合物またはその薬理学的に許容される塩の使用。
（９）ＰＬＫが関与する疾患の予防及び／または治療剤の製造のための、前記（１）または（２）に記載の化合物またはその薬理学的に許容される塩の使用。
（１０）前記（１）または（２）に記載の化合物またはその薬理学的に許容される塩の有効量を投与する工程を含む、ＰＬＫが関与する疾患の予防及び／または治療方法。
（１１）前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩を有効成分として含有するＰＬＫ阻害剤。
（１２）前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩を有効成分として含有するＰＬＫが関与する疾患の予防及び／または治療剤。
（１３）前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩を有効成分として含有する抗腫瘍剤。
（１４）前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩を有効成分として含有する医薬。
（１５）ＰＬＫ阻害剤の製造のための、前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩の使用。
（１６）ＰＬＫが関与する疾患の予防及び／または治療剤の製造のための、前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩の使用。
（１７）前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩の有効量を投与する工程を含む、ＰＬＫが関与する疾患の予防及び／または治療方法。
（１８）抗腫瘍剤の製造のための、前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩の使用。
（１９）前記（３）〜（６）のいずれかに記載のピリミジン誘導体またはその薬理学的に許容される塩の有効量を投与する工程を含む、腫瘍の予防及び／または治療方法。
以下、式（Ｉ）、（ＩＡ）及び（ＩＢ）で表される化合物をそれぞれ化合物（Ｉ）、（ＩＡ）及び（ＩＢ）という。他の式番号の化合物についても同様である。
式（Ｉ）、（ＩＡ）及び（ＩＢ）の各基の定義において、以下の例示が挙げられる。
（ｉ）ハロゲンは、フッ素、塩素、臭素及びヨウ素の各原子を表す。
（ｉｉ）低級アルキル、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分としては、例えば直鎖または分岐状の炭素数１〜１０のアルキルが挙げられ、具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、ヘプチル、オクチル、イソオクチル、ノニル、デシル等が挙げられる。
（ｉｉｉ）シクロアルキル及びシクロアルキルアルキルのシクロアルキル部分としては、例えば炭素数３〜８のシクロアルキルが挙げられ、具体的にはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。
（ｉｖ）低級アルケニルとしては、例えば直鎖、分岐または環状の炭素数２〜８のアルケニルが挙げられ、具体的にはビニル、アリル、１−プロペニル、ブテニル、ペンテニル、ヘキセニル、ヘプテニル、オクテニル、シクロヘキセニル、２，６−オクタジエニル等が挙げられる。
（ｖ）低級アルキニルとしては、例えば直鎖または分岐状の炭素数２〜８のアルキニルが挙げられ、具体的にはエチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル等が挙げられる。
（ｖｉ）アリールとしては、例えば炭素数６〜１４の単環式、二環式または三環式のアリール及び炭素数８〜１４のベンゾシクロアルキルが挙げられ、具体的にはフェニル、ナフチル、インデニル、アントラニル、インダニル、１，２，３，４−テトラヒドロナフチル、６，７，８，９−５Ｈ−ベンゾシクロヘプチル等が挙げられる。
（ｖｉｉ）アラルキル、複素環アルキル、脂環式複素環アルキル、含酸素脂環式複素環アルキル及びシクロアルキルアルキルのアルキレン部分は、前記低級アルキル（ｉｉ）の定義から水素を一つ除いたものと同義である。
（ｖｉｉｉ）アラルキルのアリール部分としては、前記アリール（ｖｉ）の定義で挙げた基が挙げられる。
（ｉｘ）複素環基及び複素環アルキルの複素環基部分としては、例えば窒素原子、酸素原子及び硫黄原子から選ばれる少なくとも１個の原子を含む５員、６員または７員の単環式複素環基、３〜８員の環が縮合した二環または三環式であって窒素原子、酸素原子及び硫黄原子から選ばれる少なくとも１個の原子を含む縮環式複素環基等が挙げられ、具体的にはピリジル、ピラジニル、ピリミジニル、ピリダジニル、ベンゾイミダゾリル、２−オキソベンゾイミダゾリル、ベンゾトリアゾリル、ベンゾフリル、ベンゾチエニル、プリニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾジオキソリル、インダゾリル、インドリル、イソインドリル、キノリル、イソキノリル、フタラジニル、ナフチリジニル、キノキサリニル、ピロリル、ピラゾリル、キナゾリニル、シンノリニル、トリアゾリル、テトラゾリル、イミダゾリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、チエニル、フリル、ピロリジニル、２，５−ジオキソピロリジニル、チアゾリジニル、オキサゾリジニル、ピペリジル、ピペリジノ、ピペラジニル、ホモピペラジニル、ホモピペリジル、ホモピペリジノ、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ピラニル、テトラヒドロピリジル、テトラヒドロピラニル、テトラヒドロフラニル、テトラヒドロキノリル、テトラヒドロイソキノリル、オクタヒドロキノリル、インドリニル等が挙げられる。脂環式複素環アルキルの脂環式複素環基部分は、上記のうち芳香族性を有さないものを表し、芳香族複素環基は上記のうち芳香族性を有するものを表す。また、含酸素脂環式複素環アルキルの含酸素脂環式複素環基部分としては、例えばテトラヒドロフラニル、テトラヒドロピラニル、ジヒドロピラニル、ピラニル等が挙げられる。
（ｘ）隣接する窒素原子と一緒になって形成される複素環基としては、少なくとも１個の窒素原子を含む５員または６員の単環式複素環基（該単環式複素環基は、他の窒素原子、酸素原子または硫黄原子を含んでいてもよい）、３〜８員の環が縮合した二環または三環式で少なくとも１個の窒素原子を含む縮環式複素環基（該縮環式複素環基は、他の窒素原子、酸素原子または硫黄原子を含んでいてもよい）等が挙げられ、具体的にはテトラヒドロピリジル、インドリニル、イソインドリニル、ピロリジニル、チアゾリジニル、オキサゾリジニル、ピペリジノ、ホモピペリジノ、ピペラジニル、ホモピペラジニル、モルホリノ、チオモルホリノ、ペルヒドロアゼピニル、ペルヒドロアゾシニル、テトラヒドロキノリル、テトラヒドロイソキノリル、オクタヒドロキノリル、ベンゾイミダゾリル、インダゾリル、インドリル、イソインドリル、プリニル、ジヒドロインドリル、ピロリル、ピラゾリル、トリアゾリル、テトラゾリル、イミダゾリル等が挙げられる。
（ｘｉ）置換低級アルキルにおける置換基としては、同一または異なって、例えば置換数１〜３の、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルカノイル、低級アルコキシ、シクロアルキル、アリールオキシ、置換アリールオキシ［該置換アリールオキシにおける置換基としては、同一または異なって、例えば置換数１〜３の、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルキル、低級アルコキシ、低級アルコキシカルボニル等が挙げられる。ここでハロゲンは前記ハロゲン（ｉ）と同義であり、低級アルキルは前記低級アルキル（ｉｉ）と同義であり、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］、アラルキルオキシ、置換アラルキルオキシ［該置換アラルキルオキシにおける置換基としては、同一または異なって、例えば置換数１〜３の、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルキル、低級アルコキシ、低級アルコキシカルボニル等が挙げられる。ここでハロゲンは前記ハロゲン（ｉ）と同義であり、低級アルキルは前記低級アルキル（ｉｉ）と同義であり、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］、複素環基、置換複素環基［該置換複素環基における置換基としては、同一または異なって、例えば置換数１〜３の、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルキル、低級アルコキシ、低級アルコキシカルボニル等が挙げられる。ここでハロゲンは前記ハロゲン（ｉ）と同義であり、低級アルキルは前記低級アルキル（ｉｉ）と同義であり、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］、低級アルカノイルオキシ、低級アルコキシカルボニル、低級アルキルチオ、モノまたはジ低級アルキルアミノ、低級アルキルスルホニル、低級アルキルスルフィニル、低級アルコキシカルボニルアミノ、低級アルカノイルアミノ、モノまたはジ低級アルキルアミノカルボニル、モノまたはジ低級アルキルアミノカルボニルオキシ等が挙げられる。
ここで示したハロゲン、アリールオキシ及びアラルキルオキシのアリール部分、シクロアルキル、複素環基ならびに低級アルカノイル、低級アルコキシ、低級アルカノイルオキシ、低級アルコキシカルボニル、低級アルキルチオ、モノまたはジ低級アルキルアミノ、低級アルキルスルホニル、低級アルキルスルフィニル、低級アルコキシカルボニルアミノ、低級アルカノイルアミノ、モノまたはジ低級アルキルアミノカルボニル及びモノまたはジ低級アルキルアミノカルボニルオキシの低級アルキル部分は、それぞれ前記ハロゲン（ｉ）、アリール（ｖｉ）、シクロアルキル（ｉｉｉ）、複素環基（ｉｘ）ならびに低級アルキル（ｉｉ）と同義であり、アラルキルオキシのアルキレン部分は、前記低級アルキル（ｉｉ）から水素を一つ除いたものと同義である。
ジ低級アルキルアミノ、ジ低級アルキルアミノカルボニル及びジ低級アルキルアミノカルボニルオキシの２つの低級アルキル部分は、それぞれ同一でも異なっていてもよい。
（ｘｉｉ）置換アリール、置換アラルキル、置換シクロアルキル、置換低級アルケニル、置換低級アルキニル、置換複素環基、置換複素環アルキル、置換芳香族複素環基及び隣接する窒素原子と一緒になって形成される置換複素環基における置換基としては、前記置換低級アルキルにおける置換基（ｘｉ）の定義で挙げた基に加え、低級アルキル、ハロゲン置換低級アルキル［該ハロゲン置換低級アルキルは、１から置換可能な数のハロゲン、好ましくは１〜６個のハロゲン、より好ましくは１〜３個のハロゲンで置換された低級アルキルである］、アリール、置換アリール［該置換アリールにおける置換基としては、同一または異なって、例えば置換数１〜３の、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルキル、低級アルコキシ、低級アルコキシカルボニル等が挙げられる。ここでハロゲンは前記ハロゲン（ｉ）と同義であり、低級アルキルは前記低級アルキル（ｉｉ）と同義であり、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］、アラルキル、置換アラルキル［該置換アラルキルにおける置換基としては、同一または異なって、例えば置換数１〜３の、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルキル、低級アルコキシ、低級アルコキシカルボニル等が挙げられる。ここでハロゲンは前記ハロゲン（ｉ）と同義であり、低級アルキルは前記低級アルキル（ｉｉ）と同義であり、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］、アリールカルボニル、置換アリールカルボニル［該置換アリールカルボニルにおける置換基としては、同一または異なって、例えば置換数１〜３の、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルキル、低級アルコキシ、低級アルコキシカルボニル等が挙げられる。ここでハロゲンは前記ハロゲン（ｉ）と同義であり、低級アルキルは前記低級アルキル（ｉｉ）と同義であり、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］、複素環アルキル、置換複素環アルキル［該置換複素環アルキルにおける置換基としては、同一または異なって、例えば置換数１〜３の、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルキル、低級アルコキシ、低級アルコキシカルボニル等が挙げられる。ここでハロゲンは前記ハロゲン（ｉ）と同義であり、低級アルキルは前記低級アルキル（ｉｉ）と同義であり、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］、Ｎ−低級アルキル−Ｎ−低級アルカノイルアミノ等が挙げられる。さらに、置換アリール及び隣接する窒素原子と一緒になって形成される置換複素環基における置換基は置換低級アルキル［該低級アルキルは前記低級アルキル（ｉｉ）と同義であり、該置換低級アルキルにおける置換基としては、同一または異なって、例えば置換数１〜３の、ヒドロキシ、カルボキシ、低級アルコキシカルボニル等が挙げられる。ここで低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］であってもよい。
ここで示したハロゲン置換低級アルキルのハロゲン部分、低級アルキル及びＮ−低級アルキル−Ｎ−低級アルカノイルアミノの２つの低級アルキル部分、アリール、アラルキル及びアリールカルボニルのアリール部分、アラルキル、複素環アルキルの複素環基部分ならびにアラルキル及び複素環アルキルのアルキレン部分は、それぞれ前記ハロゲン（ｉ）、低級アルキル（ｉｉ）、アリール（ｖｉ）、複素環基（ｉｘ）、アラルキルのアルキレン部分（ｖｉｉ）及びアラルキルのアリール部分（ｖｉｉｉ）と同義である。またハロゲン置換低級アルキルのアルキレン部分は、前記低級アルキル（ｉｉ）から水素を一つ除いたものと同義である。
また置換アリール及び置換アラルキルにおける置換アリール部分は、以下に示すアルキレンジオキシフェニルであってもよい。

（式中、ｎ^ｃは１〜３の整数を表す）
また置換シクロアルキルは、例えば以下に示す縮合環基のような、シクロアルキルがアリールまたは置換アリールと縮合して形成される縮合環基であってもよい。

［式中、ｎ^ｄは１〜５の整数を表し、Ｒ^１７、Ｒ^１８及びＲ^１９は、同一または異なって水素原子、ハロゲン、アミノ、ニトロ、ヒドロキシ、シアノ、カルボキシ、低級アルキル、低級アルコキシ、低級アルコキシカルボニル等を表す。ここでハロゲンは前記ハロゲン（ｉ）と同義であり、低級アルキルは前記低級アルキル（ｉｉ）と同義であり、低級アルコキシ及び低級アルコキシカルボニルの低級アルキル部分は前記低級アルキル（ｉｉ）と同義である］
化合物（Ｉ）、（ＩＡ）及び（ＩＢ）の薬理学的に許容される塩としては、毒性のない、水溶性のものが好ましく、例えば塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩等の無機酸塩、ベンゼンスルホン酸塩、安息香酸塩、クエン酸塩、フマル酸塩、グルコン酸塩、乳酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、メタンスルホン酸塩、酒石酸塩等の有機酸塩等の酸付加塩、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩等の金属塩、アンモニウム、テトラメチルアンモニウム等のアンモニウム塩、モルホリン付加塩、ピペリジン付加塩等の有機アミン付加塩、グリシン付加塩、フェニルアラニン付加塩、リジン付加塩、アスパラギン酸付加塩、グルタミン酸付加塩等のアミノ酸付加塩等が挙げられる。
次に化合物（ＩＡ）、（ＩＢ）の製造法について説明する。
なお、以下に示した製造法において、定義した基が反応条件下変化するか、または方法を実施するのに不適切な場合、有機合成化学で常用される方法、例えば官能基の保護、脱保護等［例えば、プロテクティブ・グループス・イン・オーガニック・シンセシス 第三版（Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，ｔｈｅ ｔｈｉｒｄ ｅｄｉｔｉｏｎ）、グリーン（Ｔ．Ｗ．Ｇｒｅｅｎｅ）、ワッツ（Ｐｅｔｅｒ Ｇ．Ｍ．Ｗｕｔｓ）著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ Ｉｎｃ．）（１９９９年）］の手段に付すことにより容易に製造を実施することができる。また、必要に応じて置換基導入等の反応工程の順序を変えることもできる。
化合物（ＩＡ）は、例えば以下に示す製造法１によって得ることが出来る。
製造法１：

（式中、Ａｒ^Ａ、Ｒ^８、Ｒ^９ａ、Ｒ^９ｂ、Ｒ^９ｃ、Ｒ^９ｄ及びｎは、それぞれ前記と同義であり、ｍｃは１または２を表す）
［工程１］
２−エトキシメチレン−２−シアノ酢酸エチル（Ａ）を溶媒中、アルカリ存在下、０．５当量から大過剰量、好ましくは０．５〜２当量の硫酸メチルイソチオ尿素（Ｂ）と反応させることにより、化合物（Ｃ）を得ることができる。
溶媒としては、例えばメタノール、エタノール、２−プロパノール、テトラヒドロフラン、１，４−ジオキサン等を単独でまたはそれらを混合して用いることができ、中でもエタノールが好ましい。
アルカリとしては、例えば水酸化リチウム、水酸化カリウム、水酸化ナトリウム、水酸化マグネシウムまたは水酸化カルシウム等のアルカリ水溶液、カリウムｔｅｒｔ−ブトキシドの水溶液、テトラヒドロフラン溶液もしくは２−メチル−２−プロパノール溶液、ナトリウムメトキシドの水溶液もしくはメタノール溶液等を用いることができ、中でも水酸化ナトリウム水溶液が好ましい。
反応は、０〜５０℃の間の温度、好ましくは０〜１５℃の間の温度で行われ、通常１〜４８時間で終了する。
［工程２］
工程１で得られる化合物（Ｃ）を、反応に不活性な溶媒中または無溶媒で、１当量から大過剰量の塩素化剤と反応させることにより化合物（Ｄ）を得ることができる。
塩素化剤としては、例えばオキシ塩化リン等が用いられる。
反応に不活性な溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えば１，２−ジクロロエタン、テトラヒドロフラン、ジオキサン、クロロホルム、ベンゼン、トルエン、キシレン、酢酸エチル、トリエチルアミン、ピリジン、Ｎ，Ｎ−ジメチルアニリン等を単独でまたはそれらを混合して用いることができる。
反応は、０℃から溶媒の沸点の間の温度、好ましくは５０℃から溶媒の沸点の間の温度で行われ、通常１〜４８時間で終了する。
なお、本工程で得られる化合物（Ｄ）は上記の方法以外に、ジャーナル・オブ・ヘテロサイクリック・ケミストリー（Ｊ．Ｈｅｔｅｒｏｃｙｃｌ．Ｃｈｅｍ．）、８（３）巻、４４５頁（１９７１年）、ＷＯ９９／６１４４４等に記載の方法またはそれらに準じた方法によっても得ることができる。
［工程３］
工程２で得られる化合物（Ｄ）を反応に不活性な溶媒中、１当量から大過剰量、好ましくは１〜１０当量の塩基の存在下に、１当量から大過剰量、好ましくは１〜３当量の化合物（Ｅ）と反応させることにより、化合物（Ｆ）を得ることができる。
反応に不活性な溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばテトラヒドロフラン、ジオキサン、ジエチルエーテル、ジイソプロピルエーテル、ベンゼン、トルエン、キシレン、酢酸エチル、アセトニトリル、ジクロロメタン、クロロホルム、１，２−ジクロロエタン、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等を単独でまたはそれらを混合して用いることができ、中でもテトラヒドロフラン、クロロホルムまたはそれらの混合溶媒が好ましい。
反応は、０〜１００℃の間の温度、好ましくは０〜５０℃の間の温度で行われ、通常１０分間から４８時間で終了する。
塩基としては、例えばトリエチルアミン、ジイソプロピルエチルアミン、１，８−ジアザビシクロ［５．４．０］ウンデセ−７−エン（ＤＢＵ）、Ｎ，Ｎ−ジメチルアニリン、ピリジン、キノリン等の有機塩基、炭酸カリウム、炭酸ナトリウム、炭酸リチウム、炭酸水素ナトリウム、水酸化カリウム、水酸化ナトリウム、水酸化リチウム、カリウムｔｅｒｔ−ブトキシド等の無機塩基、アンバーリストＡ−２１（ロームアンドハース社製）、ＡＧ １−Ｘ８（バイオラッド社製）等の塩基性アニオン交換レジン、ポリビニルピリジン、モルホリノメチルポリスチレン等の固相に担持された塩基等が用いられ、中でもモルホリノメチルポリスチレン、ＤＢＵが好ましい。
化合物（Ｅ）は、市販品としてまたはコンプリヘンシブ・オーガニック・トランスフォーメーションズ第二版（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，ｓｅｃｏｎｄ ｅｄｉｔｉｏｎ）、ラロック（Ｒ．Ｃ．Ｌａｒｏｃｋ）著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ Ｉｎｃ．）（１９９９年）等に記載の方法に準じて得ることができる。
［工程４］
工程３で得られる化合物（Ｆ）を、反応に不活性な溶媒中、１当量から大過剰量、好ましくは１〜５当量の酸化剤で処理することにより、化合物（Ｇ）を得ることができる。
反応に不活性な溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばジクロロメタン、クロロホルム、１，２−ジクロロエタン、テトラヒドロフラン、ジオキサン、ジエチルエーテル、ジイソプロピルエーテル、メタノール、エタノール、イソプロピルアルコール、ベンゼン、トルエン、キシレン、酢酸エチル、アセトニトリル、水等を単独でまたはそれらを混合して用いることができ、中でもジクロロメタンが好ましい。
酸化剤としては、例えばメタクロロ過安息香酸、過酸化ベンゾイル、過酢酸、過酸化水素水、過ヨウ素酸ナトリウム等を用いることができ、中でもメタクロロ過安息香酸が好ましい。
反応は０〜１００℃の間の温度、好ましくは０〜５０℃の間の温度で行われ、通常１０分間から２４時間で終了する。
なお、化合物（Ｇ）において、ｍｃが１である化合物とｍｃが２である化合物は、例えば酸化剤の当量数、反応の温度等の条件等を調節することにより一方を選択的に得ることも可能であり、それらが混在することもある。混在する場合、その比率は特に限定されず、いずれの場合もそのまま次工程に使用することができる。
［工程５］
工程４で得られる化合物（Ｇ）を、反応に不活性な溶媒中、１〜５当量の化合物（Ｈ）と反応させることにより、化合物（Ｊ）を得ることができる。
反応に不活性な溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばジクロロメタン、クロロホルム、１，２−ジクロロエタン、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド、テトラヒドロフラン、ジオキサン、ジエチルエーテル、ジイソプロピルエーテル、ベンゼン、トルエン、キシレン、酢酸エチル、アセトニトリル等を単独でまたはそれらを混合して用いることができ、中でもテトラヒドロフランが好ましい。
反応は０〜１００℃の間の温度、好ましくは２０〜６０℃の間の温度で行われ、通常１〜７２時間で終了する。
化合物（Ｈ）は、市販品としてまたはコンプリヘンシブ・オーガニック・トランスフォーメーションズ第二版（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｎｓ，ｓｅｃｏｎｄ ｅｄｉｔｉｏｎ）、ラロック（Ｒ．Ｃ．Ｌａｒｏｃｋ）著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ Ｉｎｃ．）（１９９９年）等に記載の方法に準じて得ることができる。
［工程６］
工程５で得られる化合物（Ｊ）を、反応に不活性な溶媒中、１〜１０当量のアジ化ナトリウムまたはアジ化アンモニウムと反応させることにより、化合物（ＩＡ）を得ることができる。
反応に不活性な溶媒は、反応に不活性なものであればいずれでもよく、特に限定されないが、例えばクロロホルム、１，２−ジクロロエタン、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド、テトラヒドロフラン、ジオキサン、ジイソプロピルエーテル、ベンゼン、トルエン、キシレン、酢酸エチル、アセトニトリル等を単独でまたはそれらを混合して用いることができ、中でもジメチルホルムアミドが好ましい。また、反応を加速する目的で、反応系中へ塩化アンモニウム、塩化エチルアンモニウム等を１当量以上添加することもできる。
反応は０〜１８０℃の間の温度、好ましくは５０〜１２０℃の間の温度で行われ、通常１〜７２時間で終了する。
化合物（ＩＢ）は、例えば以下に示す製造法２によって得ることができる。
製造法２：

（式中、Ｒ^１３、Ｒ^１４ａ、Ｒ^１４ｂ、Ｒ^１４ｃ、Ｒ^１４ｄ、Ｒ^１５、Ｒ^１６、ｎ^ａ及びｍｃは、それぞれ前記と同義である）
［工程７］
製造法１の工程３に記した方法に準じ、製造法１の工程２で得られる化合物（Ｄ）を化合物（Ｋ）と反応させることにより、化合物（Ｌ）を得ることができる。
工程７において溶媒、塩基、温度、当量、反応時間等は、製造法１の工程３に記載したものに準じて化合物（Ｌ）を製造することができる。
［工程８］
製造法１の工程４に記した方法に準じ、工程７で得られる化合物（Ｌ）から化合物（Ｍ）を得ることができる。
工程８において溶媒、塩基、温度、当量、反応時間等は、製造法１の工程４に記載したものに準じて化合物（Ｍ）を製造することができる。
［工程９］
製造法１の工程５に記した方法に準じ、工程８で得られる化合物（Ｍ）を化合物（Ｎ）と反応させることにより、化合物（ＩＢ）を得ることが出来る。
工程９において溶媒、塩基、温度、当量、反応時間等は、製造法１の工程５に記載したものに準じて化合物（ＩＢ）を製造することができる。
化合物（ＩＡ）、（ＩＢ）及び原料化合物における各官能基の変換ならびに置換基に含まれる官能基の変換は、公知の方法［例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ 第二版（Ｃｏｍｐｒｅｈｅｎｓｉｖｅ Ｏｒｇａｎｉｃ Ｔｒａｎｓｆｏｒｍａｔｉｏｓ，ｔｈｅ ｓｅｃｏｎｄ ｅｄｉｔｉｏｎ）、Ｒ．Ｃ．ラロック（Ｌａｒｏｃｋ）著、ジョン・・ワイリー・アンド・サンズ・インコーポレーティッド（Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ Ｉｎｃ．）（１９９９年）に記載の方法］等によって行うことができる。
上記の方法等を適宜組み合わせて実施することにより、所望の位置に所望の官能基を有する化合物（ＩＡ）、（ＩＢ）を得ることができる。
上記製造法における中間体及び生成物の単離・精製は、通常の有機合成で用いられる方法、例えば濾過、抽出、洗浄、乾燥、濃縮、結晶化、各種クロマトグラフィー等を適宜組み合わせて行うことができる。さらに一般的な並列合成法で常用される精製法、例えばスカベンジャーレジン、イオン交換レジンを用いた精製法によって行うことができる。また、中間体においては、特に精製することなく次の反応に供することもできる。
化合物（ＩＡ）、（ＩＢ）には、位置異性体、幾何異性体、光学異性体または互変異性体のような異性体が存在し得るものもあるが、これらを含め可能な全ての異性体及び該異性体のいかなる比率における混合物も本発明に包含される。
化合物（ＩＡ）、（ＩＢ）の塩を取得したい場合には、化合物（ＩＡ）、（ＩＢ）の塩が得られるときはそのまま精製すればよく、また化合物（ＩＡ）、（ＩＢ）が遊離の形で得られるときは化合物（ＩＡ）、（ＩＢ）を適当な溶媒に溶解または懸濁し、酸または塩基を加えて単離・精製すればよい。
また、化合物（ＩＡ）、（ＩＢ）またはその薬理学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、これらの付加物も本発明に包含される。
化合物（Ｉ）の中で、化合物（ＩＡ）、（ＩＢ）以外の化合物（Ｉ）は、公知の方法［例えば、シンレット（Ｓｙｎｌｅｔｔ）、６２５頁（２０００年）；ジャーナル・オブ・ケミカル・ソサエティー（Ｊ．Ｃｈｅｍ．Ｓｏｃ．）、８００頁（１９５２年）；テトラヘドロン（Ｔｅｔｒａｈｅｄｒｏｎ）、４３巻、２５５７頁（１９８７年）；ジャーナル・オブ・ヘテロサイクリック・ケミストリー（Ｊ．Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ．）、２４巻、８５頁（１９８７年）；ジャーナル・オブ・オーガニック・ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅｍ．）、６０巻、１８７５頁（１９９５年）］等によって合成することができる。
以下、第１表〜第２表に本発明によって得られる化合物（ＩＡ）、（ＩＢ）の具体例を示すが、本発明の範囲はこれらの化合物に限定されることはない。

次に、代表的な化合物（Ｉ）の薬理作用について試験例により具体的に説明する。
「試験例１」ＰＬＫ酵素に対する阻害活性
以下に示す方法にてＰＬＫ酵素に対する阻害活性を測定した。ＧＳＴ（グルタチオンＳ−トランスフェラーゼ）をＮ末端に融合した全長のマウスＰＬＫ［セル・グロウス・アンド・ディファレンシエーション（Ｃｅｌｌ Ｇｒｏｗｔｈ ＆ Ｄｉｆｆ．）、５巻、２４９頁（１９９４年）］を発現するバキュロウイルスを、Ｓｐｏｄｏｐｔｅｒａ ｆｒｕｇｉｐｅｒｄａ（スポドプテラ フルギペルダ）（Ｓｆ）９昆虫細胞に感染させた。その後、Ｓｆ９細胞をＥＳＦ９２１培地（ＥＸＰＲＥＳＳＩＯＮ ＳＹＳＴＥＭＳ、カタログ番号９６−００１）を用いて、２８℃で４８時間振とう培養した。培養後、細胞を遠心して沈殿物を回収し、−２０℃で凍結した。凍結した細胞沈殿物を融解し、２００ｍＬのＬｙｓｉｓ Ｂｕｆｆｅｒ〔２０ｍｍｏｌ／Ｌ Ｈｅｐｅｓ（ｐＨ７．５）、２０ｍｍｏｌ／Ｌβグリセロホスフェート、１％ＣＨＡＰＳ｛３−［（３−Ｃｈｏｌａｍｉｄｏｐｒｏｐｙｌ）ｄｉｍｅｔｈｙｌａｍｍｏｎｉｏ］ｐｒｏｐａｎｅｓｕｌｆｏｎｉｃ ａｃｉｄ｝、１ｍｍｏｌ／Ｌ ＤＴＴ（Ｄｉｔｈｉｏｔｈｒｅｉｔｏｌ）、１０μｍｏｌ／Ｌ ＭＧ１３２（カルビオケム社、カタログ番号４７４７９０）、１×Ｃｏｍｐｌｅｔｅ Ｍｉｘ ＥＤＴＡ ｆｒｅｅ（ロシュ・ダイアグノスティックス社、カタログ番号１８７３５８０）〕に懸濁した。氷上で１０分間静置後、４℃、１０，０００ｇで１５分間遠心し、上清を回収した。上清にＬｙｓｉｓ Ｂｕｆｆｅｒで平衡化した５０％グルタチオンビーズ（アマシャムファルマシア社、カタログ番号２７−４５７４−０１）８ｍＬを加えて、ローテーターＲＴ−ｔ（タイテック社）で回転させながら４℃で５時間反応させた。反応液を４℃、３，０００ｇ、１分間遠心後、上清を取り除き沈殿したビーズを回収した。Ｌｙｓｉｓ Ｂｕｆｆｅｒ ８ｍＬで２回洗浄後、Ｗａｓｈ Ｂｕｆｆｅｒ［５０ｍｍｏｌ／Ｌ Ｔｒｉｓ／ＨＣｌ（ｐＨ７．５）］１６ｍＬで２回洗浄した。洗浄したビーズに９ｍＬのＥｌｕｔｅ Ｂｕｆｆｅｒ［５０ｍｍｏｌ／Ｌ Ｔｒｉｓ／ＨＣｌ（ｐＨ７．５）、１０ｍｍｏｌ／Ｌグルタチオン、１０μｍｏｌ／Ｌ ＭＧ１３２、１００ｎｍｏｌ／Ｌオカダ酸］を加え、ローテーターで回転させながら４℃で５時間反応させた。反応液を４℃、３，０００ｇ、１分間遠心後、上清８ｍＬを回収した。回収した溶出液を最終的に以下の保存状態になるように保存した［最終保存条件；ＧＳＴ−ＰＬＫ ３８μｇ／ｍＬ、２５ｍｍｏｌ／Ｌ Ｔｒｉｓ／ＨＣｌ（ｐＨ７．５）、３．３ｍｍｏｌ／Ｌグルタチオン、０．５ｍｍｏｌ／Ｌ ＥＤＴＡ、５ｍｍｏｌ／Ｌ ＮａＣｌ、０．５ｍｍｏｌ／Ｌ ＤＴＴ、５μｍｏｌ／Ｌ ＭＧ１３２、５０ｎｍｏｌ／Ｌオカダ酸、５０％グリセロールで−２０℃で保存］。
ＰＬＫ酵素阻害５０％の濃度を求めるために、以下の系を構築した。試験用薬剤サンプルはＤＭＳＯ（ジメチルスルホキシド）に溶解した１ｍｍｏｌ／Ｌサンプルを順次希釈して調製した。コントロールとブランクには薬剤を溶解していないＤＭＳＯを用いた。４０μＬの容量で最終濃度がＧＳＴ−ＰＬＫ ５μｇ／μＬ、脱リン酸化型α−カゼイン（シグマアルドリッチ社、カタログ番号Ｃ−８０３２）２５０μｇ／μＬ、２０ｍｍｏｌ／Ｌ Ｈｅｐｅｓ（ｐＨ７．５）、１ｍｍｏｌ／Ｌ ＤＴＴ、ＤＭＳＯ１％、試験用薬剤濃度が０．１２、０．３７、１．１１、３．３３、１０μｍｏｌ／Ｌになるようにそれぞれ溶液を調整した。ブランクにはＧＳＴ−ＰＬＫを加えないサンプルを用いた。その後５×ＡＴＰ溶液｛［γ−^３３Ｐ］−ＡＴＰ １．６μＣｉ（アマシャムファルマシア社、カタログ番号ＡＨ９９６８、１０００−３０００Ｃｉ／ｍｍｏｌ）、２５μｍｏｌ／Ｌ ｃｏｌｄ ＡＴＰ、１００ｍｍｏｌ／Ｌ ＭｇＣｌ_２、２０ｍｍｏｌ／Ｌ Ｈｅｐｅｓ（ｐＨ７．５）、１ｍｍｏｌ／Ｌ ＤＴＴ｝を１０μＬ加え、３０℃で５０分間反応させた。反応液５０μＬのうち２０μＬをＰ８１フィルター（ワットマン社、カタログ番号３６９８０２３）に添加し、０．７５％リン酸液に入れた。フィルターは０．７５％リン酸液で４回洗浄し、６５℃で３０分間乾燥させた。乾燥させたフィルターの^３３Ｐ放射能のカウントはＴＲＩ−ＣＡＲＢ ２７００ＴＲ液体シンチレーションアナライザー（パッカード社）によって測定した。フィルターに添加してから測定までの操作は２連で行った。このアッセイによって測定した化合物濃度１０μｍｏｌ／ＬにおけるＰＬＫ阻害率（％）を第３表に、また一部の化合物についてＰＬＫ酵素阻害５０％の濃度（ＩＣ_５０）を第４表に示した。

「試験例２」ＰＫＡキナーゼアッセイ
酵素阻害の選択性を調べるため、ＰＬＫと同じセリンスレオニンキナーゼであるＰＫＡに対する酵素阻害率を求めるために、以下の系を構築した。ＰＫＡ酵素はｃＡＭＰ−ｄｅｐｅｎｄｅｎｔ Ｐｒｏｔｅｉｎ Ｋｉｎａｓｅ（ＰＫＡ）、ｃａｔａｌｙｔｉｃ ｓｕｂｕｎｉｔ（ニューイングランドバイオラブ社、カタログ番号６０００Ｓ）を用いた。試験用薬剤サンプルはＤＭＳＯに溶解した１ｍｍｏｌ／Ｌサンプルを順次希釈して調整した。コントロールとブランクには薬剤を溶解していないＤＭＳＯを用いた。４０μＬの容量で最終濃度がＰＫＡ ５ｕｎｉｔ／ｍＬ、ＭＢＰ，ｂｏｖｉｎｅ，ｐｕｒｉｆｉｅｄ（アップステート社、カタログ番号１３−１０４）４００μｇ／μＬ、５０ｍｍｏｌ／Ｌ Ｔｒｉｓ（ｐＨ７．５）、１ｍｍｏｌ／Ｌ ＤＴＴ、ＤＭＳＯ １％、試験用薬剤濃度が５０または１０μｍｏｌ／Ｌになるようにそれぞれ溶液を調整した。ブランクにはＰＫＡを加えないサンプルを用いた。その後５×ＡＴＰ溶液｛［γ−^３３Ｐ］−ＡＴＰ １．６μＣｉ（１０００−３０００Ｃｉ／ｍｍｏｌ）、２５μｍｏｌ／Ｌ ｃｏｌｄ ＡＴＰ、１００ｍｍｏｌ／Ｌ ＭｇＣｌ_２、５０ｍｍｏｌ／Ｌ Ｔｒｉｓ（ｐＨ７．５）、１ｍｍｏｌ／Ｌ ＤＴＴ｝を１０μＬ加え、３０℃で３０分間反応させた。１０μＬの１０％リン酸バッファーを添加して、反応を止めた。反応液６０μＬのうち２０μＬをＰ８１フィルターに添加し、０．７５％リン酸液に入れた。フィルターは０．７５％リン酸液で４回洗浄し、６５℃で３０分間乾燥させた。乾燥させたフィルターの^３３Ｐ放射能のカウントはＴＲＩ−ＣＡＲＢ ２７００ＴＲ液体シンチレーションアナライザー（パッカード社）によって測定した。フィルターに添加してから測定までの操作は２連で行った。このアッセイによって測定した化合物濃度５０μｍｏｌ／Ｌ及び１０μｍｏｌ／ＬでのＰＫＡ酵素阻害率（％）を第５表に示した。
いずれの化合物も５０μｍｏｌ／Ｌという高濃度でも阻害活性を示さず、ＰＫＡとＰＬＫの阻害作用に選択性があることが示された。
「試験例３」Ｅｒｋ２キナーゼアッセイ
酵素阻害の選択性を調べるため、ＰＬＫと同じセリンスレオニンキナーゼであるＥｘｔｒａｃｅｌｌｕｌａｒ Ｓｉｇｎａｌ−Ｒｅｇｕｌａｔｅｄ Ｋｉｎａｓｅ ２（Ｅｒｋ２）酵素に対する阻害率を求めるために、以下の系を構築した。Ｅｒｋ２酵素はＭＡＰ Ｋｉｎａｓｅ ２／ Ｅｒｋ２，ａｃｔｉｖｅ（アップステート社、カタログ番号１４−１７３）を用いた。試験用薬剤サンプルはＤＭＳＯに溶解した１ｍｍｏｌ／Ｌサンプルを順次希釈して調整した。コントロールとブランクには薬剤を溶解していないＤＭＳＯを用いた。４０μＬの容量で最終濃度がＥｒｋ２ ４００ｎｇ／ｍＬ、ＭＢＰ，ｂｏｖｉｎｅ，ｐｕｒｉｆｉｅｄ ４００μｇ／μＬ、５０ｍｍｏｌ／Ｌ Ｔｒｉｓ（ｐＨ７．５）、１ｍｍｏｌ／Ｌ ＤＴＴ、ＤＭＳＯ １％、試験用薬剤濃度が５０または１０μｍｏｌ／Ｌになるようにそれぞれ溶液を調整した。ブランクにはＥｒｋ２を加えないサンプルを用いた。その後５×ＡＴＰ溶液｛［γ−^３３Ｐ］−ＡＴＰ １．６μＣｉ（１０００−３０００Ｃｉ／ｍｍｏｌ）、２５μｍｏｌ／Ｌ ｃｏｌｄ ＡＴＰ、１００ｍｍｏｌ／Ｌ ＭｇＣｌ_２、５０ｍｍｏｌ／Ｌ Ｔｒｉｓ（ｐＨ７．５）、１ｍｍｏｌ／Ｌ ＤＴＴ｝を１０μＬ加え、３０℃で３０分間反応させた。１０μＬの１０％リン酸バッファーを添加して、反応を止めた。反応液６０μＬのうち２０μＬをＰ８１フィルターに添加し、０．７５％リン酸液に入れた。フィルターは０．７５％リン酸液で４回洗浄し、６５℃で３０分間乾燥させた。乾燥させたフィルターの^３３Ｐ放射能のカウントはＴＲＩ−ＣＡＲＢ ２７００ＴＲ液体シンチレーションアナライザー（パッカード社）によって測定した。フィルターに添加してから測定までの操作は２連で行った。このアッセイによって測定した化合物濃度５０μｍｏｌ／Ｌ及び１０μｍｏｌ／ＬでのＥｒｋ２酵素阻害率（％）を第５表に示した。
いずれの化合物も５０μｍｏｌ／Ｌという高濃度でも５０％を超える阻害活性を示さず、Ｅｒｋ２とＰＬＫの阻害作用に選択性があることが示された。
以上の結果より、本発明で見出されたＰＬＫ阻害剤は、他のキナーゼとの選択性が高く、ＰＬＫ阻害剤として優れた特徴を有する化合物と結論された。

「試験例４」抗細胞試験
ヒト子宮頚癌ＨｅＬａ細胞（ＡＴＣＣ番号：ＣＣＬ−２）に対する増殖阻害を以下の方法で実施した。ＨｅＬａ細胞の培養には１０％ＦＢＳ入りＲＰＭＩ［ＲＰＭＩ１６４０（ＧＩＢＣＯ ＢＲＬカタログ番号１１８７５−０９３）］培地を用いた。１×１０^３個／ウェルのＨｅＬａ細胞をＴＣ ＭＩＣＲＯＷＥＬＬ ９６Ｆプレート（ナルジェン・ヌンク社、カタログ番号１６７００８）に１００μＬずつ播種し、３７℃で２４時間、５％炭酸ガスインキューベーター内で培養した。ブランクには培地のみを１００μＬ添加したサンプルを使用した。その後、段階的に希釈した試験化合物を５０μＬ加え、さらに３７℃で７２時間、５％炭酸ガスインキュベーター内で培養した。コントロールとブランクには０．３％のＤＭＳＯ入りＲＰＭＩ培地を５０μＬ添加した。ＲＰＭＩ培地を取り除き、１００μＬのＰＢＳ（Ｐｈｏｓｐｈａｔｅ ｂｕｆｆｅｒ ｓａｌｉｎｅ）を加えた後、取り除いた。その後ＲＰＭＩ培地で１０％に希釈したＷＳＴ｛４−［３−（４−Ｉｏｄｏｐｈｅｎｙｌ）−２−（４−ｎｉｔｒｏｐｈｅｎｙｌ）−２Ｈ−５−ｔｅｔｒａｚｏｌｉｏ］−１，３−ｂｅｎｚｅｎｅ ｄｉｓｕｌｆｏｎａｔｅ｝試薬（ロシュ・ダイアグノスティックス社、カタログ番号１６４４８０７）を１００μＬ加え、３７℃で４０分間インキュベートした。マイクロプレート分光光度計ＳＰＥＣＴＲＡ ｍａｘ ３４０ＰＣ（モレキュラーデバイス社）を用い、４５０ｎｍ（対照波長６９０ｎｍ）の吸光度を測定した。代表的な化合物の結果をＨｅＬａ細胞増殖阻害５０％の濃度として第６表に示した。

「試験例５」Ｍ期集積能試験
ＰＬＫは細胞周期のＭ期への進入から脱出までの過程で機能することが知られており、ＰＬＫの活性阻害により、細胞周期、特にＭ期の進行に影響が出ると予想される。ＰＬＫ阻害剤による細胞周期への影響を、Ｍ期の細胞数を調べる方法（Ｍ期集積能試験）により測定した。ＨｅＬａ細胞の培養には１０％ＦＢＳ入りＲＰＭＩ培地を用いた。ＭＵＬＴＩＤＩＳＨ６プレート（ナルジェン・ヌンク社、カタログ番号１５２７９５）にカバーグラスを入れておき、ＨｅＬａ細胞を１×１０^５ｃｅｌｌｓ／ｍＬを２ｍＬ播種し、３７℃で２４時間、５％炭酸ガスインキュベーター内で培養した。ＲＰＭＩ培地を取り除き、さらに２ｍＬのＰＢＳを加えた後、取り除いた。その後ＲＰＭＩ培地で希釈した試験化合物を２ｍＬ加え、さらに３７℃で１５時間、５％炭酸ガスインキュベーター内で培養した。培地を静かに取り除き、３．７％ホルムアルデヒドを含むＰＢＳを２ｍＬずつ添加し、１０分間固定した。１００μｍｏｌ／Ｌ Ｈｏｅｃｈｅｓｔ ３３３４２（シグマアルドリッチ社、カタログ番号Ｂ−２２６１）を含むＰＢＳを２ｍＬずつ添加し、静かに揺らした後、１０分間室温に放置した。カバーグラスを取り出し、倒立顕微鏡ＥＣＬＩＰＳＥ ＴＥ３００（ニコン社）で観察した。染色体が核一様に染まる細胞を間期の細胞とし、染色体が凝集したパターンを示す細胞をＭ期の細胞として、各細胞数を生細胞のみカウントした。なお核の断片化、細胞膜の湾曲等のアポトーシスの兆候が認められない細胞を生細胞と定義した。各条件下最低１００個以上の細胞をカウントし、各形態の細胞の割合（％）を算出した。カウントは２連で行った。Ｍ期集積作用が知られている微小管作用性物質ノコダゾール（Ｎｏｃｏｄａｚｏｌｅ）をコントロールに用いた。代表的な化合物の結果を第７表に示す。ＰＬＫ阻害活性を有する化合物１６及び２０では、化合物未処理の細胞に比べ明らかにＭ期の細胞数が増大しており、これら化合物がＨｅＬａ細胞に対しＭ期集積作用を有することが明らかになった。この結果は、本発明で見出されたＰＬＫ阻害剤がＭ期集積という作用を介して、癌細胞の増殖を抑制する効果、すなわち抗腫瘍作用を有することを示している。

本発明に係る医薬は、式（Ｉ）で表される化合物及びその薬理学的に許容される塩、ならびにそれらの水和物及び溶媒和物からなる群から選ばれる物質を有効成分として含むことを特徴とする。本発明に係る医薬としては、有効成分である上記物質をそのまま投与してもよいが、一般的には、有効成分である上記の物質と１または２以上の製剤用添加物とを含む医薬組成物の形態で投与することが望ましい。このような医薬組成物は、それ自体製剤学の分野で周知または慣用の方法に従って製造することが可能である。また、医薬組成物の形態である本発明に係る医薬には、他の医薬の有効成分が１または２以上含まれていてもよい。なお、本発明の医薬は、ヒトを含む哺乳類動物に適用可能である。
本発明の医薬の投与経路は特に限定されず、経口投与または静脈内投与等の非経口投与のいずれかから治療及び／または予防のために最も効果的な投与経路を適宜選択することができる。経口投与に適する製剤の例としては、例えば、錠剤等を挙げることができ、非経口投与に適する製剤の例としては、例えば、注射剤等を挙げることができる。
錠剤等の固形製剤の製造には、例えば、乳糖、マンニット等の賦形剤；デンプン等の崩壊剤；ステアリン酸マグネシウム等の滑沢剤；ヒドロキシプロピルセルロース等の結合剤；脂肪酸エステル等の界面活性剤；グリセリン等の可塑剤を用いることができる。
非経口投与に適する製剤のうち注射剤等の血管内投与用製剤は、好ましくはヒト血液と等張の水性媒体を用いて調製することができる。例えば、注射剤は、塩溶液、ブドウ糖溶液、塩水とブドウ糖溶液の混合物等から選ばれる水性媒体を用い、常法に従って適当な助剤とともに溶液、懸濁液または分散液として調製することができる。非経口用の製剤の製造には、例えば、希釈剤、香料、防腐剤、賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、可塑剤等から選択される１または２以上の製剤用添加物を用いることもできる。
本発明の医薬の投与量及び投与頻度は特に限定されず、有効成分である上記物質の種類、投与経路、治療及び／または予防の目的、患者の年齢及び体重、症状の性質及び重篤度等の種々の条件に応じて適宜選択することが可能である。例えば、成人１日当り０．１〜１００ｍｇ／ｋｇを３〜４回に分けて投与するのが好ましい。しかしながら、これら投与量及び投与回数は前述の種々の条件等により変動する。An object of the present invention is to provide a PLK inhibitor, a pyrimidine derivative having a PLK inhibitory action or an antitumor action, or a pharmacologically acceptable salt thereof.
The present invention relates to the following (1) to (19).
(1) Formula (I)

[Wherein Ar represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group;
Z ¹ And Z ² Are the same or different and each represents a nitrogen atom (N) or CH,
X is a hydrogen atom, nitro, carboxy, lower alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, —CONHR ⁷ (Wherein R ⁷ Is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted heterocycle Represents alkyl), cyano or tetrazolyl,
1) when X represents cyano or tetrazolyl
Y represents a hydrogen atom,
R ¹ Is -OR ² (Wherein R ² Represents substituted or unsubstituted lower alkyl) or -NR ³ R ⁴ (Wherein R ³ Represents substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl, R ⁴ Represents a hydrogen atom or substituted or unsubstituted lower alkyl, or R ³ And R ⁴ Together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group)
W is -NHCR ⁵ R ⁶ -(Wherein R ⁵ And R ⁶ Are the same or different and each represents a hydrogen atom or substituted or unsubstituted lower alkyl) or -NHCR ⁵ R ⁶ CR ^5A R ^6A -(Wherein R ⁵ And R ⁶ Each is as defined above, R ^5A And R ^6A Are the R ⁵ And R ⁶ Is synonymous with
2) When X represents a group other than cyano and tetrazolyl,
Y is a hydrogen atom, nitro, carboxy, lower alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or —CONHR ^7A (Wherein R ^7A Is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted heterocycle Represents alkyl)
R ¹ Is -OR ^2A (Wherein R ^2A Is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted Represents a substituted heterocyclic group), -SR ^2B (Wherein R ^2B Is R ^2A Or -NR ^3A R ^4A (Wherein R ^3A Is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted Represents a substituted heterocyclic group, R ^4A Represents a hydrogen atom or substituted or unsubstituted lower alkyl, or R ^3A And R ^4A Together with the adjacent nitrogen atom form a substituted or unsubstituted heterocyclic group)
W is -NHCR ^5B R ^6B -(Wherein R ^5B And R ^6B Are the same or different and each represents a hydrogen atom, halogen or substituted or unsubstituted lower alkyl), -NHCR ^5B R ^6B CR ^5C R ^6C -(Wherein R ^5B And R ^6B Each is as defined above, R ^5C And R ^6C Are the R ^5B And R ^6B Or -NHCR ^5B R ^6B CR ^5C R ^6C CR ^5D R ^6D -(Wherein R ^5B , R ^6B , R ^5C And R ^6C Each is as defined above, R ^5D And R ^6D Are the R ^5B And R ^6B And a pharmacologically acceptable salt thereof as an active ingredient.
(2) X is cyano or tetrazolyl,
R ¹ Is -OR ^2a (Wherein R ^2a Represents lower alkyl, cycloalkylalkyl or alicyclic heterocyclic alkyl) or -NR ³ R ⁴ (Wherein R ³ And R ⁴ Are as defined above),
Z ¹ And Z ² The PLK inhibitor according to (1), wherein is a nitrogen atom (N).
(3) Formula (IA)

[Wherein Ar ^A Represents a substituted or unsubstituted aromatic heterocyclic group,
n represents 0 or 1,
R ⁸ Is -OR ¹⁰ (Wherein R ¹⁰ Represents lower alkyl, cycloalkylalkyl or alicyclic heterocyclic alkyl) or -NR ¹¹ R ¹² (Wherein R ¹¹ Represents lower alkyl, cycloalkylalkyl or substituted or unsubstituted aryl, R ¹² Represents a hydrogen atom or lower alkyl, or R ¹¹ And R ¹² Together with the adjacent nitrogen atom form tetrahydroisoquinolin-2-yl, 3,5-dimethylpiperidino or 2,6-dimethylmorpholino)
R ^9a , R ^9b , R ^9c And R ^9d Are the same or different and each represents a hydrogen atom or lower alkyl], or a pharmacologically acceptable salt thereof.
(4) R ⁸ -NHR ^11a (Wherein R ^11a Represents substituted or unsubstituted aryl), and R ^9a , R ^9b , R ^9c And R ^9d The pyrimidine derivative or a pharmaceutically acceptable salt thereof according to (3), wherein is a hydrogen atom.
(5) Formula (IB)

{Where n ^a Represents 0 or 1,
R ¹³ Is -OR ¹⁷ (Wherein R ¹⁷ Represents cycloalkylalkyl or oxygen-containing alicyclic heterocyclic alkyl) or -NR ¹⁸ R ¹⁹ [Wherein R ¹⁸ Is lower alkyl, cycloalkylalkyl, substituted or unsubstituted aryl or formula (II)

(Where n ^b Represents an integer of 1 to 3), and R ¹⁹ Represents a hydrogen atom or lower alkyl, or R ¹⁸ And R ¹⁹ Together with the adjacent nitrogen atom form tetrahydroisoquinolin-2-yl, 3,5-dimethylpiperidino or 2,6-dimethylmorpholino]
R ^14a , R ^14b , R ^14c And R ^14d Are the same or different and each represents a hydrogen atom or lower alkyl, R ¹⁵ And R ¹⁶ Are the same or different and each represents a hydrogen atom, halogen, lower alkyl or lower alkoxy, or R ¹⁵ And R ¹⁶ Together -O (CH ₂ ) _m Or a pharmacologically acceptable salt thereof. O— (wherein m represents 1 or 2)}.
(6) n ^a Is 0 and R ¹⁵ And R ¹⁶ Are the same or different and each represents a hydrogen atom or lower alkoxy, or R ¹⁵ And R ¹⁶ Together -OCH ₂ The pyrimidine derivative or the pharmaceutically acceptable salt thereof according to (5), which is O-.
(7) A prophylactic and / or therapeutic agent for a disease involving PLK comprising the compound according to (1) or (2) or a pharmacologically acceptable salt thereof as an active ingredient.
(8) Use of the compound according to (1) or (2) or a pharmaceutically acceptable salt thereof for the production of a PLK inhibitor.
(9) Use of the compound according to (1) or (2) above or a pharmacologically acceptable salt thereof for the manufacture of a preventive and / or therapeutic agent for a disease involving PLK.
(10) A method for preventing and / or treating a disease involving PLK, comprising a step of administering an effective amount of the compound according to (1) or (2) or a pharmaceutically acceptable salt thereof.
(11) A PLK inhibitor comprising the pyrimidine derivative according to any one of (3) to (6) or a pharmacologically acceptable salt thereof as an active ingredient.
(12) A prophylactic and / or therapeutic agent for a disease involving PLK, comprising as an active ingredient the pyrimidine derivative according to any one of (3) to (6) or a pharmacologically acceptable salt thereof.
(13) An antitumor agent comprising the pyrimidine derivative according to any one of (3) to (6) or a pharmacologically acceptable salt thereof as an active ingredient.
(14) A medicament comprising the pyrimidine derivative according to any one of (3) to (6) or a pharmacologically acceptable salt thereof as an active ingredient.
(15) Use of the pyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (6) for the production of a PLK inhibitor.
(16) Use of the pyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (6) for the manufacture of a preventive and / or therapeutic agent for a disease involving PLK.
(17) Prevention and / or treatment of a disease associated with PLK, comprising a step of administering an effective amount of the pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of (3) to (6). Method.
(18) Use of the pyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (6) for the production of an antitumor agent.
(19) A method for preventing and / or treating a tumor, comprising a step of administering an effective amount of the pyrimidine derivative or the pharmaceutically acceptable salt thereof according to any one of (3) to (6).
Hereinafter, the compounds represented by formulas (I), (IA) and (IB) are referred to as compounds (I), (IA) and (IB), respectively. The same applies to the compounds of other formula numbers.
In the definition of each group of the formulas (I), (IA) and (IB), the following examples are given.
(I) Halogen represents each atom of fluorine, chlorine, bromine and iodine.
(Ii) Examples of the lower alkyl part of lower alkyl, lower alkoxy and lower alkoxycarbonyl include linear or branched alkyl having 1 to 10 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, isooctyl, nonyl, decyl and the like.
(Iii) Examples of cycloalkyl and the cycloalkyl part of cycloalkylalkyl include cycloalkyl having 3 to 8 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. It is done.
(Iv) Examples of lower alkenyl include linear, branched or cyclic alkenyl having 2 to 8 carbon atoms, specifically vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, cyclo Hexenyl, 2,6-octadienyl and the like can be mentioned.
Examples of (v) lower alkynyl include linear or branched alkynyl having 2 to 8 carbon atoms, and specific examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the like.
(Vi) Examples of aryl include monocyclic, bicyclic or tricyclic aryl having 6 to 14 carbon atoms and benzocycloalkyl having 8 to 14 carbon atoms, specifically phenyl, naphthyl and indenyl. , Anthranyl, indanyl, 1,2,3,4-tetrahydronaphthyl, 6,7,8,9-5H-benzocycloheptyl and the like.
(Vii) The alkylene part of aralkyl, heterocyclic alkyl, alicyclic heterocyclic alkyl, oxygen-containing alicyclic heterocyclic alkyl and cycloalkylalkyl is defined as the above-mentioned definition of lower alkyl (ii) with one hydrogen removed. It is synonymous.
(Viii) Examples of the aryl moiety of aralkyl include the groups mentioned in the definition of aryl (vi).
(Ix) The heterocyclic group part of the heterocyclic group and the heterocyclic alkyl includes, for example, a 5-membered, 6-membered or 7-membered monocyclic heterocycle containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Ring groups, bicyclic or tricyclic condensed 3- to 8-membered rings, and a condensed heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, etc. Specifically, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzoimidazolyl, 2-oxobenzoimidazolyl, benzotriazolyl, benzofuryl, benzothienyl, purinyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, indazolyl, indolyl, isoindolyl, quinolyl , Isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, pyrrolyl, pyra Ryl, quinazolinyl, cinnolinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thienyl, furyl, pyrrolidinyl, 2,5-dioxopyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, piperidinyl, homopiperidinyl, homopiperazinyl, homopiperidinyl , Homopiperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, pyranyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, octahydroquinolyl, indolinyl and the like. The alicyclic heterocyclic group part of the alicyclic heterocyclic alkyl represents those having no aromaticity among the above, and the aromatic heterocyclic group represents those having aromaticity among the above. In addition, examples of the oxygen-containing alicyclic heterocyclic group part of the oxygen-containing alicyclic heterocyclic alkyl include tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, pyranyl and the like.
(X) The heterocyclic group formed together with the adjacent nitrogen atom includes a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , May contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed ring having 3 to 8 members and containing at least one nitrogen atom ( The condensed heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and specifically includes tetrahydropyridyl, indolinyl, isoindolinyl, pyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidino, Homopiperidino, piperazinyl, homopiperazinyl, morpholino, thiomorpholino, perhydroazepinyl, perhydroazosinyl, tetrahydroquinolyl, tetrahydroisoquino Le, octa-tetrahydroquinolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, purinyl, dihydroindolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, and the like.
(Xi) Substituents in substituted lower alkyl are the same or different, for example, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkanoyl, lower alkoxy, cycloalkyl, aryloxy, substituted, having 1 to 3 substituents Aryloxy [substituents in the substituted aryloxy are the same or different and include, for example, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl, etc. having 1 to 3 substituents. It is done. Here, the halogen has the same meaning as the halogen (i), the lower alkyl has the same meaning as the lower alkyl (ii), and the lower alkyl part of lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl (ii). Aralkyloxy, substituted aralkyloxy [substituents in the substituted aralkyloxy are the same or different, for example, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkyl, lower alkoxy, lower alkoxy having 1 to 3 substituents. Examples include alkoxycarbonyl. Here, the halogen has the same meaning as the halogen (i), the lower alkyl has the same meaning as the lower alkyl (ii), and the lower alkyl part of lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl (ii). A heterocyclic group, a substituted heterocyclic group [substituents in the substituted heterocyclic group are the same or different, for example, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkyl, lower Examples include alkoxy and lower alkoxycarbonyl. Here, the halogen has the same meaning as the halogen (i), the lower alkyl has the same meaning as the lower alkyl (ii), and the lower alkyl part of lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl (ii). , Lower alkanoyloxy, lower alkoxycarbonyl, lower alkylthio, mono or dilower alkylamino, lower alkylsulfonyl, lower alkylsulfinyl, lower alkoxycarbonylamino, lower alkanoylamino, mono or dilower alkylaminocarbonyl, mono or dilower alkylamino And carbonyloxy.
The aryl part of halogen, aryloxy and aralkyloxy shown here, cycloalkyl, heterocyclic group and lower alkanoyl, lower alkoxy, lower alkanoyloxy, lower alkoxycarbonyl, lower alkylthio, mono- or di-lower alkylamino, lower alkylsulfonyl, Lower alkyl sulfinyl, lower alkoxycarbonylamino, lower alkanoylamino, mono- or di-lower alkylaminocarbonyl and lower alkyl moiety of mono- or di-lower alkylaminocarbonyloxy are the halogen (i), aryl (vi), cycloalkyl ( iii) Synonymous with heterocyclic group (ix) and lower alkyl (ii), wherein the alkylene part of aralkyloxy has one hydrogen removed from the lower alkyl (ii). Noto is synonymous.
The two lower alkyl moieties of di-lower alkylamino, di-lower alkylaminocarbonyl, and di-lower alkylaminocarbonyloxy may be the same or different.
(Xii) formed with a substituted aryl, substituted aralkyl, substituted cycloalkyl, substituted lower alkenyl, substituted lower alkynyl, substituted heterocyclic group, substituted heterocyclic alkyl, substituted aromatic heterocyclic group and adjacent nitrogen atom As the substituent in the substituted heterocyclic group, in addition to the groups mentioned in the definition of the substituent (xi) in the substituted lower alkyl, lower alkyl, halogen-substituted lower alkyl [the halogen-substituted lower alkyl is a number that can be substituted from 1 Are preferably lower alkyl substituted with 1 to 6 halogens, more preferably 1 to 3 halogens], aryl, substituted aryl [substituents in the substituted aryl are the same or different, For example, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkyl having 1 to 3 substituents , Lower alkoxy, and lower alkoxycarbonyl, and the like. Here, the halogen has the same meaning as the halogen (i), the lower alkyl has the same meaning as the lower alkyl (ii), and the lower alkyl part of lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl (ii). Aralkyl, substituted aralkyl [substituents in the substituted aralkyl are the same or different, for example, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl, etc. having 1 to 3 substituents. Is mentioned. Here, the halogen has the same meaning as the halogen (i), the lower alkyl has the same meaning as the lower alkyl (ii), and the lower alkyl part of lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl (ii). Arylcarbonyl, substituted arylcarbonyl [substituents in the substituted arylcarbonyl are the same or different, for example, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkyl, lower alkoxy, lower alkoxy having 1 to 3 substituents. Examples include alkoxycarbonyl. Here, the halogen has the same meaning as the halogen (i), the lower alkyl has the same meaning as the lower alkyl (ii), and the lower alkyl part of lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl (ii). , Heterocyclic alkyl, substituted heterocyclic alkyl [substituents in the substituted heterocyclic alkyl are the same or different, for example, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkyl, lower alkyl having 1 to 3 substituents. Examples include alkoxy and lower alkoxycarbonyl. Here, the halogen has the same meaning as the halogen (i), the lower alkyl has the same meaning as the lower alkyl (ii), and the lower alkyl part of lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl (ii). , N-lower alkyl-N-lower alkanoylamino and the like. Further, the substituent in the substituted heterocyclic group formed together with the substituted aryl and the adjacent nitrogen atom is a substituted lower alkyl [the lower alkyl is as defined above for the lower alkyl (ii), and the substitution in the substituted lower alkyl is Examples of the group are the same or different, and examples thereof include hydroxy, carboxy, and lower alkoxycarbonyl having 1 to 3 substituents. Here, the lower alkyl part of the lower alkoxycarbonyl has the same meaning as the lower alkyl (ii).
The halogen part of the halogen-substituted lower alkyl shown here, two lower alkyl parts of lower alkyl and N-lower alkyl-N-lower alkanoylamino, aryl part of aryl, aralkyl and arylcarbonyl, aralkyl, heterocyclic alkyl heterocycle The group part and the alkylene part of aralkyl and heterocyclic alkyl are the halogen (i), lower alkyl (ii), aryl (vi), heterocyclic group (ix), alkylene part (vii) of aralkyl and aryl part of aralkyl, respectively. It is synonymous with (viii). The alkylene part of the halogen-substituted lower alkyl has the same meaning as that obtained by removing one hydrogen from the lower alkyl (ii).
The substituted aryl moiety in the substituted aryl and substituted aralkyl may be alkylenedioxyphenyl shown below.

(Where n ^c Represents an integer of 1 to 3)
The substituted cycloalkyl may be a condensed ring group formed by condensing cycloalkyl with aryl or substituted aryl, such as the following condensed ring group.

[Where n ^d Represents an integer of 1 to 5 and R ¹⁷ , R ¹⁸ And R ¹⁹ Are the same or different and each represents a hydrogen atom, halogen, amino, nitro, hydroxy, cyano, carboxy, lower alkyl, lower alkoxy, lower alkoxycarbonyl or the like. Here, the halogen has the same meaning as the halogen (i), the lower alkyl has the same meaning as the lower alkyl (ii), and the lower alkyl part of lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl (ii).
The pharmacologically acceptable salts of compounds (I), (IA) and (IB) are preferably non-toxic and water-soluble salts such as hydrochloride, hydrobromide, nitrate, sulfate, Inorganic acid salts such as phosphate, benzenesulfonate, benzoate, citrate, fumarate, gluconate, lactate, maleate, malate, oxalate, methanesulfonate, Acid addition salts such as organic acid salts such as tartrate, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, metal salts such as aluminum and zinc salts, ammonium and tetra Ammonium salts such as methylammonium, morpholine addition salts, organic amine addition salts such as piperidine addition salts, glycine addition salts, phenylalanine addition salts, lysine addition salts, aspartic acid addition salts, Amino acid addition salts such as amine acid addition salts.
Next, a method for producing compounds (IA) and (IB) will be described.
In the production method shown below, when the defined group changes under the reaction conditions or is inappropriate for carrying out the method, a method commonly used in organic synthetic chemistry, for example, functional group protection and deprotection. [E.g., Protective Groups in Organic Synthesis, the third edition, by TW Greene, Peter GM Wuts, John, et al. Manufacturing can be easily carried out by attaching to the means of John Wiley & Sons Inc. (1999)]. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
Compound (IA) can be obtained, for example, by Production Method 1 shown below.
Production method 1:

(Wherein Ar ^A , R ⁸ , R ^9a , R ^9b , R ^9c , R ^9d And n are as defined above, and mc represents 1 or 2.
[Step 1]
By reacting ethyl 2-ethoxymethylene-2-cyanoacetate (A) with 0.5 to 2 equivalents, preferably 0.5 to 2 equivalents of methyl isothiourea sulfate (B) in a solvent in the presence of alkali. A compound (C) can be obtained.
As the solvent, for example, methanol, ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane and the like can be used alone or as a mixture thereof, and ethanol is particularly preferable.
Examples of the alkali include alkaline aqueous solutions such as lithium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide and calcium hydroxide, aqueous solutions of potassium tert-butoxide, tetrahydrofuran solutions or 2-methyl-2-propanol solutions, sodium methoxy An aqueous solution of methanol or a methanol solution can be used, and among them, an aqueous sodium hydroxide solution is preferable.
The reaction is carried out at a temperature between 0 ° C. and 50 ° C., preferably at a temperature between 0 ° C. and 15 ° C., and is usually completed in 1 to 48 hours.
[Step 2]
Compound (D) can be obtained by reacting compound (C) obtained in step 1 with 1 equivalent to a large excess of chlorinating agent in a solvent inert to the reaction or without solvent.
As the chlorinating agent, for example, phosphorus oxychloride is used.
The solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. For example, 1,2-dichloroethane, tetrahydrofuran, dioxane, chloroform, benzene, toluene, xylene, ethyl acetate, triethylamine, Pyridine, N, N-dimethylaniline and the like can be used alone or in combination.
The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent, preferably at a temperature between 50 ° C. and the boiling point of the solvent, and is usually completed in 1 to 48 hours.
In addition to the above method, the compound (D) obtained in this step may be used in Journal of Heterocyclic Chemistry (J. Heterocycl. Chem.), 8 (3), 445 (1971), WO99. / 61444 etc., or a method according to them.
[Step 3]
1 equivalent to a large excess, preferably 1 to 3 in the presence of 1 equivalent to a large excess, preferably 1 to 10 equivalents of a base, in a solvent inert to the reaction of the compound (D) obtained in Step 2. Compound (F) can be obtained by reacting with an equivalent amount of compound (E).
The solvent inert to the reaction may be any solvent that is inert to the reaction and is not particularly limited. For example, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, xylene, ethyl acetate, acetonitrile, dichloromethane, Chloroform, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and the like can be used alone or in admixture thereof, among which tetrahydrofuran, chloroform or a mixed solvent thereof is preferable.
The reaction is carried out at a temperature between 0 ° C. and 100 ° C., preferably between 0 ° C. and 50 ° C., and is usually completed in 10 minutes to 48 hours.
Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N-dimethylaniline, pyridine, quinoline and other organic bases, potassium carbonate, carbonate Inorganic bases such as sodium, lithium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium tert-butoxide, Amberlyst A-21 (Rohm and Haas), AG 1-X8 (Bio-Rad) A base supported on a solid phase such as polyvinyl anion exchange resin, polyvinyl pyridine, morpholinomethyl polystyrene, etc., among which morpholinomethyl polystyrene and DBU are preferred.
Compound (E) can be obtained commercially or by Comprehensive Organic Transformations, Second Edition, by R. C. Larock, John Wylie and Sons Incorporated. (John Wiley & Sons Inc.) (1999) and the like.
[Step 4]
Compound (G) can be obtained by treating compound (F) obtained in step 3 with an oxidizing agent in an amount of 1 equivalent to a large excess, preferably 1 to 5 equivalents, in a solvent inert to the reaction. .
The solvent inert to the reaction may be any solvent as long as it is inert to the reaction, and is not particularly limited. For example, dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methanol, ethanol , Isopropyl alcohol, benzene, toluene, xylene, ethyl acetate, acetonitrile, water and the like can be used alone or in admixture thereof, with dichloromethane being preferred.
As the oxidizing agent, for example, metachloroperbenzoic acid, benzoyl peroxide, peracetic acid, hydrogen peroxide solution, sodium periodate and the like can be used, and among them, metachloroperbenzoic acid is preferable.
The reaction is carried out at a temperature between 0 to 100 ° C., preferably at a temperature between 0 to 50 ° C. and is usually completed in 10 minutes to 24 hours.
In addition, in the compound (G), one of the compound having mc of 1 and the compound having mc of 2 can be selectively obtained by adjusting conditions such as the number of equivalents of the oxidizing agent and the reaction temperature. Yes, they can be mixed. When mixed, the ratio is not particularly limited, and in any case, the ratio can be used as it is in the next step.
[Step 5]
Compound (J) can be obtained by reacting compound (G) obtained in step 4 with 1 to 5 equivalents of compound (H) in a solvent inert to the reaction.
The solvent inert to the reaction may be any solvent as long as it is inert to the reaction and is not particularly limited. For example, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide , Tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, xylene, ethyl acetate, acetonitrile and the like can be used alone or in admixture thereof, among which tetrahydrofuran is preferred.
The reaction is carried out at a temperature between 0 to 100 ° C., preferably at a temperature between 20 to 60 ° C. and is usually completed in 1 to 72 hours.
Compound (H) can be obtained commercially or by Comprehensive Organic Transformations, Second Edition, by RC Larock, John Wiley and Sons Incorporated. (John Wiley & Sons Inc.) (1999) and the like.
[Step 6]
Compound (IA) can be obtained by reacting compound (J) obtained in step 5 with 1 to 10 equivalents of sodium azide or ammonium azide in a solvent inert to the reaction.
The solvent inert to the reaction is not particularly limited as long as it is inert to the reaction. For example, chloroform, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran , Dioxane, diisopropyl ether, benzene, toluene, xylene, ethyl acetate, acetonitrile and the like can be used alone or in admixture thereof. Among them, dimethylformamide is preferable. Further, for the purpose of accelerating the reaction, 1 equivalent or more of ammonium chloride, ethylammonium chloride or the like can be added to the reaction system.
The reaction is carried out at a temperature between 0 ° C. and 180 ° C., preferably at a temperature between 50 ° C. and 120 ° C., and is usually completed in 1 to 72 hours.
Compound (IB) can be obtained, for example, by Production Method 2 shown below.
Production method 2:

(Wherein R ¹³ , R ^14a , R ^14b , R ^14c , R ^14d , R ¹⁵ , R ¹⁶ , N ^a And mc are as defined above.
[Step 7]
In accordance with the method described in Step 3 of Production Method 1, compound (L) can be obtained by reacting Compound (D) obtained in Step 2 of Production Method 1 with Compound (K).
In Step 7, the compound (L) can be produced according to the solvent, base, temperature, equivalent weight, reaction time and the like described in Step 3 of Production Method 1.
[Step 8]
In accordance with the method described in Step 4 of Production Method 1, compound (M) can be obtained from compound (L) obtained in Step 7.
In Step 8, the compound (M) can be produced according to the solvent, base, temperature, equivalent weight, reaction time and the like described in Step 4 of Production Method 1.
[Step 9]
According to the method described in Step 5 of Production Method 1, compound (IB) can be obtained by reacting compound (M) obtained in Step 8 with compound (N).
In Step 9, the compound (IB) can be produced according to the solvent, base, temperature, equivalent weight, reaction time and the like described in Step 5 of Production Method 1.
The conversion of each functional group in compound (IA), (IB) and the raw material compound and the conversion of the functional group contained in the substituent can be carried out by a known method [for example, Comprehensive Organic Transformations Second Edition (Comprehensive Organic Transformation). Transformios, the second edition), R.C. C. By Larock, a method described in John Wiley & Sons Inc. (1999)] and the like.
By appropriately combining the above methods and the like, compounds (IA) and (IB) having a desired functional group at a desired position can be obtained.
Isolation and purification of intermediates and products in the above production method can be performed by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various chromatography, and the like. it can. Furthermore, it can be performed by a purification method commonly used in a general parallel synthesis method, for example, a purification method using a scavenger resin or an ion exchange resin. In addition, the intermediate can be subjected to the next reaction without any particular purification.
Compound (IA) and (IB) may have isomers such as positional isomers, geometric isomers, optical isomers or tautomers, but all possible isomers including these isomers And mixtures of the isomers in any ratio are encompassed by the present invention.
When it is desired to obtain a salt of compound (IA) or (IB), the salt of compound (IA) or (IB) may be purified as it is, and compound (IA) or (IB) is free. When obtained in a form, the compounds (IA) and (IB) may be dissolved or suspended in an appropriate solvent, and then acid or base may be added for isolation and purification.
In addition, compound (IA), (IB) or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. The
Among compounds (I), compounds (I) other than compounds (IA) and (IB) can be prepared by known methods [for example, Synlett, page 625 (2000); Journal of Chemical Society ( J. Chem. Soc.), 800 (1952); Tetrahedron, 43, 2557 (1987); Journal of Heterocyclic Chem., 24 85 (1987); Journal of Organic Chemistry (J. Org. Chem.), 60, 1875 (1995)].
Specific examples of the compounds (IA) and (IB) obtained by the present invention are shown in Tables 1 and 2 below, but the scope of the present invention is not limited to these compounds.

Next, the pharmacological action of typical compound (I) will be specifically described with reference to test examples.
"Test Example 1" Inhibitory activity against PLK enzyme
The inhibitory activity against the PLK enzyme was measured by the following method. Baculovirus expressing full-length mouse PLK [Cell Growth & Diff., 5, 249 (1994)] fused with N-terminal GST (glutathione S-transferase) Were infected with Spodoptera frugiperda (Sf) 9 insect cells. Thereafter, Sf9 cells were cultured with shaking at 28 ° C. for 48 hours using ESF921 medium (EXPRESSION SYSTEMS, catalog number 96-001). After culturing, the cells were centrifuged to collect a precipitate and frozen at -20 ° C. Thaw the frozen cell pellet and add 200 mL of Lysis Buffer [20 mmol / L Hepes (pH 7.5), 20 mmol / Lβ glycerophosphate, 1% CHAPS {3-[(3-Cholamidopropionyl) dimethylaminosulfonate], 1 mmol / L DTT (Dithiothreitol), 10 μmol / L MG132 (Calbiochem, catalog number 474790), 1 × Complete Mix EDTA free (Roche Diagnostics, catalog number 1873580)]. The mixture was allowed to stand on ice for 10 minutes, and then centrifuged at 4 ° C. and 10,000 g for 15 minutes to collect the supernatant. 8 mL of 50% glutathione beads (Amersham Pharmacia, Catalog No. 27-4574-01) equilibrated with Lysis Buffer were added to the supernatant, and the mixture was reacted at 4 ° C. for 5 hours while rotating with a rotator RT-t (Tytec). It was. After the reaction solution was centrifuged at 3,000 g for 1 minute at 4 ° C., the supernatant was removed and the precipitated beads were collected. After washing twice with 8 mL of Lysis Buffer, it was washed twice with 16 mL of Wash Buffer [50 mmol / L Tris / HCl (pH 7.5)]. To the washed beads, 9 mL of Elute Buffer [50 mmol / L Tris / HCl (pH 7.5), 10 mmol / L glutathione, 10 μmol / L MG132, 100 nmol / L okadaic acid] was added, and rotated at 4 ° C. for 5 hours while rotating with a rotator. Reacted. The reaction solution was centrifuged at 3,000 g for 1 minute at 4 ° C., and 8 mL of the supernatant was recovered. The collected eluate was finally stored in the following storage state [final storage conditions: GST-PLK 38 μg / mL, 25 mmol / L Tris / HCl (pH 7.5), 3.3 mmol / L glutathione, 0 5 mmol / L EDTA, 5 mmol / L NaCl, 0.5 mmol / L DTT, 5 μmol / L MG132, 50 nmol / L okadaic acid, stored at −20 ° C. with 50% glycerol].
In order to determine the concentration of PLK enzyme inhibition 50%, the following system was constructed. The test drug sample was prepared by sequentially diluting a 1 mmol / L sample dissolved in DMSO (dimethyl sulfoxide). DMSO in which the drug was not dissolved was used for the control and blank. Final concentration of GST-PLK 5 μg / μL in a volume of 40 μL, dephosphorylated α-casein (Sigma Aldrich, Catalog No. C-8032) 250 μg / μL, 20 mmol / L Hepes (pH 7.5), 1 mmol / L DTT The solution was adjusted so that DMSO 1% and test drug concentrations were 0.12, 0.37, 1.11, 3.33, and 10 μmol / L, respectively. As the blank, a sample to which GST-PLK was not added was used. Then 5 × ATP solution {[γ− ³³ P] -ATP 1.6 μCi (Amersham Pharmacia, catalog number AH9968, 1000-3000 Ci / mmol), 25 μmol / L cold ATP, 100 mmol / L MgCl ₂ , 20 mmol / L Hepes (pH 7.5), 1 mmol / L DTT} was added at 10 μL and reacted at 30 ° C. for 50 minutes. 20 μL of 50 μL of the reaction solution was added to a P81 filter (Whatman, catalog number 3698023) and placed in a 0.75% phosphoric acid solution. The filter was washed 4 times with a 0.75% phosphoric acid solution and dried at 65 ° C. for 30 minutes. Of the dried filter ³³ The P radioactivity count was measured with a TRI-CARB 2700TR liquid scintillation analyzer (Packard). The operation from the addition to the filter to the measurement was performed in duplicate. The PLK inhibition rate (%) at a compound concentration of 10 μmol / L measured by this assay is shown in Table 3, and for some compounds, the concentration of PLK enzyme inhibition (IC) (IC ₅₀ ) Is shown in Table 4.

"Test Example 2" PKA kinase assay
In order to examine the selectivity of enzyme inhibition, the following system was constructed in order to determine the enzyme inhibition rate against PKA, which is the same serine threonine kinase as PLK. As the PKA enzyme, cAMP-dependent Protein Kinase (PKA) and catalytic subunit (New England Biolab, catalog number 6000S) were used. The test drug sample was prepared by sequentially diluting a 1 mmol / L sample dissolved in DMSO. DMSO in which the drug was not dissolved was used for the control and blank. Final concentration of PKA 5 unit / mL, MBP, bovine, purified (Upstate, catalog number 13-104) 400 μg / μL, 50 mmol / L Tris (pH 7.5), 1 mmol / L DTT, DMSO 1% in a volume of 40 μL The solutions were adjusted so that the test drug concentration was 50 or 10 μmol / L, respectively. As the blank, a sample to which no PKA was added was used. Then 5 × ATP solution {[γ− ³³ P] -ATP 1.6 μCi (1000-3000 Ci / mmol), 25 μmol / L cold ATP, 100 mmol / L MgCl ₂ , 50 mmol / L Tris (pH 7.5), 1 mmol / L DTT} was added at 10 μL and reacted at 30 ° C. for 30 minutes. The reaction was stopped by adding 10 μL of 10% phosphate buffer. 20 μL of 60 μL of the reaction solution was added to a P81 filter and placed in a 0.75% phosphoric acid solution. The filter was washed 4 times with a 0.75% phosphoric acid solution and dried at 65 ° C. for 30 minutes. Of the dried filter ³³ The P radioactivity count was measured with a TRI-CARB 2700TR liquid scintillation analyzer (Packard). The operation from the addition to the filter to the measurement was performed in duplicate. The PKA enzyme inhibition rate (%) at the compound concentrations of 50 μmol / L and 10 μmol / L measured by this assay is shown in Table 5.
None of the compounds showed inhibitory activity even at a high concentration of 50 μmol / L, indicating that the inhibitory action of PKA and PLK is selective.
"Test Example 3" Erk2 kinase assay
In order to examine the selectivity of enzyme inhibition, the following system was constructed in order to determine the inhibition rate against the Extracellular Signal-Regulated Kinase 2 (Erk2) enzyme, which is the same serine threonine kinase as PLK. As the Erk2 enzyme, MAP Kinase 2 / Erk2, active (Upstate, catalog number 14-173) was used. The test drug sample was prepared by sequentially diluting a 1 mmol / L sample dissolved in DMSO. DMSO in which the drug was not dissolved was used for the control and blank. Final concentration of Erk2 400 ng / mL, MBP, bovine, purified 400 μg / μL, 40 mmol / L Tris (pH 7.5), 1 mmol / L DTT, DMSO 1%, test drug concentration 50 or 10 μmol / L Each solution was adjusted so that A sample to which Erk2 was not added was used as a blank. Then 5 × ATP solution {[γ− ³³ P] -ATP 1.6 μCi (1000-3000 Ci / mmol), 25 μmol / L cold ATP, 100 mmol / L MgCl ₂ , 50 mmol / L Tris (pH 7.5), 1 mmol / L DTT} was added at 10 μL and reacted at 30 ° C. for 30 minutes. The reaction was stopped by adding 10 μL of 10% phosphate buffer. 20 μL of 60 μL of the reaction solution was added to a P81 filter and placed in a 0.75% phosphoric acid solution. The filter was washed 4 times with a 0.75% phosphoric acid solution and dried at 65 ° C. for 30 minutes. Of the dried filter ³³ The P radioactivity count was measured with a TRI-CARB 2700TR liquid scintillation analyzer (Packard). The operation from the addition to the filter to the measurement was performed in duplicate. The Erk2 enzyme inhibition rate (%) at the compound concentrations of 50 μmol / L and 10 μmol / L measured by this assay is shown in Table 5.
None of the compounds showed inhibitory activity exceeding 50% even at a high concentration of 50 μmol / L, indicating that the inhibitory action of Erk2 and PLK is selective.
From the above results, it was concluded that the PLK inhibitor found in the present invention has high selectivity with other kinases and has excellent characteristics as a PLK inhibitor.

"Test Example 4" anti-cell test
Growth inhibition for human cervical cancer HeLa cells (ATCC number: CCL-2) was carried out by the following method. For the culture of HeLa cells, RPMI [RPMI1640 (GIBCO BRL catalog number 11875-093)] medium containing 10% FBS was used. 1 × 10 ³ Individual / well HeLa cells were seeded at 100 μL each on a TC MICROWELL 96F plate (Nalgen Nunc, Cat. No. 167008), and cultured at 37 ° C. for 24 hours in a 5% carbon dioxide incubator. As a blank, a sample added with 100 μL of medium alone was used. Thereafter, 50 μL of the test compound diluted in stages was added, and further cultured at 37 ° C. for 72 hours in a 5% carbon dioxide incubator. 50 μL of 0.3% DMSO-containing RPMI medium was added to the control and blank. The RPMI medium was removed, 100 μL of PBS (Phosphate buffer saline) was added, and then removed. Subsequently, WST {4- [3- (4-Iodophenyl) -2- (4-nitrophenyl) -2H-5-tetrazio] -1,3-benzene disulfonate} reagent (Roche Diagnostics) diluted to 10% with RPMI medium. 100 μL of Sticks, catalog number 1644807) was added and incubated at 37 ° C. for 40 minutes. Absorbance at 450 nm (control wavelength 690 nm) was measured using a microplate spectrophotometer SPECTRA max 340PC (Molecular Devices). The results of representative compounds are shown in Table 6 as the concentration of HeLa cell growth inhibition 50%.

"Test Example 5" M-phase accumulation ability test
PLK is known to function in the process from entry to exit of the M cycle of the cell cycle, and inhibition of PLK activity is expected to affect the progression of the cell cycle, particularly the M phase. The effect of the PLK inhibitor on the cell cycle was measured by a method for examining the number of cells in the M phase (M phase accumulation ability test). RPMI medium containing 10% FBS was used for the culture of HeLa cells. Put a cover glass on a MULTIDISH6 plate (Nalgen Nunk, catalog number 152795) and add 1 × 10 HeLa cells. ⁵ 2 mL of cells / mL was inoculated and cultured at 37 ° C. for 24 hours in a 5% carbon dioxide incubator. The RPMI medium was removed and another 2 mL of PBS was added and then removed. Thereafter, 2 mL of a test compound diluted with RPMI medium was added, and further cultured at 37 ° C. for 15 hours in a 5% carbon dioxide incubator. The medium was gently removed, and 2 mL of PBS containing 3.7% formaldehyde was added and fixed for 10 minutes. 2 mL of PBS containing 100 μmol / L Hoechest 33342 (Sigma Aldrich, Catalog No. B-2261) was added, gently shaken, and left at room temperature for 10 minutes. The cover glass was taken out and observed with an inverted microscope ECLIPSE TE300 (Nikon Corporation). The number of cells was counted only for living cells, with cells having chromosomes uniformly dyed as nuclei and cells showing a pattern of chromosome aggregation as M phases. Cells that showed no signs of apoptosis such as fragmentation of the nucleus and curvature of the cell membrane were defined as living cells. At least 100 cells were counted under each condition, and the percentage (%) of cells in each form was calculated. Counting was performed in duplicate. The microtubule active substance Nocodazole (Nocodazole), which is known to have M-phase accumulation action, was used as a control. The results for representative compounds are shown in Table 7. In the compounds 16 and 20 having PLK inhibitory activity, the number of cells in the M phase was clearly increased as compared with the cells not treated with the compound, and it was revealed that these compounds have an M phase accumulation action on HeLa cells. . This result indicates that the PLK inhibitor found in the present invention has an effect of suppressing the growth of cancer cells, that is, an antitumor effect through the action of M-phase accumulation.

The medicament according to the present invention contains, as an active ingredient, a compound selected from the group consisting of the compound represented by formula (I) and pharmacologically acceptable salts thereof, and hydrates and solvates thereof. It is characterized by. As the medicament according to the present invention, the above-mentioned substance which is an active ingredient may be administered as it is, but generally a pharmaceutical composition comprising the above-mentioned substance which is an active ingredient and one or more pharmaceutical additives. It is desirable to administer in the form of a product. Such a pharmaceutical composition itself can be produced according to a method well known or commonly used in the field of pharmaceutics. In addition, the medicament according to the present invention in the form of a pharmaceutical composition may contain one or more active ingredients of other medicaments. The medicament of the present invention can be applied to mammals including humans.
The administration route of the medicament of the present invention is not particularly limited, and the most effective administration route for treatment and / or prevention can be appropriately selected from either oral administration or parenteral administration such as intravenous administration. Examples of preparations suitable for oral administration include tablets and the like, and examples of preparations suitable for parenteral administration include injections and the like.
For the production of solid preparations such as tablets, for example, excipients such as lactose and mannitol; disintegrants such as starch; lubricants such as magnesium stearate; binders such as hydroxypropylcellulose; interfaces such as fatty acid esters Activator: A plasticizer such as glycerin can be used.
Among preparations suitable for parenteral administration, preparations for intravascular administration such as injections can be prepared preferably using an aqueous medium isotonic with human blood. For example, the injection can be prepared as a solution, suspension or dispersion with an appropriate auxiliary agent according to a conventional method using an aqueous medium selected from a salt solution, a glucose solution, a mixture of brine and a glucose solution, and the like. For the production of a parenteral preparation, for example, one or two or more selected from diluents, fragrances, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. Pharmaceutical additives can also be used.
The dosage and administration frequency of the medicament of the present invention are not particularly limited, and the kind of the above-mentioned substance as an active ingredient, the administration route, the purpose of treatment and / or prevention, the age and weight of the patient, the nature and severity of symptoms, etc. It is possible to select appropriately according to the various conditions. For example, 0.1-100 mg / kg per day for an adult is preferably administered in 3 to 4 divided doses. However, these doses and the number of doses vary depending on the various conditions described above.

EXAMPLES The present invention will be described more specifically with reference to examples and reference examples. However, the scope of the present invention is not limited by these examples.
The physicochemical data of each compound in the following examples and reference examples were measured by the following instruments.
¹ H NMR: JEOL EX-270 type (270 MHz) or JEOL GX-270 type (270 MHz)
IR: HORIBA FT-200
MS: JEOL JMS-DX303 (FAB method) or Micromass Quattro (APCI method)
Reference Example 1: Synthesis of 4-chloro-5-cyano-2-methylthiopyrimidine 1: Synthesis of 5-cyano-3,4-dihydro-2-methylthiopyrimidin-4-one Methylisothiourea sulfate (90.5 g, 0 .325 mmol) was dissolved in an aqueous sodium hydroxide solution (2 mol / L, 325 mL), and an ethanol solution (350 mL) of ethyl 2-ethoxymethylene-2-cyanoacetate (100 g, 0.591 mmol) was added to the aqueous solution under ice cooling. The solution was added dropwise little by little while taking care that the internal temperature did not exceed 15 ° C. After all the ethanol solution was added, aqueous sodium hydroxide solution (2 mol / L, 300 mL) was added little by little, ethanol (150 mL) was further added, and the mixture was stirred overnight at room temperature. Crystals precipitated in the reaction mixture were collected by filtration and washed with ethanol (500 mL). The obtained white crystals were dried under reduced pressure to obtain the desired 5-cyano-3,4-dihydro-2-methylthiopyrimidin-4-one (113.3 g, 100%).
Step 2: Synthesis of 4-chloro-5-cyano-2-methylthiopyrimidine To 5-cyano-3,4-dihydro-2-methylthiopyrimidin-4-one (30.0 g, 0.159 mmol) obtained in Step 1 Phosphorus oxychloride (150 mL) was added, and the mixture was heated to reflux for 7 hours. After the reaction mixture was allowed to cool, phosphorus oxychloride was distilled off under reduced pressure. The obtained residue was poured into ice (about 1000 mL), and the precipitated pale yellow solid was collected by filtration and washed with water. The solid was dried under reduced pressure to obtain the desired 4-chloro-5-cyano-2-methylthiopyrimidine (11.9 g, 40%).
Example 1: Synthesis step 1 of compound 1
4-chloro-5-cyano-2-methylthiopyrimidine (0.25 mol / L chloroform solution, 0.20 mL, 0.050 mmol) obtained in Reference Example 1 and 6-amino-1,4-benzodioxane (1. To a mixed solution of 0 mol / L chloroform solution, 0.060 mL, 0.060 mmol), morpholinomethylpolystyrene (35 mg, 0.12 mmol) was added and stirred at 50 ° C. for 1 day. Thereafter, benzoyl chloride polymer bound (23 mg, 0.058 mmol) and chloroform (0.50 mL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 day. The resin in the reaction mixture was filtered off, and the resin was washed with a mixed solvent of chloroform and methanol (chloroform / methanol = 3/1, 1.2 mL). All of the obtained solutions were combined and the solvent was distilled off to obtain the corresponding compound.
Process 2
The compound obtained in Step 1 was dissolved in dichloromethane (0.20 mL), metachloroperbenzoic acid (0.50 mol / L dichloromethane solution, 0.125 mL, 0.063 mmol) was added, and the mixture was stirred at room temperature for 0.5 to 1 hour. Stir. Saturated aqueous sodium hydrogen carbonate (0.20 mL) was added to the reaction mixture and stirred, and then the aqueous layer was removed. Thereafter, saturated sodium bicarbonate water (0.20 mL) was added again and stirred, followed by liquid separation. The organic layer was dried with a mixture of magnesium sulfate and diatomaceous earth (magnesium sulfate / diatomaceous earth = 1/1, 140 mg). The mixture of magnesium sulfate and diatomaceous earth was washed with dichloromethane (0.80 mL). All the obtained solutions were combined, and the solvent was distilled off to obtain the corresponding compound.
Process 3
The compound obtained in Step 2 was dissolved in tetrahydrofuran (0.20 mL), 2- (2-thienyl) ethylamine (1.0 mol / L chloroform solution, 0.060 mL, 0.060 mmol) was added, and the mixture was stirred at room temperature for 1 day. Stir. Thereafter, chloroform (0.40 mL), benzoyl chloride polymer bound (23 mg, 0.058 mmol) and poly (4-vinylpyridine) (23 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 day. The resin in the reaction mixture was filtered off, and the resin was washed with a mixed solvent of chloroform and methanol (chloroform / methanol = 3/1, 1.4 mL). All the obtained solutions were combined, and the solvent was distilled off to obtain the corresponding compound.
Process 4
The compound obtained in Step 3 was dissolved in dimethylformamide (0.10 mL), a solution of ammonium azide in dimethylformamide (1.0 mol / L, 0.080 mL, 0.080 mmol) was added, and the mixture was stirred at 100 ° C. for 1 day. did. Thereafter, the solvent was distilled off, and the residue was dissolved in a mixture of chloroform and 1,1,1,3,3,3-hexafluoro-2-propanol (3: 1, 0.40 mL), and a 5% citric acid aqueous solution was dissolved. Washed with. After drying and concentrating the organic layer, the residue was dissolved in ethanol (0.300 mL), ion exchange resin AG1-X8 (manufactured by Bio-Rad) was added, and the mixture was stirred at room temperature for 2 hours. After washing the resin with methanol (0.60 mL), a mixture of chloroform and methanol (1: 1, 0.40 mL) and hydrochloric acid in ethyl acetate (4 mol / L, 0.050 mL) were added to the resin to elute the desired product. did. The resin was washed with a mixture of chloroform and methanol (1: 1, 1.2 mL), and the eluate and the washing solution were combined and concentrated to obtain the target compound 1.
Other compounds (IA) (compounds 2 to 14) were synthesized in the same manner as described above using the corresponding reagents in step 1 and step 3. Their total yield was about 30%.
The obtained compound was identified by mass spectrometry. The analysis results of each compound are described as instrument data in Table 1-1 to Table 1-2. Also describes a proton ^NMR (1 H ^NMR) of representative compounds are shown below.
Compound 1
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 3.07 (t, J = 6.8 Hz, 2H), 3.49-3.50 (br, 2H), 4.24 (s, 4H), 6.84-7.10 (m, 5H), 7.32-7.47 (m, 2H), 8.53 (s, 1H), 8.76 (s, 1H), 10.77. (S, 0.2H), 10.58 (s, 0.8H)
Compound 2
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 1.79 (s, 3H), 3.11 (t, J = 7.8 Hz, 2H), 3.16 (s, 3H), 3 .61 (t, J = 7.8 Hz, 2H), 6.88 (s, 1H), 6.94 (dd, J = 3.5 Hz, 5.0 Hz, 1H), 7.25-7.33 ( m, 3H), 7.79 (d, J = 8.4 Hz, 2H), 7.86 (s, 1H), 8.12 (s, 1H), 8.69 (s, 1H), 10.50. (S, 0.4H), 10.77 (s, 0.6H)
Compound 3
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 3.10 (t, J = 7.3 Hz, 2H), 3.50-3.51 (m, 2H), 3.66 (s, 6H), 3.72 (s, 3H), 6.85-6.95 (m, 2H), 7.07 (s, 2H), 7.31 (dd, J = 1.2 Hz, 5.1 Hz, 1H), 7.63 (br, 1H), 7.81 (br, 1H), 8.64 (s, 1H), 10.24 (br, 0.4H), 10.68 (br, 0.6H) )
Compound 7 (main peak)
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 1.30 (s, 9H), 4.58 (s, 2H), 7.22-7.76 (m, 5H), 7.95 (S, 1H), 8.13-8.25 (m, 1H), 8.45 (d, J = 3.5 Hz, 1H), 8.56 (s, 1H), 8.66 (s, 1H) ), 10.28 (s, 0.4H), 10.55 (s, 0.6H)
Compound 8
¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm): 4.60 (d, J = 5.6 Hz, 2H), 7.35 (dd, J = 4.9 Hz, 7.7 Hz, 1H), 7.51-7.70 (br, 2H), 7.77 (d, J = 7.4 Hz, 2H), 8.10 (br, 1H), 8.25 (br, 1H), 8.38 ( br, 1H), 8.45 (d, J = 4.9 Hz, 1H), 8.59 (s, 1H), 8.72 (s, 1H), 10.70 (br, 1H)
Example 2: Synthesis of Compound 15 4-Chloro-5-cyano-2-methylthiopyrimidine (0.25 mol / L chloroform solution, 0.20 mL, 0.050 mmol) obtained in Step 1 Reference Example 1 and 3-ethyl To a mixed solution of aniline (1.0 mol / L chloroform solution, 0.060 mL, 0.060 mmol), morpholinomethylpolystyrene (35 mg, 0.12 mmol) was added and stirred at 50 ° C. for 1 day. Thereafter, benzoyl chloride polymer bound (23 mg, 0.058 mmol) and chloroform (0.50 mL) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 day. The resin in the reaction mixture was filtered off, and the resin was washed with a mixed solvent of chloroform and methanol (chloroform / methanol = 3/1, 1.2 mL). All of the obtained solutions were combined and the solvent was distilled off to obtain the corresponding compound.
Process 2
The compound obtained in Step 1 was dissolved in dichloromethane (0.20 mL), metachloroperbenzoic acid (0.50 mol / L dichloromethane solution, 0.125 mL, 0.063 mmol) was added, and the mixture was stirred at room temperature for 0.5 to 1 hour. Stir. Saturated aqueous sodium hydrogen carbonate (0.20 mL) was added to the reaction mixture and stirred, and then the aqueous layer was removed. Thereafter, saturated sodium bicarbonate water (0.20 mL) was added again and stirred, followed by liquid separation. The organic layer was dried with a mixture of magnesium sulfate and diatomaceous earth (magnesium sulfate / diatomaceous earth = 1/1, 140 mg). The mixture of magnesium sulfate and diatomaceous earth was washed with dichloromethane (0.80 mL). All the obtained solutions were combined, and the solvent was distilled off to obtain the corresponding compound.
Process 3
The compound obtained in Step 2 was dissolved in tetrahydrofuran (0.20 mL), 1-phenylethylamine (1.0 mol / L chloroform solution, 0.060 mL, 0.060 mmol) was added, and the mixture was stirred at room temperature for 1 day. Thereafter, chloroform (0.40 mL), benzoyl chloride polymer bound (23 mg, 0.058 mmol) and poly (4-vinylpyridine) (23 mg) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 day. The resin in the reaction mixture was filtered off, and the resin was washed with a mixed solvent of chloroform and methanol (chloroform / methanol = 3/1, 1.4 mL). All of the obtained solutions were combined, and the solvent was distilled off to obtain Compound 15.
Among compounds (IB), compound (IBa) (compounds 16-22 and compounds 25-28) in which R ¹³ is represented by —NR ¹⁸ R ¹⁹ is the same as described above in steps 1 and 3. Synthesized by using the corresponding reagents.
The obtained compound (IBa) was identified by mass spectrometry. The analysis results of each compound are described as instrument data in Tables 2-1 to 2-2. Also describes a proton ^NMR (1 H ^NMR) of representative compounds are shown below.
Compound 16
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm): 1.55 (d, J = 6.9 Hz, 3H), 3.79 (s, 3H), 5.02 to 5.17 (m, 1H) 5.90-6.04 (br, 1H), 6.70 (dd, J = 2.3 Hz, 8.2 Hz, 1H), 6.83-6.90 (m, 1H), 7.10 ( s, 1H), 7.13-7.43 (m, 6H), 8.17 (s, 1H), 8.27 (br s, 1H)
Compound 20
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm): 0.11-0.26 (m, 2H), 0.39-0.58 (m, 2H), 0.89 (t, J = 7. 3Hz, 3H), 0.81-1.03 (br, 1H), 1.53 (d, J = 6.9 Hz, 3H), 1.48-1.70 (m, 2H), 3.24- 3.70 (m, 4H), 4.90-5.08 (br, 1H), 5.53-5.73 (br, 1H), 7.13-7.42 (m, 5H), 8. 11 (s, 1H)
Compound 22
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm): 1.56 (d, J = 6.9 Hz, 3H), 2.80-3.05 (br, 2H), 3.80-4.09 ( br, 2H), 4.63-4.90 (m, 2H), 5.00 (br, 1H), 5.87 (br, 1H), 7.11-7.41 (m, 9H), 8 .12 (s, 1H)
Compound 28
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm): 0.23-0.29 (m, 2H), 0.51-0.58 (m, 2H), 0.93 (t, J = 7. 3Hz, 3H), 1.01-1.14 (m, 1H), 1.55-1.76 (m, 2H), 3.52 (d, J = 6.6 Hz, 2H), 3.63 ( t, J = 7.9 Hz, 2H), 4.45 (d, J = 5.3 Hz, 2H), 5.95 (s, 2H), 6.38 (br, 1H), 6.76-6. 79 (m, 3H), 7.90 (s, 1H)
Example 3: Synthesis step 1 of compound 23
4-Chloro-5-cyano-2-methylthiopyrimidine (223 mg, 1.20 mmol) obtained in Reference Example 1 was dissolved in chloroform (5 mL), and tetrahydropyran-2-ylmethanol (1.44 mmol), 1,8 -Diazabicyclo [5.4.0] undec-7-ene (0.215 mL, 1.44 mmol) was added and stirred at room temperature for 1-2 hours. The reaction solution was diluted with 5% aqueous citric acid solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the residue obtained by concentration was dissolved in chloroform (12 mL), and benzoyl chloride polymer bound (552 mg, 1.66 mmol) and poly (4-vinylpyridine) (552 mg) were added. In addition, the mixture was stirred at room temperature for 12 to 24 hours. The reaction solution was filtered and concentrated to give the corresponding compound.
Process 2
The compound obtained in Step 1 was reacted by the same method as shown in Step 2 of Example 2 to obtain the corresponding compound.
Process 3
The compound obtained in Step 2 was reacted with 1-phenylethylamine by the same method as shown in Step 3 of Example 2 to obtain Compound 23.
Compound 24 can also be synthesized by using cyclohexylmethanol in step 1 in the same manner as described above.
Compound 23
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm): 1.24-1.76 (m, 3H), 1.57 (d, J = 6.9 Hz, 3H), 1.77-1.95 ( m, 2H), 3.30-3.74 (m, 4H), 3.85-4.07 (m, 2H), 4.90-5.12 (m, 1H), 6.36 (br, 1H), 7.23-7.40 (m, 5H), 8.13 (s, 1H)
Compound 24
¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm): 0.74-1.08 (m, 2H), 1.13-1.38 (m, 2H), 1.51-1.80 (m, 7H), 1.58 (d, J = 6.9 Hz, 3H), 4.05 (d, J = 6.2 Hz, 2H), 4.90-5.15 (m, 1H), 6.58 ( d, J = 6.5 Hz, 1H), 7.24-7.38 (m, 5H), 8.17 (s, 1H)
Formulation Example 1: Tablet A tablet having the following composition is prepared by a conventional method.
Formulation Compound 1 20 mg
Lactose 143.4mg
Potato starch 30 mg
Hydroxypropylcellulose 6 mg
Magnesium stearate 0.6mg
200 mg
Formulation Example 2: Injection An injection having the following composition is prepared by a conventional method.
Formulation Compound 10 2 mg
Refined soybean oil 200 mg
Purified egg yolk lecithin 24 mg
Glycerin for injection 50 mg
Distilled water for injection 1.72ml
2.00ml

  The present invention provides a PLK inhibitor, a pyrimidine derivative having a PLK inhibitory action, an antitumor activity, or the like.

Claims (19)

Formula (I)

[Wherein Ar represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group;
Z ¹ and Z ² are the same or different and each represents a nitrogen atom (N) or CH;
X is a hydrogen atom, nitro, carboxy, lower alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, —CONHR ⁷ (wherein R ⁷ is a hydrogen atom, substituted or unsubstituted lower alkyl, Represents substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted heterocyclic alkyl), cyano or tetrazolyl;
1) when X represents cyano or tetrazolyl
Y represents a hydrogen atom,
R ¹ is —OR ² (wherein R ² represents a substituted or unsubstituted lower alkyl) or —NR ³ R ⁴ (wherein R ³ is a substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl). Represents alkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl, R ⁴ represents a hydrogen atom or substituted or unsubstituted lower alkyl, or R ³ and R ⁴ together with the adjacent nitrogen atom To form a substituted or unsubstituted heterocyclic group)
W is —NHCR ⁵ R ⁶ — (wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or substituted or unsubstituted lower alkyl) or —NHCR ⁵ R ⁶ CR ^5A R ^6A — (wherein R ⁵ and R ⁶ are as defined above, and R ^5A and R ^6A are as defined above as R ⁵ and R ⁶ , respectively.
2) When X represents a group other than cyano and tetrazolyl,
Y is a hydrogen atom, nitro, carboxy, lower alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or —CONHR ^7A (wherein R ^7A is a hydrogen atom, substituted or unsubstituted lower alkyl, Represents substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl or substituted or unsubstituted heterocyclic alkyl)
R ¹ is —OR ^2A (wherein R ^2A is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group), —SR ^2B (wherein R ^2B has the same meaning as R ^2A ) or —NR ^3A R ^4A (wherein R ^3A is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or represents an unsubstituted heterocyclic group, R ^4A is lower hydrogen atom or a substituted or unsubstituted Or represents alkyl, or R ^3A and R ^4A together with the adjacent nitrogen atom to form a substituted or unsubstituted heterocyclic group) represents,
W is —NHCR ^5B R ^6B — (wherein R ^5B and R ^6B are the same or different and each represents a hydrogen atom, halogen, or substituted or unsubstituted lower alkyl), —NHCR ^5B R ^6B CR ^5C R ^6C — (formula Wherein R ^5B and R ^6B are as defined above, and R ^5C and R ^6C are as defined above for R ^5B and R ^6B , respectively, or —NHCR ^5B R ^6B CR ^5C R ^6C CR ^5D R ^6D — (formula Wherein R ^5B , R ^6B , R ^5C and R ^6C are as defined above, and R ^5D and R ^6D are as defined above for R ^5B and R ^6B , respectively, or a drug thereof Polo-like kinase (PLK) inhibitor containing a physically acceptable salt as an active ingredient. X is cyano or tetrazolyl,
R ¹ is —OR ^2a (wherein R ^2a represents lower alkyl, cycloalkylalkyl or alicyclic heterocyclic alkyl) or —NR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), Is)
The PLK inhibitor according to claim ^1, wherein Z ¹ and Z ² are nitrogen atoms (N). Formula (IA)

[In the formula, Ar ^A represents a substituted or unsubstituted aromatic heterocyclic group;
n represents 0 or 1,
R ⁸ is —OR ¹⁰ (wherein R ¹⁰ represents lower alkyl, cycloalkylalkyl or alicyclic heterocyclic alkyl) or —NR ¹¹ R ¹² (wherein R ¹¹ is lower alkyl, cycloalkylalkyl or substituted) Alternatively, it represents unsubstituted aryl, R ¹² represents a hydrogen atom or lower alkyl, or R ¹¹ and R ¹² together with the adjacent nitrogen atom together with tetrahydroisoquinolin-2-yl, 3,5-dimethylpiperidi Or 2,6-dimethylmorpholino)
R ^9a , R ^9b , R ^9c and R ^9d are the same or different and each represents a hydrogen atom or lower alkyl], or a pharmacologically acceptable salt thereof. The pyrimidine derivative according to claim 3, wherein R ⁸ is -NHR ^11a (wherein R ^11a represents substituted or unsubstituted aryl), and R ^9a , R ^9b , R ^9c and R ^9d are hydrogen atoms. Its pharmacologically acceptable salt. Formula (IB)

{Wherein n ^a represents 0 or 1,
R ¹³ is —OR ¹⁷ (wherein R ¹⁷ represents cycloalkylalkyl or oxygen-containing alicyclic heterocyclic alkyl) or —NR ¹⁸ R ^{19 wherein} R ¹⁸ is lower alkyl, cycloalkylalkyl, substituted or Unsubstituted aryl or formula (II)

(Wherein, ^{n b} represents an integer of 1 to 3) a group represented ^{by, R 19} is taken together with a hydrogen atom or a lower alkyl, or a nitrogen atom ^{to which R 18} and ^{R 19} are adjacent Form tetrahydroisoquinolin-2-yl, 3,5-dimethylpiperidino or 2,6-dimethylmorpholino]
R ^14a , R ^14b , R ^14c and R ^14d are the same or different and each represents a hydrogen atom or lower alkyl, and R ¹⁵ and R ¹⁶ are the same or different and each represents a hydrogen atom, halogen, lower alkyl or lower alkoxy, or R ¹⁵ and R ¹⁶ together form —O (CH ₂ ) _m O— (wherein m represents 1 or 2)} or a pharmacologically acceptable derivative thereof. salt. The n ^a is 0, and R ¹⁵ and R ¹⁶ are the same or different and are a hydrogen atom or lower alkoxy, or R ¹⁵ and R ¹⁶ together are -OCH ₂ O-. A pyrimidine derivative or a pharmacologically acceptable salt thereof. A preventive and / or therapeutic agent for a disease involving PLK, comprising as an active ingredient the compound according to claim 1 or 2 or a pharmacologically acceptable salt thereof. Use of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof for the production of a PLK inhibitor. Use of the compound according to claim 1 or a pharmacologically acceptable salt thereof for the manufacture of an agent for preventing and / or treating a disease involving PLK. A method for preventing and / or treating a disease involving PLK, comprising a step of administering an effective amount of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof. A PLK inhibitor comprising the pyrimidine derivative according to any one of claims 3 to 6 or a pharmacologically acceptable salt thereof as an active ingredient. A prophylactic and / or therapeutic agent for a disease involving PLK, comprising the pyrimidine derivative according to any one of claims 3 to 6 or a pharmacologically acceptable salt thereof as an active ingredient. The antitumor agent which contains the pyrimidine derivative in any one of Claims 3-6, or its pharmacologically acceptable salt as an active ingredient. The pharmaceutical which contains the pyrimidine derivative in any one of Claims 3-6, or its pharmacologically acceptable salt as an active ingredient. Use of the pyrimidine derivative according to any one of claims 3 to 6 or a pharmaceutically acceptable salt thereof for the production of a PLK inhibitor. Use of the pyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 6 for the manufacture of a preventive and / or therapeutic agent for a disease involving PLK. A method for preventing and / or treating a disease involving PLK, comprising a step of administering an effective amount of the pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 3 to 6. Use of the pyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 6 for the production of an antitumor agent. A method for preventing and / or treating a tumor, comprising a step of administering an effective amount of the pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 3 to 6.